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Sample records for cancer loss-of-heterozygosity region

  1. Frequent loss of heterozygosity in the region of the D7S523 locus in advanced ovarian cancer.

    PubMed

    Koike, M; Takeuchi, S; Yokota, J; Park, S; Hatta, Y; Miller, C W; Tsuruoka, N; Koeffler, H P

    1997-05-01

    Loss of heterozygosity (LOH) of the long arm of chromosome 7 occurs frequently in many types of primary cancers. We analyzed 22 primary ovarian cancers for LOH of chromosome arm 7q using a set of 16 microsatellite markers in order to determine the location of a putative tumor suppressor gene (TSG). Eleven samples (50%) showed LOH at least at one locus on chromosome arm 7q. We identified the smallest commonly deleted region to be at 7q31.1, which includes D7S523. LOH of chromosome arm 7q was more frequent in advanced stages (III-IV) (7/9, 78%) than in early stages (I-II) (4/13.31%) of ovarian cancer (P < 0.05). These data suggest that alteration of a TSG at 7q31.1 gene plays an important role in advanced ovarian cancer.

  2. CHARACTERIZATION OF A LOSS OF HETEROZYGOSITY CANCER HAZARD IDENTIFICATION ASSAY.

    EPA Science Inventory

    Tumor development generally requires the loss of heterozygosity (LOH) at one or more loci. Thus, the ability to determine whether a chemical is capable of causing LOH is an important part of cancer hazard identification. The mouse lymphoma assay detects a broad spectrum of geneti...

  3. CHARACTERIZATION OF A LOSS OF HETEROZYGOSITY CANCER HAZARD IDENTIFICATION ASSAY.

    EPA Science Inventory

    Tumor development generally requires the loss of heterozygosity (LOH) at one or more loci. Thus, the ability to determine whether a chemical is capable of causing LOH is an important part of cancer hazard identification. The mouse lymphoma assay detects a broad spectrum of geneti...

  4. Microsatellite instability and loss of heterozygosity in gastric cancer

    SciTech Connect

    Schneider, B.G.; Pulitzer, D.R.; Moehlmann, R.D.

    1994-09-01

    In order to detect regions of DNA containing tumor suppressor genes involved in the development of gastric cancer, we evaluated loss of heterozygosity (LOH) in 78 gastric adenocarcinomas. A total of 46 microsatellite markers were employed, which detected at least one site per arm of each autosome in the human genome, including several markers linked to known tumor suppressor genes (TP53, APC, DCC, RB1, and BRCA1). We detected elevated rates of LOH at D3S1478 on chromosome 3p21 (44%, or 22 of 50 cases), at D12S78 at 12q14q24.33 (39%), and 37% at D9S157 on 9p, three sites not previously known to be affected in gastric cancer. Another locus on chromosome 12q, D12S97, showed LOH in 40% of informative cases. LOH was detected on chromosome 17p near TP53 in 66% of informative cases (23 of 35). Microsatellite instability (MI) was observed in 22% of the cancers. Tumors varied greatly in percentage of sites exhibiting MI, from 0% to 77% of sites tested. These findings expand the description of the genetic lesions occurring in gastric cancer.

  5. Identification and cloning in yeast artificial chromosomes of a region of elevated loss of heterozygosity on chromosome 1p31.1 in human breast cancer

    SciTech Connect

    Hoggard, N.; Hey, Y.; Brintnell, B.; James, L.

    1995-11-20

    We have mapped a region of high loss of heterozygosity in breast cancer to a 2-cM interval between the loci D1S430 and D1S465 on chromosome 1p31.1. This region shows allelic imbalance in around 60% of breast tumors. As part of a strategy to clone the target gene(s) within this interval, we have generated a yeast artificial chromosome contig spanning over 7 Mb. YACs from the CEPH and Zeneca (formerly ICI) libraries have been obtained by screening with PCR-based STSs from the region for both previously identified loci and newly isolated STSs. The YACs have been assembled into a contig by a combination of approaches, including analysis of their STS content, generation of new STSs from the ends of key YACs, and long-range restriction mapping. These YAC clones provide the basis for complete characterization of the region of high loss in breast cancer and for the ultimate identification of the target gene(s). 84 refs., 3 figs., 3 tabs.

  6. Frequent microsatellite instability and loss of heterozygosity in the region including BRCA1 (17q21) in young patients with gastric cancer.

    PubMed

    Semba, S; Yokozaki, H; Yasui, W; Tahara, E

    1998-06-01

    It is known that nearly 5% of gastric carcinomas arise under the age of 40. To elucidate genetic alterations in these patients, we performed studies using microsatellite assay in 27 gastric cancers under 35 years of age, composed of 5 well and 22 poorly differentiated adenocarcinomas. We detected replication errors (RERs) in 18 (67%) of 27 tumors, but no germline mutation in DNA mismatch repair genes (hMLH1 and hMSH2), except fory 3 somatic mutations in the hMLH1 gene. Loss of heterozygosity (LOH) at D17S855, located on chromosome 17q21 (BRCA1), was detected in 8 (40%) of 20 informative cases. In 12 (44%) of 27 cases, LOH on chromosome 17q12-21 including the BRCA1 was found in several neighboring markers in this region, while no mutation was found in the BRCA1 gene. Four (40%) of 10 scirrhous type gastric cancers exhibited wide allelic deletions on chromosome 17q12-21. These results overall suggest that young gastric cancer patients display highly frequent micro-satellite instability that might be due to defect of DNA repair system rather than hMLH1 and hMSH2. In addition, chromosome 17q12-21 including BRCA1 locus may contain a candidate for tumor suppressor gene, particularly in scirrhous type gastric cancers arising in young patients.

  7. [Loss of heterozygosity analysis to define putative region involved in tumor differentiation and metastases in sporadic colorectal cancer patients].

    PubMed

    Peng, Zhihai; Zhang, Fang; Zhou, Chongzhi; Qiu, Guoqiang; Bai, Shaochun; Liu, Wanqing; He, Lin

    2002-10-01

    To detect putative suppressor loci involved in tumor progressing or metastases. Thirty microsatellite marker primers were employed to amply the corresponding loci of the genome DNA from 83 patients with sporadic colorectal cancer. The PCR products were electrophoresed on a 377 PRISM sequencer and the fluorescent signals were analyzed by Genotyper and Genescan software. The data were obtained from 24 loci, with an average LOH frequency of 15.16%. The LOH at D2S206 and D2S364 was more frequent than 30%, and was less than 20% at the rest loci. Significant difference was observed between the percentage of LOH and tumor staging or differentiation at D2S142 (2q24.1), D2S126 (2q35), D2S2211 (2p24.2), D2S305 (2p23.3). Occarrence of deletion at the later two loci was correlative. Frequent LOH was not observed at the loci around known mismatch repair genes on chr. 2. The region between D2S305 (2p23.3) and D2S2211 (2p24.2) deleted holistically, and was correlated to the stage and differentiation of tumor attended by D2S142 (2q24.1) and D2S126 (2q35) on 2q. It is suggested that unknown genes associated with tumor progressing or metastases reside in the two loci on 2q or the region on 2p.

  8. Ovarian cancer has frequent loss of heterozygosity at chromosome 12p12.3-13.1 (region of TEL and Kip1 loci) and chromosome 12q23-ter: evidence for two new tumour-suppressor genes.

    PubMed Central

    Hatta, Y.; Takeuchi, S.; Yokota, J.; Koeffler, H. P.

    1997-01-01

    Identification of the key genetic alterations leading to ovarian cancer is in its infancy. Polymerase chain reaction (PCR)-based analysis of loss of heterozygosity (LOH) is a powerful method for detecting regions of altered tumour-suppressor genes. Focusing on chromosome 12, we examined 23 ovarian cancer samples for LOH using 31 highly polymorphic microsatellite markers and found the chromosomal localization of two putative tumour-suppressor genes. Two commonly deleted regions were 12p12.3-13.1 in 6/23 (26%) and 12q23-ter in 7/23 (30%) samples. LOH on chromosome 12 was more common in late-stage ovarian carcinomas. The region of LOH at 12p12.3-13.1 includes the genes that code for the ETS-family transcriptional factor, known as TEL, and the cyclin-dependent kinase inhibitor, known as p27Kip1. Mutational analysis of both TEL and p27Kip1 using single-strand conformation polymorphism (SSCP) showed no abnormalities, suggesting that the altered gene in this region is neither of these genes. Taken together, our data suggest that new tumour-suppressor genes in the region of chromosomes 12p12.3-13.1 and 12q23-ter may be involved in the development of ovarian cancer. Images Figure 1 Figure 2 Figure 4 PMID:9155043

  9. Loss of heterozygosity and microsatellite instability as predictive markers among Iranian esophageal cancer patients

    PubMed Central

    Forghanifard, Mohammad Mahdi; Vahid, Elham Emami; Dadkhah, Ezzat; Gholamin, Mehran; Noghabi, Samaneh Broumand; Ghahraman, Martha; Farzadnia, Mehdi; Abbaszadegan, Mohammad Reza

    2016-01-01

    Objective(s): Variation in microsatellite sequences that are dispersed in the genome has been linked to a deficiency in cellular mismatch repair system and defects in several genes of this system are involved in carcinogenesis. Our aim in this study was to illustrate microsatellite DNA alteration in esophageal cancer. Materials and Methods: DNA was extracted from formalin fixed paraffin embedded (FFPE) tissues from surgical and matched margin-normal samples. Microsatellite instability (MSI) and loss of heterozygosity (LOH) were studied in 50 cases of esophageal squamous cell carcinoma (ESCC) by amplifying six microsatellite markers: D13S260 (13q12.3), D13S267 (13q12.3), D9S171 (9p21), D2S123 (2p), D5S2501 (5q21) and TP53 (17p13.1) analyzed on 6% denaturing polyacrylamide gel electrophoresis. Results: Statistical analysis indicated a near significant reverse correlation between grade and LOH (P= 0.068, correlation coefficient= -0.272). Specifically, increased LOH in tumor DNA has a significant correlation with increased differentiation from poorly differentiated to well differentiated tumors (P= 0.002 and P= 0.016 respectively). In addition, higher number of chromosomal loci with LOH showed a reverse correlation with lymph node metastasis (P= 0.026, correlation coefficient= -0.485). Furthermore, there was a positive correlation between addiction and MSI (P= 0.026, correlation coefficient= 0.465). Conclusion: Microsatellite DNA alterations may be a prognostic tool for detection and the evolution of prognosis in patients with SCC of esophagus. It can be concluded that regional lymph node metastasis would be less likely with increased heterozygote loci and addiction with any of opium, cigarette, water pipe or alcohol can be a susceptibility factor(s) for MSI. PMID:27635196

  10. Loss of heterozygosity and homozygous deletion of the tpr locus in human gastric cancer.

    PubMed

    Cunningham, J D; Schwartz, G K; Karpeh, M; Blundell, M; Kelson, D P; Jhanwar, S C; Albino, A P

    1997-06-01

    Despite being one of the world's most common neoplasias, there is little information on the molecular events that lead to gastric cancer. Molecular studies have shown that inactivation of tumor suppressor genes by mutation and/or allelic loss is an important genetic alteration in the multistep process of tumorigenesis. In an attempt to identify a putative tumor suppressor gene involved in the carcinogenesis of gastric cancer, we performed Southern blot analysis using the tpr probe for 44 patients with gastric cancer, using tumor tissue and normal tissue from the same specimen. Of the 44 samples, 7 (16%) were informative, heterozygous cases for the tpr probe. Three of the informative cases showed a loss of heterozygosity and 3 cases showed homozygous deletion for the tpr probe (6 of 7; 85%). These findings suggest that tpr gene plays a role in gastric tumorigenesis, and this may be due to a tumor suppressor effect for the tpr gene.

  11. Loss-of-heterozygosity on chromosome 19q in early-stage serous ovarian cancer is associated with recurrent disease

    PubMed Central

    2012-01-01

    Background Ovarian cancer is a heterogeneous disease and prognosis for apparently similar cases of ovarian cancer varies. Recurrence of the disease in early stage (FIGO-stages I-II) serous ovarian cancer results in survival that is comparable to those with recurrent advanced-stage disease. The aim of this study was to investigate if there are specific genomic aberrations that may explain recurrence and clinical outcome. Methods Fifty-one women with early stage serous ovarian cancer were included in the study. DNA was extracted from formalin fixed samples containing tumor cells from ovarian tumors. Tumor samples from thirty-seven patients were analysed for allele-specific copy numbers using OncoScan single nucleotide polymorphism arrays from Affymetrix and the bioinformatic tool Tumor Aberration Prediction Suite. Genomic gains, losses, and loss-of-heterozygosity that associated with recurrent disease were identified. Results The most significant differences (p < 0.01) in Loss-of-heterozygosity (LOH) were identified in two relatively small regions of chromosome 19; 8.0-8,8 Mbp (19 genes) and 51.5-53.0 Mbp (37 genes). Thus, 56 genes on chromosome 19 were potential candidate genes associated with clinical outcome. LOH at 19q (51-56 Mbp) was associated with shorter disease-free survival and was an independent prognostic factor for survival in a multivariate Cox regression analysis. In particular LOH on chromosome 19q (51-56 Mbp) was significantly (p < 0.01) associated with loss of TP53 function. Conclusions The results of our study indicate that presence of two aberrations in TP53 on 17p and LOH on 19q in early stage serous ovarian cancer is associated with recurrent disease. Further studies related to the findings of chromosomes 17 and 19 are needed to elucidate the molecular mechanism behind the recurring genomic aberrations and the poor clinical outcome. PMID:22967087

  12. The Adaptive Response in p53 Cancer Prone Mice: Loss of heterozygosity and Genomic Instability

    SciTech Connect

    Josee, Lavoie; Dolling, Jo-Anna; Mitchel, Ron E.J.; Boreham, Douglas R.

    2004-09-28

    mice, only numerical aberrations were observed in 5 to 20% of the cells. There seem to be an age related increase in numerical aberrations as mice grow old. The results indicate that the presence of a defective copy of the Trp53 gene does not seem to affect spontaneous chromosomal instability or in response to chronic low dose exposure to g-radiation. In previous studies it was speculated that low dose and low dose rate in vivo exposure to g-radiation induces an adaptive response, which reduces the risk of cancer death generated by subsequent DNA damage from either spontaneous or radiation induced events due to enhanced recombinational repair. Induced recombination could result from reversion to homozygosity at Trp53 gene locus (Trp53 +/- to +/+) or loss of heterozygosity in unexposed mice (Trp53 +/- to -/-). This hypothesis was investigated using the quantitative real-time Polymerase Chain Reaction (QRT-PCR) quantification method and the novel Rolling Circle Amplification technique (RCA). For these purposes, spleenocytes and bone marrow cells from all the mice were isolated for cell fixation and DNA extraction. The defective Trp53 allele is generated by integration of a portion of the cloning vector pKONEO DNA into the coding sequence. Therefore, the genotypic changes are monitored based on the detection of the NEO allele and the normal Trp53 allele in the cells. To evaluate loss of heterozygosity at the Trp53 gene locus in a cell, detection of the NEO allele and the normal Trp53 allele using the dual color RCA was utilized. In our hands, this protocol did not give the required sensitivity. The gene signal enumeration was inconsistent and not reproducible. The protocol was modified and could not be optimized. Therefore, the QRT-PCR method was selected to evaluate the loss of heterozygosity with greater sensitivity and efficiency. A set of 4 primers was designed to target the NEO allele and the normal Trp53 allele in a PCR experiment using the LightCycler instrument

  13. Loss of heterozygosity at 7q31.1 and 12p13-12 in advanced prostate cancer.

    PubMed

    Kawana, Yoko; Ichikawa, Tomohiko; Suzuki, Hiroyoshi; Ueda, Takeshi; Komiya, Akira; Ichikawa, Yayoi; Furuya, Yuzo; Akakura, Koichiro; Igarashi, Tatsuo; Ito, Haruo

    2002-09-15

    Allelic losses on chromosome arms 2q, 3p, 5q, 6q, 7q, 8p, 9p, 10p, 10q, 11p, 11q, 12p, 13q, 16q, 17p, 17q, 18q, and 21q are reportedly associated with progression and/or initiation of prostate cancer. In the present study, we performed a polymerase chain reaction (PCR) analysis of polymorphic microsatellite loci on the human chromosomes 7 and 12p13-12 in prostate cancer tissue to investigate the extent of involvement of these regions, which may contain putative tumor suppressor genes. Tissue samples were obtained at autopsy from 17 men who died of hormone-refractory prostate cancer at Chiba University, Japan, and affiliated hospitals between June of 1992 and June of 1995. DNA from normal tumor or metastatic tissue was used as the template for PCR amplification of a set of 16 polymorphic microsatellite loci on human chromosome 7 and 6 loci on the human chromosome region 12p13-12. The frequencies of cases with loss of heterozygosity (LOH) at 7q31.1 were 8% in primary tumor tissue and 11% in metastatic tissue. The frequencies of cases with LOH at 12p13-12 were 12% in primary tumor tissue and 25% in metastatic tumor tissue. In the present study, the frequencies of LOH at 7q31.1 were lower than in Western patients, suggesting that LOH in this region is not related to progression of prostate cancer in Japanese patients. The frequency of LOH at 12p13-12 was similar to that reported in Western countries, indicating that 12p13-12 may contain a tumor suppressor gene of prostate cancer. Copyright 2002 Wiley-Liss, Inc.

  14. Allelotype of uterine cancer by analysis of RFLP and microsatellite polymorphisms: frequent loss of heterozygosity on chromosome arms 3p, 9q, 10q, and 17p.

    PubMed

    Jones, M H; Koi, S; Fujimoto, I; Hasumi, K; Kato, K; Nakamura, Y

    1994-02-01

    Cancers in which mutations have been identified in putative tumor suppressor genes, such as the TP53 gene, the retinoblastoma (RBI) gene, the adenomatous polyposis coli (APC) gene, and the Wilms tumor (WTI) gene, frequently show loss of the corresponding allele on the homologous chromosome. To identify locations of tumor suppressor genes involved in uterine cancer, we examined loss of heterozygosity (LOH) by using genomic probes detecting RFLPs in 35 uterine cancers at 29 loci throughout the genome, and with highly informative microsatellite markers in 21 uterine cancers at nine putative or known tumor suppressor gene loci. High frequencies of allelic loss found at loci on 3p (71%), 9q (38%), 10q (35%), and 17p (35%) suggest that tumor suppressor genes involved in uterine carcinogenesis exist in these regions. There were no significant differences in frequencies of LOH between cancers of the uterine cervix and cancers of the uterine endometrium at any of the loci tested.

  15. A preliminary study of the relationship between breast cancer metastasis and loss of heterozygosity by using exome sequencing

    PubMed Central

    Li, Hongsheng; Yang, Bo; Xing, Ke; Yuan, Nangui; Wang, Bo; Chen, Zhenyu; He, Weixing; Zhou, Jie

    2014-01-01

    We explored the feasibility of studying loss of heterozygosity (LOH) by using exome sequencing and compared the differences in genetic LOH between primary breast tumors and metastatic lesions. Exome sequencing was conducted to investigate the genetic LOH in the peripheral blood, a primary tumor, and a metastatic lesion from the same patient. LOH was observed in 30 and 48 chromosomal loci of the primary tumor and metastatic lesion, respectively. The incidence of LOH was the highest on chromosome 19, followed by chromosomes 14, 3, and 11 in the metastatic lesion. Among these ‘hot' regions, LOH was observed for multiple genes of the CECAM, MMP and ZNF families. Therefore, the use of exome sequencing for studying LOH is feasible. More members of gene families appeared with LOH in ‘hot' regions, suggesting that these gene families had synergistic effects in tumorigenesis. PMID:24964733

  16. Clinical impact of detection of loss of heterozygosity of BRCA1 and BRCA2 markers in sporadic breast cancer.

    PubMed Central

    Beckmann, M. W.; Picard, F.; An, H. X.; van Roeyen, C. R.; Dominik, S. I.; Mosny, D. S.; Schnürch, H. G.; Bender, H. G.; Niederacher, D.

    1996-01-01

    The development of familial and sporadic breast cancer is based on genetic alterations of tumour-suppressor genes, for which loss of heterozygosity (LOH) is one mechanism of gene inactivation. To investigate LOH of BRCA1 (17q21) and BRCA2 (13-q12-13) in sporadic breast cancer, polymerase chain reaction (PCR)-based fluorescent DNA technology for detection of microsatellite polymorphisms was applied. A total of 137 breast cancer and 15 benign breast specimens with matched normal tissue were examined. Fluorescent-labelled PCR products were analysed in an automated DNA sequencer (ALFTM Pharmacia). Losses at both loci were correlated with different histological types, age, tumour size, lymph node status, grading and steroid hormone receptor expression, [SHR: oestrogen receptor (ER), progesterone receptor (PgR)]. For BRCA1 (D17S855, THRA1, D17S579) losses could be detected in invasive ductal carcinoma (IDC; n = 108) in 32-38%, invasive lobular carcinoma (ILC; n = 19) in 21-42% depending on the marker applied, but not in benign breast tumours (n = 15). Losses of BRCA1 markers correlated with larger tumour size, higher grade, and PgR expression. For BRCA2 (D13S260, D13S267, D13S171) losses could be detected in 108 IDCs in 30-38%, in 19 ILCs in 17-39% depending on the marker applied, but not in benign breast tumours. Losses of BRCA2 markers correlated only with higher grade. Microsatellite analyses combined with detection of fluorescent-labelled PCR products by an automated laser DNA sequencer can be used for routine determination of LOH. In sporadic breast cancer, LOH of BRCA1 of BRCA2 does not add decisive prognostic value as stated for familial breast cancer. Images Figure 1 PMID:8630282

  17. Conflicting HLA assignment by three different typing methods due to the apparent loss of heterozygosity in the MHC region.

    PubMed

    Linjama, T; Impola, U; Niittyvuopio, R; Kuittinen, O; Kaare, A; Rimpiläinen, J; Volin, L; Peräsaari, J; Jaatinen, T; Lauronen, J; Saarinen, T; Juvonen, E; Partanen, J; Koskela, S

    2016-05-01

    Loss of heterozygosity (LOH) has been reported to cause false human leukocyte antigen (HLA) homozygous typing results in pre-transplant patients suffering from haematological malignancies, who in fact are HLA heterozygous. This poses a challenge for histocompatibility testing, as a stem cell graft from a genuinely HLA homozygous donor to a mistyped patient may lead to acute life-threatening graft-vs-host disease. LOH in the HLA region on chromosome 6 is known to be quite common in solid tumours, helping malignant cells to escape T-cell surveillance, but the incidence in haematological malignancies is less well known and the estimates vary. Here we report LOH in the HLA region of five patients with haematological malignancy. We found considerable differences in sensitivity between the three different HLA typing methods used in our laboratory: SSP was clearly the most sensitive method for detecting the lost haplotype, followed by rSSO, while SBT was the least sensitive technique. A subsequent, retrospective genotyping of 65 HLA homozygous haematological patients by SSP method showed no mistyped LOH cases in our laboratory in the past 10 years. The frequency of HLA homozygosity was found to be similar between haematological patients and control groups. It is important for an HLA laboratory to be aware of the differences in various HLA typing techniques' sensitivity for detecting an under-represented haplotype between HLA typing techniques when genotyping patients with haematological diseases. It is advisable for HLA laboratories to have at least two different methods with different sensitivities in their repertoire to be able to retype samples when a false homozygous result is suspected. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers

    PubMed Central

    Muzumdar, Mandar Deepak; Dorans, Kimberly Judith; Chung, Katherine Minjee; Robbins, Rebecca; Tammela, Tuomas; Gocheva, Vasilena; Li, Carman Man-Chung; Jacks, Tyler

    2016-01-01

    Although it has become increasingly clear that cancers display extensive cellular heterogeneity, the spatial growth dynamics of genetically distinct clones within developing solid tumours remain poorly understood. Here we leverage mosaic analysis with double markers (MADM) to trace subclonal populations retaining or lacking p53 within oncogenic Kras-initiated lung and pancreatic tumours. In both models, p53 constrains progression to advanced adenocarcinomas. Comparison of lineage-related p53 knockout and wild-type clones reveals a minor role of p53 in suppressing cell expansion in lung adenomas. In contrast, p53 loss promotes both the initiation and expansion of low-grade pancreatic intraepithelial neoplasia (PanINs), likely through differential expression of the p53 regulator p19ARF. Strikingly, lineage-related cells are often dispersed in lung adenomas and PanINs, contrasting with more contiguous growth of advanced subclones. Together, these results support cancer type-specific suppressive roles of p53 in early tumour progression and offer insights into clonal growth patterns during tumour development. PMID:27585860

  19. Identification of loss of heterozygosity on circulating free DNA in peripheral blood of prostate cancer patients: potential and technical improvements.

    PubMed

    Müller, Imke; Beeger, Cord; Alix-Panabières, Catherine; Rebillard, Xavier; Pantel, Klaus; Schwarzenbach, Heidi

    2008-04-01

    Accurate identification of loss of heterozygosity (LOH) on circulating free DNA is often restricted by technical limitations such as poor quality and quantity of tumor-specific DNA and contamination by normal DNA. However, plasma DNA may harbor tumor-specific genetic alterations and could therefore be an interesting target for noninvasive examinations of tumor DNA. By PCR-based fluorescence microsatellite analysis using 12 polymorphic markers, we investigated LOH on cell-free DNA in blood plasma from 59 patients with localized prostate cancer (PCa) and 12 with metastatic disease (MPCa). In addition, plasma DNA from 21 PCa patients was fractionated into high- and low-molecular-weight DNA by 2 different column systems. To avoid appearance of artificial allelic loss and stabilize the amplification, TMAC (tetramethylammonium chloride) was added to each PCR. Overall incidences of LOH at all markers analyzed were 10% in PCa and 12% in MPCa samples. Highest frequencies were found at markers D11S898 (28%) in PCa and D6S1631 (27%) in MPCa. Statistical evaluation showed significant associations between LOH and increasing Gleason scores for the marker combinations D6S1631*D8S286*D9S171 (P = 0.03) and D8S286*D9S171 (P = 0.05). Fractionation of plasma DNA resulted in a higher overall LOH frequency in the low-molecular-weight DNA fraction (23%) compared with the high-molecular-weight DNA (7%). LOH analysis of circulating DNA can provide tumor-specific genetic information on PCa patients. Fractionation of plasma DNA and addition of TMAC improved LOH detection and general assay performance.

  20. Loss of Heterozygosity at the CYP2D6 Locus in Breast Cancer: Implications for Germline Pharmacogenetic Studies

    PubMed Central

    Goetz, Matthew P.; Sun, James X.; Suman, Vera J.; Silva, Grace O.; Perou, Charles M.; Nakamura, Yusuke; Cox, Nancy J.; Stephens, Philip J.; Miller, Vincent A.; Ross, Jeffrey S.; Chen, David; Safgren, Stephanie L.; Kuffel, Mary J.; Ames, Matthew M.; Kalari, Krishna R.; Gomez, Henry L.; Gonzalez-Angulo, Ana M.; Burgues, Octavio; Brauch, Hiltrud B.; Ingle, James N.; Ratain, Mark J.; Yelensky, Roman

    2015-01-01

    Background: Controversy exists regarding the impact of CYP2D6 genotype on tamoxifen responsiveness. We examined loss of heterozygosity (LOH) at the CYP2D6 locus and determined its impact on genotyping error when tumor tissue is used as a DNA source. Methods: Genomic tumor data from the adjuvant and metastatic settings (The Cancer Genome Atlas [TCGA] and Foundation Medicine [FM]) were analyzed to characterize the impact of CYP2D6 copy number alterations (CNAs) and LOH on Hardy Weinberg equilibrium (HWE). Additionally, we analyzed CYP2D6 *4 genotype from formalin-fixed paraffin-embedded (FFPE) tumor blocks containing nonmalignant tissue and buccal (germline) samples from patients on the North Central Cancer Treatment Group (NCCTG) 89-30-52 tamoxifen trial. All statistical tests were two-sided. Results: In TCGA samples (n =627), the CYP2D6 LOH rate was similar in estrogen receptor (ER)–positive (41.2%) and ER-negative (35.2%) but lower in HER2-positive tumors (15.1%) (P < .001). In FM ER+ samples (n = 290), similar LOH rates were observed (40.8%). In 190 NCCTG samples, the agreement between CYP2D6 genotypes derived from FFPE tumors and FFPE tumors containing nonmalignant tissue was moderate (weighted Kappa = 0.74; 95% CI = 0.63 to 0.84). Comparing CYP2D6 genotypes derived from buccal cells to FFPE tumor DNA, CYP2D6*4 genotype was discordant in six of 31(19.4%). In contrast, there was no disagreement between CYP2D6 genotypes derived from buccal cells with FFPE tumors containing nonmalignant tissue. Conclusions: LOH at the CYP2D6 locus is common in breast cancer, resulting in potential misclassification of germline CYP2D6 genotypes. Tumor DNA should not be used to determine germline CYP2D6 genotype without sensitive techniques to detect low frequency alleles and quality control procedures appropriate for somatic DNA. PMID:25490892

  1. Genome-wide allelotyping indicates increased loss of heterozygosity on 9p and 14q in early age of onset colorectal cancer.

    PubMed

    Weber, T K; Conroy, J; Keitz, B; Rodriguez-Bigas, M; Petrelli, N J; Stoler, D L; Anderson, G R; Shows, T B; Nowak, N J

    1999-01-01

    Colorectal cancer remains a significant public health challenge, despite our increased understanding of the genetic mechanisms involved in the initiation and progression of this disorder. It has become clear that multiple mechanisms lead to the tumorigenic phenotype, with familial predisposition syndromes accounting for less than 15% of all colorectal cancers. A genome-wide scan for loss of heterozygosity (LOH) was carried out with 150 highly polymorphic markers in an effort to identify additional loci involved in colorectal tumorigenesis in DNA samples from 42 colorectal cancer patients. The results confirm earlier observations that tumor DNAs from patients with hereditary nonpolyposis colon cancer (HNPCC) either maintain heterozygosity or exhibit altered or additional alleles. DNAs from patients with early onset colorectal carcinomas (diagnosed prior to age 50) revealed a higher overall degree of LOH than DNAs from patients with sporadic colorectal cancers diagnosed later in life (after age 50). While regions on 1p, 10q and 14q are suggestive, statistical analysis of LOH at these regions failed to reach significance. However, LOH at 9p did reveal a statistically significant increase in the early onset patient group, compared to the greater than age 50 group. LOH on 9p may involve inactivation of p16/CDKN2 through aberrant DNA methylation on the remaining chromosome, resulting in a situation analogous to a homozygous deletion of p16 and providing a selective growth advantage to these cells. This marker may prove to be a useful prognostic indicator for patient stratification in the design of therapy for early onset colorectal cancer patients.

  2. Integrative analysis of genome-wide loss of heterozygosity and monoallelic expression at nucleotide resolution reveals disrupted pathways in triple-negative breast cancer.

    PubMed

    Ha, Gavin; Roth, Andrew; Lai, Daniel; Bashashati, Ali; Ding, Jiarui; Goya, Rodrigo; Giuliany, Ryan; Rosner, Jamie; Oloumi, Arusha; Shumansky, Karey; Chin, Suet-Feung; Turashvili, Gulisa; Hirst, Martin; Caldas, Carlos; Marra, Marco A; Aparicio, Samuel; Shah, Sohrab P

    2012-10-01

    Loss of heterozygosity (LOH) and copy number alteration (CNA) feature prominently in the somatic genomic landscape of tumors. As such, karyotypic aberrations in cancer genomes have been studied extensively to discover novel oncogenes and tumor-suppressor genes. Advances in sequencing technology have enabled the cost-effective detection of tumor genome and transcriptome mutation events at single-base-pair resolution; however, computational methods for predicting segmental regions of LOH in this context are not yet fully explored. Consequently, whole transcriptome, nucleotide-level resolution analysis of monoallelic expression patterns associated with LOH has not yet been undertaken in cancer. We developed a novel approach for inference of LOH from paired tumor/normal sequence data and applied it to a cohort of 23 triple-negative breast cancer (TNBC) genomes. Following extensive benchmarking experiments, we describe the nucleotide-resolution landscape of LOH in TNBC and assess the consequent effect of LOH on the transcriptomes of these tumors using RNA-seq-derived measurements of allele-specific expression. We show that the majority of monoallelic expression in the transcriptomes of triple-negative breast cancer can be explained by genomic regions of LOH and establish an upper bound for monoallelic expression that may be explained by other tumor-specific modifications such as epigenetics or mutations. Monoallelically expressed genes associated with LOH reveal that cell cycle, homologous recombination and actin-cytoskeletal functions are putatively disrupted by LOH in TNBC. Finally, we show how inference of LOH can be used to interpret allele frequencies of somatic mutations and postulate on temporal ordering of mutations in the evolutionary history of these tumors.

  3. Integrative analysis of genome-wide loss of heterozygosity and monoallelic expression at nucleotide resolution reveals disrupted pathways in triple-negative breast cancer

    PubMed Central

    Ha, Gavin; Roth, Andrew; Lai, Daniel; Bashashati, Ali; Ding, Jiarui; Goya, Rodrigo; Giuliany, Ryan; Rosner, Jamie; Oloumi, Arusha; Shumansky, Karey; Chin, Suet-Feung; Turashvili, Gulisa; Hirst, Martin; Caldas, Carlos; Marra, Marco A.; Aparicio, Samuel; Shah, Sohrab P.

    2012-01-01

    Loss of heterozygosity (LOH) and copy number alteration (CNA) feature prominently in the somatic genomic landscape of tumors. As such, karyotypic aberrations in cancer genomes have been studied extensively to discover novel oncogenes and tumor-suppressor genes. Advances in sequencing technology have enabled the cost-effective detection of tumor genome and transcriptome mutation events at single-base-pair resolution; however, computational methods for predicting segmental regions of LOH in this context are not yet fully explored. Consequently, whole transcriptome, nucleotide-level resolution analysis of monoallelic expression patterns associated with LOH has not yet been undertaken in cancer. We developed a novel approach for inference of LOH from paired tumor/normal sequence data and applied it to a cohort of 23 triple-negative breast cancer (TNBC) genomes. Following extensive benchmarking experiments, we describe the nucleotide-resolution landscape of LOH in TNBC and assess the consequent effect of LOH on the transcriptomes of these tumors using RNA-seq-derived measurements of allele-specific expression. We show that the majority of monoallelic expression in the transcriptomes of triple-negative breast cancer can be explained by genomic regions of LOH and establish an upper bound for monoallelic expression that may be explained by other tumor-specific modifications such as epigenetics or mutations. Monoallelically expressed genes associated with LOH reveal that cell cycle, homologous recombination and actin-cytoskeletal functions are putatively disrupted by LOH in TNBC. Finally, we show how inference of LOH can be used to interpret allele frequencies of somatic mutations and postulate on temporal ordering of mutations in the evolutionary history of these tumors. PMID:22637570

  4. Frequent loss of heterozygosity at the DNA mismatch-repair loci hMLH1 and hMSH3 in sporadic breast cancer

    PubMed Central

    Benachenhou, N; Guiral, S; Gorska-Flipot, I; Labuda, D; Sinnett, D

    1999-01-01

    To study the involvement of DNA mismatch-repair genes in sporadic breast cancer, matched normal and tumoral DNA samples of 22 patients were analysed for genetic instability and loss of heterozygosity (LOH) with 42 microsatellites at or linked to hMLH1 (3p21), hMSH2 (2p16), hMSH3 (5q11–q13), hMSH6 (2p16), hPMS1 (2q32) and hPMS2 (7p22) loci. Chromosomal regions 3p21 and 5q11–q13 were found hemizygously deleted in 46% and 23% of patients respectively. Half of the patients deleted at hMLH1 were also deleted at hMSH3. The shortest regions of overlapping (SRO) deletions were delimited by markers D3S1298 and D3S1266 at 3p21 and by D5S647 and D5S418 at 5q11–q13. Currently, the genes hMLH1 (3p21) and hMSH3 (5q11–q13) are the only known candidates located within these regions. The consequence of these allelic losses is still unclear because none of the breast cancers examined displayed microsatellite instability, a hallmark of mismatch-repair defect during replication error correction. We suggest that hMLH1 and hMSH3 could be involved in breast tumorigenesis through cellular functions other than replication error correction. © 1999 Cancer Research Campaign PMID:10098729

  5. Copy number of the Adenomatous Polyposis Coli gene is not always neutral in sporadic colorectal cancers with loss of heterozygosity for the gene.

    PubMed

    Zauber, Peter; Marotta, Stephen; Sabbath-Solitare, Marlene

    2016-03-12

    Changes in the number of alleles of a chromosome may have an impact upon gene expression. Loss of heterozygosity (LOH) indicates that one allele of a gene has been lost, and knowing the exact copy number of the gene would indicate whether duplication of the remaining allele has occurred. We were interested to determine the copy number of the Adenomatous Polyposis Coli (APC) gene in sporadic colorectal cancers with LOH. We selected 38 carcinomas with LOH for the APC gene region of chromosome 5, as determined by amplification of the CA repeat region within the D5S346 loci. The copy number status of APC was ascertained using the SALSA® MLPA® P043-B1 APC Kit. LOH for the DCC gene, KRAS gene mutation, and microsatellite instability were also evaluated for each tumor, utilizing standard polymerase chain reaction methods. No tumor demonstrated microsatellite instability. LOH of the DCC gene was also present in 33 of 36 (91.7%) informative tumors. A KRAS gene mutation was present in 16 of the 38 (42.1%) tumors. Twenty-four (63.2%) of the tumors were copy number neutral, 10 (26.3%) tumors demonstrated major loss, while two (5.3%) showed partial loss. Two tumors (5.3%) had copy number gain. Results of APC and DCC LOH, KRAS and microsatellite instability indicate our colorectal cancer cases were typical of sporadic cancers following the 'chromosomal instability' pathway. The majority of our colorectal carcinomas with LOH for APC gene are copy number neutral. However, one-third of our cases showed copy number loss, suggesting that duplication of the remaining allele is not required for the development of a colorectal carcinoma.

  6. Mutations of the KIT gene and loss of heterozygosity of the PTEN region in a primary malignant melanoma arising from a mature cystic teratoma of the ovary.

    PubMed

    Tate, Genshu; Tajiri, Takuma; Suzuki, Takao; Mitsuya, Toshiyuki

    2009-04-01

    A tumor suppressor gene at 10q23.3, designated PTEN, encoding a dual-specificity phosphatase with lipid and protein phosphatase activity, has been shown to play a pivotal role in the pathogenesis of a variety of human cancers. A frequent loss of heterozygosity (LOH) at 10q is found in melanoma; however, little is known about the role of PTEN in the pathogenesis of a primary malignant melanoma derived from ovarian mature cystic teratoma, which is an extremely rare melanoma. This study examined the genetic alterations involved in the mitogen-activated protein kinase and phosphatidylinositol 3 kinase pathways in an ovarian malignant melanoma. A LOH analysis revealed hemizygous deletion around and in the PTEN gene not only in the ovarian melanoma but also in a mature cystic teratoma. Another case of ovarian mature cystic teratomas in the absence of melanoma also showed allelic loss of the PTEN region. To date, mutations of BRAF, NRAS, and KIT genes have been reported in malignant melanomas. In the present study, D816H and K558E mutations of the KIT gene were revealed in the melanoma arising from a mature cystic teratoma, but not in a mature cystic teratoma. No mutations of the BRAF and NRAS genes were found in the melanoma. These results indicate that LOH of the PTEN region is one of the molecular alterations of an ovarian mature cystic teratoma and a KIT mutation is an additional promotional event associated with the oncogenesis of a melanoma arising from an ovarian mature cystic teratoma.

  7. LOHAS: loss-of-heterozygosity analysis suite.

    PubMed

    Yang, Hsin-Chou; Chang, Lun-Ching; Huggins, Richard M; Chen, Chun-Houh; Mullighan, Charles G

    2011-05-01

    Detection of loss of heterozygosity (LOH) plays an important role in genetic, genomic and cancer research. We develop computational methods to estimate the proportion of homozygous SNP calls, identify samples with structural alterations and/or unusual genotypic patterns, cluster samples with close LOH structures and map the genomic segments bearing LOH by analyzing data of genome-wide SNP arrays or customized SNP arrays. In addition to cancer genetics/genomics, we also apply the methods to study long contiguous stretches of homozygosity (LCSH) in general populations. The LCSH analysis aids in the identification of samples with complex LCSH patterns indicative of nonrandom mating and/or meiotic recombination cold spots, separation of samples with different genetic backgrounds and sex, and mapping of regions of LCSH. Affymetrix Human Mapping 500K Set SNP data from an acute lymphoblastic leukemia study containing 304 cancer patients and 50 normal controls and from the HapMap Project containing 30 African trios, 30 Caucasian trios and 90 independent Asian samples were analyzed. We identified common gene regions of LOH, e.g., ETV6 and CDKN1B, and identified frequent regions of LCSH, e.g., the region that encompasses the centromeric gene desert region of chromosome 16. Unsupervised analysis separated cancer subtypes and ethnic subpopulations by patterns of LOH/LCSH. Simulation studies considering LOH width, effect size and heterozygous interference fraction were performed, and the results show that the proposed LOH association test has good test power and controls type 1 error well. The developed algorithms are packaged into LOHAS written in R and R GUI.

  8. Loss of heterozygosity of the Mutated in Colorectal Cancer gene is not associated with promoter methylation in non-small cell lung cancer.

    PubMed

    Poursoltan, Pirooz; Currey, Nicola; Pangon, Laurent; van Kralingen, Christa; Selinger, Christina I; Mahar, Annabelle; Cooper, Wendy A; Kennedy, Catherine W; McCaughan, Brian C; Trent, Ronald; Kohonen-Corish, Maija R J

    2012-08-01

    'Mutated in Colorectal Cancer' (MCC) is emerging as a multifunctional protein that affects several cellular processes and pathways. Although the MCC gene is rarely mutated in colorectal cancer, it is frequently silenced through promoter methylation. Previous studies have reported loss of heterozygosity (LOH) of the closely linked MCC and APC loci in both colorectal and lung cancers. APC promoter methylation is a marker of poor survival in non-small cell lung cancer (NSCLC). However, MCC methylation has not been previously studied in lung cancer. Therefore, we wanted to determine if MCC is silenced through promoter methylation in lung cancer and whether this methylation is associated with LOH of the MCC locus or methylation of the APC gene. Three polymorphic markers for the APC/MCC locus were analysed for LOH in 64 NSCLC specimens and matching normal tissues. Promoter methylation of both genes was determined using methylation specific PCR in primary tumours. LOH of the three markers was found in 41-49% of the specimens. LOH within the MCC locus was less common in adenocarcinoma (ADC) (29%) than in squamous cell carcinoma (SCC) (72%; P=0.006) or large cell carcinoma (LCC) (75%; P=0.014). However, this LOH was not accompanied by MCC promoter methylation, which was found in only two cancers (3%). In contrast, 39% of the specimens showed APC methylation, which was more common in ADC (58%) than in SCC (13%). Western blotting revealed that MCC was expressed in a subset of lung tissue specimens but there was marked variation between patients rather than between cancer and matching non-cancer tissue specimens. In conclusion, we have shown that promoter methylation of the APC gene does not extend to the neighbouring MCC gene in lung cancer, but LOH is found at both loci. The variable levels of MCC expression were not associated with promoter methylation and may be regulated through other cellular mechanisms.

  9. Tumor progression stage: specific losses of heterozygosity.

    PubMed

    Cavenee, W K

    1989-01-01

    The development of human cancer is generally thought to entail a series of events that cause a progressively more malignant phenotype. This hypothesis predicts that tumor cells of the ultimate stage will carry each of the events, cells of the penultimate stage will carry each of the events less the last one and so on. That is to say, a dissection of the pathway form a normal cell to a fully malignant tumor may be viewed as the unraveling of a nested set of aberrations. In experiments designed to elucidate these events, we have compared genotypic combinations at genomic loci defined by restriction endonuclease recognition site variation in normal and tumor tissues from patients with various forms and stages of cancer. The first step, inherited predisposition, is best described for retinoblastoma in which a recessive mutation of a locus residing in the 13q14 region of the genome is unmasked by aberrant, but specific, mitotic chromosomal segregation. A similar mechanism involving the distal short arm of chromosome 17 is apparent in astrocytic tumors and the event is shared by cells in each malignancy stage. This is distinct from a loss of heterozygosity for loci on chromosome 10 which is restricted to the ultimate stage, glioblastoma multiforme. Further, this approach has has been extended to a wide variety of human cancers and shown to be generally applicable. The results suggest a genetic approach to defining degrees of tumor progression and a means for determining the genomic locations of genes involved in the pathway as a prelude to their molecular isolation and characterization. They have provided a molecular genetic-based oncology with clinical utility in differential pathology, in disease groupings for therapeutic purposes and in prenatal identification of latent disease carriers.

  10. Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity.

    PubMed

    Ahern, Thomas P; Hertz, Daniel L; Damkier, Per; Ejlertsen, Bent; Hamilton-Dutoit, Stephen J; Rae, James M; Regan, Meredith M; Thompson, Alastair M; Lash, Timothy L; Cronin-Fenton, Deirdre P

    2017-01-15

    Tamoxifen therapy for estrogen receptor-positive breast cancer reduces the risk of recurrence by approximately one-half. Cytochrome P-450 2D6, encoded by the polymorphic cytochrome P-450 2D6 gene (CYP2D6), oxidizes tamoxifen to its most active metabolites. Steady-state concentrations of endoxifen (4-hydroxy-N-desmethyltamoxifen), the most potent antiestrogenic metabolite, are reduced in women whose CYP2D6 genotypes confer poor enzyme function. Thirty-one studies of the association of CYP2D6 genotype with breast cancer survival have yielded heterogeneous results. Some influential studies genotyped DNA from tumor-infiltrated tissues, and their results may have been susceptible to germline genotype misclassification from loss of heterozygosity at the CYP2D6 locus. We systematically reviewed 6 studies of concordance between genotypes obtained from paired nonneoplastic and breast tumor-infiltrated tissues, all of which showed excellent CYP2D6 genotype agreement. We applied these concordance data to a quantitative bias analysis of the subset of the 31 studies that were based on genotypes from tumor-infiltrated tissue to examine whether genotyping errors substantially biased estimates of association. The bias analysis showed negligible bias by discordant genotypes. Summary estimates of association, with or without bias adjustment, indicated no clinically important association between CYP2D6 genotype and breast cancer survival in tamoxifen-treated women.

  11. Loss of heterozygosity of the PTCH gene in ameloblastoma.

    PubMed

    Farias, Lucyana Conceição; Gomes, Carolina Cavalieri; Brito, João Artur Ricieri; Galvão, Clarice Ferreira; Diniz, Marina Gonçalves; de Castro, Wagner Henriques; Bernardes, Vanessa de Fátima; De Marco, Luiz Armando; Gomez, Ricardo Santiago

    2012-08-01

    Ameloblastoma is a locally aggressive benign neoplasm derived from odontogenic epithelium, with high recurrence rates. Alterations in the Sonic Hedgehog signaling pathway, including PTCH gene mutations, have been associated with the pathogenesis of some odontogenic tumors. The purpose of the present study was to assess loss of heterozygosity at the PTCH locus in ameloblastoma. Twelve ameloblastomas were included, and loss of heterozygosity was assessed by using 3 microsatellite markers D9S252, D9S127, and D9S287 and 3 single-nucleotide polymorphisms rs112794371, rs111446700, and rs357564, all located at the PTCH gene locus. Furthermore, we investigated GLI1 and GLI2 transcription levels by quantitative reverse transcription polymerase chain reaction in 8 ameloblastomas and, concomitantly, PTCH protein levels by immunohistochemical analysis. Loss of heterozygosity at 9q21.33-9q.31 was detected in 4 (40.0%) of 10 informative cases of ameloblastoma. All 8 analyzed samples expressed GLI1 messenger RNA and 7 cases GLI2 messenger RNA. Interestingly, loss of heterozygosity at the PTCH locus was not correlated with GLI1 or GLI2 transcription levels, nor was there any correlation with PTCH protein expression. In conclusion, our findings suggest that loss of heterozygosity in the PTCH region may be relevant to the pathogenesis of ameloblastoma but may target a different gene than PTCH.

  12. Loss of heterozygosity at 7p in Wilms' tumour development

    PubMed Central

    Powlesland, R M; Charles, A K; Malik, K T A; Reynolds, P A; Pires, S; Boavida, M; Brown, K W

    2000-01-01

    Chromosome 7p alterations have been implicated in the development of Wilms' tumour (WT) by previous studies of tumour cytogenetics, and by our analysis of a constitutional translocation (t(1;7)(q42;p15)) in a child with WT and radial aplasia. We therefore used polymorphic microsatellite markers on 7p for a loss of heterozygosity (LOH) study, and found LOH in seven out of 77 informative WTs (9%). The common region of LOH was 7p15–7p22, which contains the region disrupted by the t(1;7) breakpoint. Four WTs with 7p LOH had other genetic changes; a germline WT1 mutation with 11p LOH, LOH at 11p, LOH at 16q, and loss of imprinting of IGF2. Analysis of three tumour-associated lesions from 7p LOH cases revealed a cystic nephroma-like area also having 7p LOH. However, a nephrogenic rest and a contralateral WT from the two other cases showed no 7p LOH. No particular clinical phenotype was associated with the WTs which showed 7p LOH. The frequency and pattern of 7p LOH demonstrated in our studies indicate the presence of a tumour suppressor gene at 7p involved in the development of Wilms' tumour. © 2000 Cancer Research Campaign PMID:10646884

  13. Allelotyping of butadiene-induced lung and mammary adenocarcinomas of B6C3F1 mice: frequent losses of heterozygosity in regions homologous to human tumor-suppressor genes.

    PubMed Central

    Wiseman, R W; Cochran, C; Dietrich, W; Lander, E S; Söderkvist, P

    1994-01-01

    To identify the potential involvement of tumor-suppressor gene inactivation during neoplastic development in B6C3F1 mice, genetic losses were determined from allelotypes of butadiene-induced lung and mammary adenocarcinomas. By using length polymorphisms in restriction fragments and simple sequence repeats, or "microsatellites," markers on each autosome were analyzed for allele losses in tumor DNAs. Losses of heterozygosity on chromosome 11 were observed at several loci surrounding the p53 tumor-suppressor gene (Trp53) in 12 of 17 mammary tumors and 2 of 8 lung tumors. Although most of these alterations appeared to result from nondisjunction, at least two examples of somatic recombination or deletion were also observed. Southern analysis revealed a homozygous deletion of the remaining Trp53 allele of one of these mammary tumors. Losses of heterozygosity were also detected at the Rb-1 tumor-suppressor gene in 7 of 17 mammary tumors and 1 lung tumor. Finally, frequent allele losses were observed on chromosome 4 in lung tumors. Analysis of nine chromosome 4 loci defined an interstitial deletion containing the Ifa gene cluster in one of the lung tumors. A tumor-suppressor gene was previously mapped to this region of chromosome 4 in studies with somatic cell hybrids. In addition, homozygous deletions have been reported in a homologous region of human chromosome 9p for acute lymphocytic leukemias, glioblastomas, melanomas, and lung carcinomas. These findings suggest that the inactivation of tumor-suppressor genes including Trp53, Rb-1, and an unidentified gene on chromosome 4 plays a significant role during carcinogenesis in mice. Images PMID:8170984

  14. Loss of heterozygosity on chromosome 5q in ovarian cancer is frequently accompanied by TP53 mutation and identifies a tumour suppressor gene locus at 5q13.1-21.

    PubMed Central

    Tavassoli, M.; Steingrimsdottir, H.; Pierce, E.; Jiang, X.; Alagoz, M.; Farzaneh, F.; Campbell, I. G.

    1996-01-01

    Forty-nine ovarian tumours were examined for loss of heterozygosity (LOH) on chromosome 5 using eight microsatellite markers spanning both arms, including one at the APC locus. LOH on 5q was a frequent event, detectable in 23 of 49 (47%) tumours, whereas 5p LOH was detected in only 1 of 22 tumours (5%). Six tumours showed partial LOH on 5q, enabling the candidate region to be localised to a 22 cM region proximal to APC, flanked by D5S424 and D5S644. An association was found between 5q LOH and TP53 mutation, with 18 of 23 (78%) tumours with LOH on 5q also harbouring a TP53 mutation. LOH on 5q was observed in 6 of 18 (33%) stage I tumours, suggesting that it may be an early event in the molecular pathogenesis of certain ovarian carcinomas. Images Figure 1 PMID:8679443

  15. Frequent loss of heterozygosity at 7q31.1 in primary prostate cancer is associated with tumor aggressiveness and progression.

    PubMed

    Takahashi, S; Shan, A L; Ritland, S R; Delacey, K A; Bostwick, D G; Lieber, M M; Thibodeau, S N; Jenkins, R B

    1995-09-15

    Cytogenetic analyses have demonstrated that chromosome region 7q22-32 is commonly altered in prostate adenocarcinomas. In addition, in recent fluorescence in situ hybridization studies, we have observed that aneusomy of chromosome 7 is frequent in prostate cancer and is associated with higher tumor grade, advanced pathological stage, and early prostate cancer death. These findings suggest that genetic alterations of chromosome 7 play a significant role in the development of prostate cancer. To better define the chromosome 7 alterations, PCR analysis of 21 microsatellite loci was performed on 54 paired prostate cancer and control DNAs. Overall, chromosome 7 allelic imbalance was identified in 16 of 54 cases (30%). Allelic imbalances of loci mapped to 7q were observed in 15 of the 16 cases. The allelic imbalances were classified as losses in 15 tumors (28%) and as gains in 1 (2%) by comparative multiplex PCR analysis. The most common site of allelic loss included loci D7S523 and D7S486 at 7q31.1. A comparison with clinicopathological features of the tested tumors revealed that the allelic loss of 7q31.1 correlated with higher tumor grade (P = 0.012) and lymph node metastasis (P = 0.017). These results indicate that 7q31 may be the site of a putative suppressor gene(s) important for the pathogenesis of prostate carcinoma, and that the genetic alterations at 7q31.1 may participate in tumor progression and metastasis.

  16. Prognostic significance of loss of heterozygosity at loci on chromosome 17p13.3-ter in sporadic breast cancer is evidence for a putative tumour suppressor gene

    PubMed Central

    Liscia, D S; Morizio, R; Venesio, T; Palenzona, C; Donadio, M; Callahan, R

    1999-01-01

    Several studies indicate that the short arm of chromosome 17 is one of the most frequently altered regions in sporadic breast carcinomas (45–60%). In the present report the 17p13.3-ter locus in tumour DNA of breast cancer patients, along with their matching normal lymphocyte DNA, have been mapped with four markers (D17S5, D17S379, ABR and D17S34), spanning nearly 3 cM of the telomer. Sixty-five of 143 heterozygous tumours had lost at least one of the markers at the minimum region of loss (45%). High levels of loss of these distal markers on 17p13.3 are independent of TP53 mutations and are associated with tumour cell proliferation. A follow-up period of over 7 years demonstrates that loss of these markers correlates both with disease-free (P = 0.004) and overall survival (P = 0.007). In addition we show that for disease-free survival the prognostic power of this genetic alteration is second only to axillary lymph node involvement (3.1 vs 6.3 relative risk), and is a better predictor than the mutational status of TP53 (1.6 relative risk). Our results are further evidence of the presence, within the region, of at least a second tumour suppressor gene distal to TP53, that might be targeted by deletions. © 1999 Cancer Research Campaign PMID:10360661

  17. Loss of heterozygosity on chromosome 7q in in vitro-immortalized human oral keratinocyte cell lines.

    PubMed

    Arai, Yasuhito; Shigeeda, Nobumasa; Uchida, Minoru; Tsutsui, Takeki

    2002-08-01

    Loss of heterozygosity in two in vitro-immortalized human oral keratinocyte cell lines was analysed by polymerase chain reaction using 42 polymorphic microsatellite markers on chromosomes 4, 6, 7 and 15. These chromosomes are regarded as candidates for harbouring genes involved in the immortalization of human cells or tumour-suppressor genes in several tumours, including oral cancers, and karyotypic analysis has revealed that both cell lines have non-random alterations in these chromosomes. No allele losses were detected at any informative loci on chromosomes 4 and 6 in the cell lines, including genomic regions adjacent to putative human tumour-suppressor genes and putative senescence genes. When analysed for loss of heterozygosity on chromosomes 7 and 15, allele losses common to both cell lines were detected in the regions at 7q11.2, 7q21.1-21.3 and 7q31.1. High frequencies of loss of heterozygosity on chromosome 7q in at least two distinct regions, particularly centred around 7q31, are observed in a variety of tumours, including oral squamous-cell carcinoma, suggesting that multiple genes involved in immortalization of these cell lines might be present on chromosome 7q.

  18. Loss of heterozygosity in endometrial carcinoma.

    PubMed

    Velasco, Ana; Pallares, Judit; Santacana, Maria; Yeramian, Andre; Dolcet, Xavier; Eritja, Nuria; Puente, Soraya; Sorolla, Anabel; Llecha, Nuria; Matias-Guiu, Xavier

    2008-07-01

    Inactivation of a tumor suppressor gene typically occurs in two steps, thus fulfilling Knudson hypothesis. One "hit" is frequently a point mutation or a small deletion. The other alteration is usually a large genomic loss of part of a gene, or even part of a chromosome, or the whole chromosome. However, it is not clear which of these two events occurs first. Loss of heterozygosity (LOH) analysis allows the identification of one of the 2 hits. Although microsatellite polymerase chain reaction is the technique most frequently used to assess LOH, other different approaches can also be used. The LOH can also be assessed by restriction fragment length polymorphism analysis, single strand conformation polymorphism analysis, oligonucleotide microarrays capable to simultaneously determine the genotype of thousands of single-nucleotide polymorphism (single-nucleotide polymorphism arrays), comparative genomic hybridization, multiplex amplification and probe hybridization, and multiplex ligation-dependent probe amplification. In this article, the authors review the results obtained with molecular analysis of LOH in the understanding of development and progression of endometrial carcinoma. Particular attention is given to: (1) the presence of widespread LOH in nonendometrioid carcinoma, probably reflecting the existence of chromosomal instability; and (2) specific LOH patterns associated with some clinicopathologic features.

  19. Reduced Fhit protein expression and loss of heterozygosity at FHIT gene in tumours from smoking and asbestos-exposed lung cancer patients.

    PubMed

    Pylkkanen, Lea; Wolff, Henrik; Stjernvall, Tuula; Tuominen, Paivi; Sioris, Thanos; Karjalainen, Antti; Anttila, Sisko; Husgafvel-Pursiainen, Kirsti

    2002-02-01

    The FHIT gene, at 3p14.2, has been suggested to form a molecular target to damage induced by human lung carcinogens. We examined aberrant expression of the Fhit protein and allele loss at the FHIT gene in a series of lung cancer cases, mainly of non-small cell carcinoma (NSCLC) histology. We had detailed data on tobacco smoke exposure and occupational asbestos exposure available for the cases. The principal aim of the present study was to investigate whether absent or reduced Fhit expression or FHIT allele loss was associated with exposure to these pulmonary carcinogens. We detected reduced Fhit expression in 62% (33/53) of the cases analysed. Prevalence of allele loss at the FHIT locus was 22% (20/89). Reduced protein expression was common both in the asbestos-exposed (67%) and non-exposed cases (59%); [odds ratio (OR) 1.4, 95% confidence interval (CI) 0.4-4.9]. LOH frequencies differed somewhat between the two groups and were 25% vs. 16%, respectively (OR 1.8; 95% CI 0.5-5.9). Absent or reduced expression was common in smokers, with no significant difference found between current smokers and non-smokers (mainly former smokers) (OR 1.4, 95% CI 0.5-4.5). NSCLCs with squamous cell histology exhibited both aberrant expression (OR 3.1, 95% CI 0.9-10.3) and allele loss (OR 3.3, 95% CI 0.9-12.7) more frequently than adenocarcinoma. Finally, we found that FHIT allele loss was increased in stage II or more advanced disease (OR 2.5, 95% CI 0.9-7.4), and in poorly differentiated tumours (grade 3, OR 2.6, 95% CI 0.8-8.1). In conclusion, our present data support significance of FHIT inactivation in development of lung cancer.

  20. High incidence of loss of heterozygosity in breast tumors from carriers of the BRCA2 999del5 mutation.

    PubMed

    Ingvarsson, S; Geirsdottir, E K; Johannesdottir, G; Sigbjörnsdóttir, B I; Eiriksdottir, G; Ragnarsson, G; Agnarsson, B A; Gudmundsson, J; Jonasson, J G; Sigurdsson, A; Egilsson, V; Barkardottir, R B

    1998-10-01

    Germ-line mutation in the BRCA2 gene confers an increased risk of breast cancer. An elevation of additional genetic defects in tumors of patients with germ-line mutation in the BRCA2 gene compared with sporadic breast tumors has been reported. To evaluate the nature of the difference, we did detailed mapping of chromosomes 1p, 3p, 6q, 11, 13q, 16q, 17, and 20q, using microsatellite markers. We found that the frequency of loss of heterozygosity was similar at some chromosomal regions in the BRCA2 999del5 and sporadic tumors but significantly different at others. These others include chromosomal arms 3p, 6q, 11p, 11q, 13q, and 17p. Loss of heterozygosity mapping suggests that the same chromosome regions are involved in both tumor groups but at elevated frequencies in BRCA2 999del5 tumors. This higher frequency of genetic aberrations could pinpoint genes that selectively promote tumor progression in individuals predisposed to breast cancer due to the BRCA2 999del5 germ-line mutation. Accumulation of somatic genetic changes during tumor progression may follow a specific and more aggressive pathway of chromosome damage in these individuals.

  1. Loss of heterozygosity and microsatellite instability in hepatocellular carcinoma in Taiwan

    PubMed Central

    Sheu, J-C; Lin, Y-W; Chou, H-C; Huang, G-T; Lee, H-S; Lin, Y-H; Huang, S-Y; Chen, C-H; Wang, J-T; Lee, P-H; Lin, J-T; Lu, F-J; Chen, D-S

    1999-01-01

    Elucidation of the basic genetic changes of human hepatocellular carcinoma is important for the understanding and treatment of this cancer. We used microsatellite polymorphism markers to study 30 cases of hepatocellular carcinoma (34 tumours) on all human chromosomes. DNA from 34 pairs of hepatocellular carcinomas and corresponding non-tumour parts was prepared. Loss of heterozygosity (LOH) and microsatellite instability on 23 chromosomes were investigated by 231 sets of microsatellite markers. More than 20% LOH was shown for loci on 16q (47.1%), 13q (32.4%), 17p (32.4%), 5q (26.5%), 11p (23.5%) and 9p (20.6%). The commonly affected regions were mapped to 16q12.1, 16q12.2, 16q24, 13q12.1–32, 17p13, 5q32, 5q34, 5q3, 11p15, 11q23–24 and 9p21. Hepatitis B virus carriers had a significantly higher frequency of LOH on chromosomes 5q, 11p and 16q. Furthermore, larger tumour size tended to have higher frequency of LOH at D16S409 locus (16q12.1). Microsatellte instability was only found in 12 of 231 markers and the frequency is very low. These data suggest that the chromosomes 16q, 13q, 17p, 5q, 11p and 9p might participate in hepatocarcinogenesis. However, microsatellite instability might play little role in the development of this cancer in Taiwan. © 1999 Cancer Research Campaign PMID:10408855

  2. Loss of heterozygosity in human ductal breast tumors indicates a recessive mutation on chromosome 13

    SciTech Connect

    Lundberg, C.; Skoog, L.; Cavenee, W.K.; Nordenskjoeld, M.

    1987-04-01

    The genotypes at chromosomal loci defined by recombinant DNA probes revealing restriction fragment length polymorphisms were determined in constitutional and tumor tissue from 10 cases of ductal breast cancer: eight premenopausal females and two males. Somatic loss of constitutional heterozygosity was observed at loci on chromosome 13 in primary tumor tissue from three females and one male. In two cases, specific loss of heterozygosity at three distinct genetic loci along the length of the chromosome was observed. In another case, concurrent loss of alleles at loci on chromosomes 2, 13, 14, and 20 was detected, whereas a fourth case showed loss of heterozygosity for chromosomes 5 and 13. In each instance, the data were consistent with loss of one of the homologous chromosomes by mitotic nondisjunction. Analysis of loci on several other chromosomes showed retention of constitutional heterozygosity suggesting the relative specificity of the events. In contrast, similar analyses of other breast cancers, including comedocarcinoma, medullary carcinoma, and juvenile secretory carcinoma, showed no loss of alleles at loci on chromosome 13. These data indicate that the pathogenesis of ductal breast cancer may, in a substantial proportion of cases, involve unmasking of a recessive locus on chromosome 13 and suggest the involvement of such a locus in heritable forms of this disease.

  3. SNP Array Analysis Reveals Novel Genomic Abnormalities Including Copy Neutral Loss of Heterozygosity in Anaplastic Oligodendrogliomas

    PubMed Central

    Idbaih, Ahmed; Ducray, François; Dehais, Caroline; Courdy, Célia; Carpentier, Catherine; de Bernard, Simon; Uro-Coste, Emmanuelle; Mokhtari, Karima; Jouvet, Anne; Honnorat, Jérôme; Chinot, Olivier; Ramirez, Carole; Beauchesne, Patrick; Benouaich-Amiel, Alexandra; Godard, Joël; Eimer, Sandrine; Parker, Fabrice; Lechapt-Zalcman, Emmanuelle; Colin, Philippe; Loussouarn, Delphine; Faillot, Thierry; Dam-Hieu, Phong; Elouadhani-Hamdi, Selma; Bauchet, Luc; Langlois, Olivier; Le Guerinel, Caroline; Fontaine, Denys; Vauleon, Elodie; Menei, Philippe; Fotso, Marie Janette Motsuo; Desenclos, Christine; Verelle, Pierre; Ghiringhelli, François; Noel, Georges; Labrousse, François; Carpentier, Antoine; Dhermain, Frédéric; Delattre, Jean-Yves; Figarella-Branger, Dominique

    2012-01-01

    Anaplastic oligodendrogliomas (AOD) are rare glial tumors in adults with relative homogeneous clinical, radiological and histological features at the time of diagnosis but dramatically various clinical courses. Studies have identified several molecular abnormalities with clinical or biological relevance to AOD (e.g. t(1;19)(q10;p10), IDH1, IDH2, CIC and FUBP1 mutations). To better characterize the clinical and biological behavior of this tumor type, the creation of a national multicentric network, named “Prise en charge des OLigodendrogliomes Anaplasiques (POLA),” has been supported by the Institut National du Cancer (InCA). Newly diagnosed and centrally validated AOD patients and their related biological material (tumor and blood samples) were prospectively included in the POLA clinical database and tissue bank, respectively. At the molecular level, we have conducted a high-resolution single nucleotide polymorphism array analysis, which included 83 patients. Despite a careful central pathological review, AOD have been found to exhibit heterogeneous genomic features. A total of 82% of the tumors exhibited a 1p/19q-co-deletion, while 18% harbor a distinct chromosome pattern. Novel focal abnormalities, including homozygously deleted, amplified and disrupted regions, have been identified. Recurring copy neutral losses of heterozygosity (CNLOH) inducing the modulation of gene expression have also been discovered. CNLOH in the CDKN2A locus was associated with protein silencing in 1/3 of the cases. In addition, FUBP1 homozygous deletion was detected in one case suggesting a putative tumor suppressor role of FUBP1 in AOD. Our study showed that the genomic and pathological analyses of AOD are synergistic in detecting relevant clinical and biological subgroups of AOD. PMID:23071531

  4. Loss of heterozygosity and SOSTDC1 in adult and pediatric renal tumors

    PubMed Central

    2010-01-01

    Background Deletions within the short arm of chromosome 7 are observed in approximately 25% of adult and 10% of Wilms pediatric renal tumors. Within Wilms tumors, the region of interest has been delineated to a 2-Mb minimal region that includes ten known genes. Two of these ten candidate genes, SOSTDC1 and MEOX2, are particularly relevant to tumor development and maintenance. This finding, coupled with evidence that SOSTDC1 is frequently downregulated in adult renal cancer and regulates both Wingless-Int (Wnt)- and bone morphogenetic protein (BMP)-induced signaling, points to a role for SOSTDC1 as a potential tumor suppressor. Methods To investigate this hypothesis, we interrogated the Oncomine database to examine the SOSTDC1 levels in adult renal clear cell tumors and pediatric Wilms tumors. We then performed single nucleotide polymorphism (SNP) and sequencing analyses of SOSTDC1 in 25 pediatric and 36 adult renal tumors. Immunohistochemical staining of patient samples was utilized to examine the impact of SOSTDC1 genetic aberrations on SOSTDC1 protein levels and signaling. Results Within the Oncomine database, we found that SOSTDC1 levels were reduced in adult renal clear cell tumors and pediatric Wilms tumors. Through SNP and sequencing analyses of 25 Wilms tumors, we identified four with loss of heterozygosity (LOH) at 7p and three that affected SOSTDC1. Of 36 adult renal cancers, we found five with LOH at 7p, two of which affected SOSTDC1. Immunohistochemical analysis of SOSTDC1 protein levels within these tumors did not reveal a relationship between these instances of SOSTDC1 LOH and SOSTDC1 protein levels. Moreover, we could not discern any impact of these genetic alterations on Wnt signaling as measured by altered beta-catenin levels or localization. Conclusions This study shows that genetic aberrations near SOSTDC1 are not uncommon in renal cancer, and occur in adult as well as pediatric renal tumors. These observations of SOSTDC1 LOH, however, did not

  5. Genomewide scan for loss of heterozygosity and chromosomal amplification in breast carcinoma using single-nucleotide polymorphism arrays.

    PubMed

    Argos, Maria; Kibriya, Muhammad G; Jasmine, Farzana; Olopade, Olufunmilayo I; Su, Tao; Hibshoosh, Hanina; Ahsan, Habibul

    2008-04-15

    In an effort to identify novel genes implicated in breast carcinogenesis, a genomewide scan for loss of heterozygosity (LOH) and copy number changes in paired-DNA samples extracted from normal and tumor tissue of frozen sections from women undergoing surgery for invasive breast cancer was conducted. The Affymetrix 10K SNP array was used to examine genomewide LOH of chromosomal regions. The number of LOH events, number of informative loci, percent heterozygosity, and percent fractional allelic loss (%FAL) were calculated. Although LOH events were detected in all samples, the proportion of LOH ranged from 0.1 to 57.2%. Elevated LOH events were detected in two samples, with a %FAL of 57.2 and 56.2. Chromosomal regions exceeding a threshold value for a P-value curve based on multiple-testing adjusted permutation methods were identified as significant regions of shared LOH across samples. Regions with significant LOH included 2p25.3; 2p21; 2p15 approximately p16.1, 2q23.3; and, 16q12.1. Chromosomal region 1q32.1 was identified as a region with significant copy number amplification. Regions of LOH and copy number changes identified from this analysis may provide insights into the underlying processes of and genes involved in breast carcinogenesis. The present study demonstrates a feasible methodological approach for the assessment of LOH and copy number changes.

  6. Loss of Heterozygosity Drives Adaptation in Hybrid Yeast

    PubMed Central

    Smukowski Heil, Caiti S.; DeSevo, Christopher G.; Pai, Dave A.; Tucker, Cheryl M.; Hoang, Margaret L.

    2017-01-01

    Abstract Hybridization is often considered maladaptive, but sometimes hybrids can invade new ecological niches and adapt to novel or stressful environments better than their parents. The genomic changes that occur following hybridization that facilitate genome resolution and/or adaptation are not well understood. Here, we examine hybrid genome evolution using experimental evolution of de novo interspecific hybrid yeast Saccharomyces cerevisiae × Saccharomyces uvarum and their parentals. We evolved these strains in nutrient-limited conditions for hundreds of generations and sequenced the resulting cultures identifying numerous point mutations, copy number changes, and loss of heterozygosity (LOH) events, including species-biased amplification of nutrient transporters. We focused on a particularly interesting example, in which we saw repeated LOH at the high-affinity phosphate transporter gene PHO84 in both intra- and interspecific hybrids. Using allele replacement methods, we tested the fitness of different alleles in hybrid and S. cerevisiae strain backgrounds and found that the LOH is indeed the result of selection on one allele over the other in both S. cerevisiae and the hybrids. This is an example where hybrid genome resolution is driven by positive selection on existing heterozygosity and demonstrates that even infrequent outcrossing may have lasting impacts on adaptation. PMID:28369610

  7. High incidence of loss of heterozygosity at chromosome 17p13 in breast tumours from BRCA2 mutation carriers.

    PubMed

    Eiriksdottir, G; Barkardottir, R B; Agnarsson, B A; Johannesdottir, G; Olafsdottir, K; Egilsson, V; Ingvarsson, S

    1998-01-08

    Breast tumours from BRCA1 and BRCA2 mutation carriers are genetically instable and display specific patterns of chromosomal aberrations, suggestive of distinct genetic pathways in tumour progression. The frequency of abnormalities affecting chromosome 17p and the TP53 gene was determined in 27 breast tumours from 26 female patients carrying the Icelandic BRCA2 founder mutation (999del5). Loss of heterozygosity (LOH) was detected in 23 of the 27 tumours (85%). The majority of tumours manifesting LOH had lost a large region on 17p, although a more restricted loss, including the TP53 locus was seen in a few tumours. Positive p53 immunostaining was observed in 18 of 26 tumours (69%). However, mutations in the TP53 gene were detected in only three tumours (11%), including a missense (codon 139) and a nonsense mutation (codon 306) in two tumours with moderate p53 expression and a frameshift deletion (codon 182) in a tumour with no detectable p53 expression. Positive p53 immunostaining, mainly weak, was observed in 16 of the 24 tumours (66%) without TP53 mutation. The high frequency of LOH at chromosome 17p13 suggests that one or more genes from this region are involved in the development of BRCA2-induced breast cancer. The frequent finding of weak overexpression of, presumably wild type p53 protein, suggests an alternative mechanism of TP53 involvement specific to these tumours.

  8. Correlation between gastric carcinoma and ZAC gene-associated microsatellite instability and loss of heterozygosity.

    PubMed

    Zhu, Xiao-Yan; Yang, Ji-Yao; He, Ying; Liu, Guo-Hong; Sun, Yun; Ding, Yi

    2017-08-01

    The present study explored the association between loss of heterozygosity (LOH) or microsatellite instability (MSI) of the zinc finger regulator of apoptosis and cell-cycle arrest (ZAC) gene and the clinicopathological factors of gastric cancer. Samples of cancer and cancer-adjacent normal tissue from 30 patients with gastric cancer were collected. The genomic DNA was extracted from each and amplified with primers specific to ZAC microsatellite mutations, then run on a polyacrylamide gel for analysis. The CA197 microsatellite locus exhibited LOH in cancer sample 4. There was LOH in the 15AAAG locus in cancer sample 27 and cancer-adjacent tissue 23, and MSI at 15AAAG in cancer-adjacent tissue 27. There was MSI at the D6S1703 microsatellite locus in cancer-adjacent tissue 28. There was no LOH or MSI in the CA340 microsatellite locus in the gastric cancer or adjacent tissues analyzed. Thus, the frequency of LOH or MSI at ZAC gene-associated microsatellite loci for all patients was 13.3% (4/30). The present study has demonstrated that LOH and MSI events may contribute to the downregulation of ZAC; however, it is unlikely to be the primary cause, as it was only identified in 13.3% of cases.

  9. Further localization of the gene for nevoid basal cell carcinoma syndrome (NBCCS) in 15 Australasian families: Linkage and loss of heterozygosity

    SciTech Connect

    Chenevix-Trench, G.; Wicking, C.; Berkman, J.; Sharpe, H.; Hockey, A.; Haan, E.; Oley, C.; Ravine, D.; Turner, A.; Searle, J.

    1993-09-01

    Nevoid basal cell carcinoma syndrome (NBCCS; basal cell nevus syndrome or Gorlin syndrome) is a cancer-predisposition syndrome characterized by multiple basal cell carcinomas (BCCs) and diverse developmental defects. The gene for NBCCS has been mapped to 9q23.1-q31 in North Americal and European families. In addition, loss of heterozygosity (LOH) for genetic markers in this region has been detected in sporadic BCCs, indicating that the NBCCs gene is probably a tumor-suppressor gene. In this study the authors have determined that the NBCCS gene is also linked to this region in Australasian pedigrees and that there is no significant evidence of heterogeneity. They have defined the localization of the gene by multipoint and haplotype analysis of 15 families, using four microsatellite markers. LOH at these loci was detected in 50% of sporadic BCCs, a rate that is significantly higher than that in other skin lesions used as controls. 21 refs., 3 figs., 2 tabs.

  10. Loss of Heterozygosity on Chromosome 11p15 during Histological Progression in Microdissected Ductal Carcinoma of the Breast

    PubMed Central

    Lichy, Jack H.; Zavar, Maryam; Tsai, Mark M.; O’Leary, Timothy J.; Taubenberger, Jeffery K.

    1998-01-01

    Microdissection of histologically identifiable components from formalin-fixed, paraffin-embedded tissue sections allows molecular genetic analyses to be correlated directly with pathological findings. In this study, we have characterized loss of heterozygosity (LOH) at chromosome 11p15 at different stages of progression in microdissected tumor components from 115 ductal carcinomas of the breast. Microdissected foci of intraductal, infiltrating, and metastatic tumors were analyzed to determine the stage of progression at which LOH at 11p15 occurs. LOH was detected in 43 (37%) of 115 cases. Foci of intraductal carcinoma could be microdissected from 85 cases, of which 30 (35%) showed LOH at some stage of progression. LOH was detected in the intraductal component in 26 of these 30 cases. Interstitial deletions were characterized by using a panel of 10 highly polymorphic markers. The smallest region of overlap (SRO) for LOH at 11p15 was bounded by the markers D11S4046 and D11S1758. LOH at 11p15.5 showed no correlation with estrogen receptor status, the presence of positive lymph nodes, tumor size, histological grade, or long-term survival. We conclude that 11p15 LOH usually occurs early in breast cancer development but less frequently does not develop until the infiltrating or metastatic stages of tumor progression. PMID:9665488

  11. Overlapping loss of heterozygosity by mitotic recombination on mouse chromosome 7F1-ter in skin carcinogenesis.

    PubMed Central

    Bianchi, A B; Navone, N M; Aldaz, C M; Conti, C J

    1991-01-01

    A significant role for mouse chromosome 7 abnormalities during chemically induced skin carcinogenesis has been advanced based on previous cytogenetic and molecular studies. To determine the frequency of allelic losses at different loci of chromosome 7 in skin tumors induced in the outbred SENCAR mouse stock by a two-stage initiation-promotion protocol, we compared the constitutional and tumor genotypes of premalignant papillomas and squamous cell carcinomas for loss of heterozygosity at different informative loci. In a previous study, these tumors had been analyzed for their allelic composition at the Harvey ras-1 (Ha-ras-1) locus and it was found that 39% of squamous cell carcinomas had lost the normal Ha-ras-1 allele exhibiting 3 or 2 copies of the mutated counterpart or gene amplification. In the present study, by combining Southern blot and polymerase chain reaction fragment length polymorphism analyses, we detected complete loss of heterozygosity at the beta-globin (Hbb) locus, distal to Ha-ras-1, in 15 of 20 (75%) skin carcinomas. In addition, 5 of 5 informative cases attained homozygosity at the int-2 locus, 27 centimorgans distal to Hbb. Polymerase chain reaction analysis of DNA extracted from papillomas devoid of stromal contamination by fluorescence-activated sorting of single cell dispersions immunolabeled with anti-keratin 13 antibody revealed loss of heterozygosity at the Hbb locus, demonstrating that this event occurs during premalignant stages of tumor development. Interestingly, loss of heterozygosity was only detected in late-stage lesions exhibiting a high degree of dysplasia and areas of microinvasion. Analysis of allelic ratios by densitometric scanning of tumors that had become homozygous at Hbb but retained heterozygosis at Ha-ras-1 indicated mitotic recombination as the mechanism underlying loss of heterozygosity on mouse chromosome 7 during chemically induced skin carcinogenesis. These findings are consistent with the presence of a putative

  12. Deconvolving tumor purity and ploidy by integrating copy number alterations and loss of heterozygosity.

    PubMed

    Li, Yi; Xie, Xiaohui

    2014-08-01

    Next-generation sequencing (NGS) has revolutionized the study of cancer genomes. However, the reads obtained from NGS of tumor samples often consist of a mixture of normal and tumor cells, which themselves can be of multiple clonal types. A prominent problem in the analysis of cancer genome sequencing data is deconvolving the mixture to identify the reads associated with tumor cells or a particular subclone of tumor cells. Solving the problem is, however, challenging because of the so-called 'identifiability problem', where different combinations of tumor purity and ploidy often explain the sequencing data equally well. We propose a new model to resolve the identifiability problem by integrating two types of sequencing information-somatic copy number alterations and loss of heterozygosity-within a unified probabilistic framework. We derive algorithms to solve our model, and implement them in a software package called PyLOH. We benchmark the performance of PyLOH using both simulated data and 12 breast cancer sequencing datasets and show that PyLOH outperforms existing methods in disambiguating the identifiability problem and estimating tumor purity. The PyLOH package is written in Python and is publicly available at https://github.com/uci-cbcl/PyLOH. xhx@ics.uci.edu Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. Carcinogens induce genome-wide loss of heterozygosity in normal stem cells without persistent chromosomal instability.

    PubMed

    Donahue, Sarah L; Lin, Qing; Cao, Shang; Ruley, H Earl

    2006-08-01

    Widespread losses of heterozygosity (LOH) in human cancer have been thought to result from chromosomal instability caused by mutations affecting DNA repair/genome maintenance. However, the origin of LOH in most tumors is unknown. The present study examined the ability of carcinogenic agents to induce LOH at 53 sites throughout the genome of normal diploid mouse ES cells. Brief exposures to nontoxic levels of methylnitrosourea, diepoxybutane, mitomycin C, hydroxyurea, doxorubicin, and UV light stimulated LOH at all loci at frequencies ranging from 1-8 x 10(-3) per cell (10-123 times higher than in untreated cells). This greatly exceeds the frequencies at which these agents have been reported to induce point mutations and is comparable to the rates of LOH observed in ES cells lacking the gene responsible for Bloom syndrome, an inherited DNA repair defect that results in greatly increased risk of cancer. These results suggest that LOH contributes significantly to the carcinogenicity of a variety of mutagens and raises the possibility that genome-wide LOH observed in some human cancers may reflect prior exposure to genotoxic agents rather than a state of chromosomal instability during the carcinogenic process. Finally, as a practical matter, chemically induced LOH is expected to enhance the recovery of homozygous recessive mutants from phenotype-based genetic screens in mammalian cells.

  14. Carcinogens induce genome-wide loss of heterozygosity in normal stem cells without persistent chromosomal instability

    PubMed Central

    Donahue, Sarah L.; Lin, Qing; Cao, Shang; Ruley, H. Earl

    2006-01-01

    Widespread losses of heterozygosity (LOH) in human cancer have been thought to result from chromosomal instability caused by mutations affecting DNA repair/genome maintenance. However, the origin of LOH in most tumors is unknown. The present study examined the ability of carcinogenic agents to induce LOH at 53 sites throughout the genome of normal diploid mouse ES cells. Brief exposures to nontoxic levels of methylnitrosourea, diepoxybutane, mitomycin C, hydroxyurea, doxorubicin, and UV light stimulated LOH at all loci at frequencies ranging from 1–8 × 10−3 per cell (10–123 times higher than in untreated cells). This greatly exceeds the frequencies at which these agents have been reported to induce point mutations and is comparable to the rates of LOH observed in ES cells lacking the gene responsible for Bloom syndrome, an inherited DNA repair defect that results in greatly increased risk of cancer. These results suggest that LOH contributes significantly to the carcinogenicity of a variety of mutagens and raises the possibility that genome-wide LOH observed in some human cancers may reflect prior exposure to genotoxic agents rather than a state of chromosomal instability during the carcinogenic process. Finally, as a practical matter, chemically induced LOH is expected to enhance the recovery of homozygous recessive mutants from phenotype-based genetic screens in mammalian cells. PMID:16868089

  15. Inferring Loss-of-Heterozygosity from Unpaired Tumors Using High-Density Oligonucleotide SNP Arrays

    PubMed Central

    Park, Yuhyun; Hao, Ke; Zhao, Xiaojun; Garraway, Levi A; Fox, Edward A; Hochberg, Ephraim P; Mellinghoff, Ingo K; Hofer, Matthias D; Descazeaud, Aurelien; Rubin, Mark A; Meyerson, Matthew; Wong, Wing Hung; Sellers, William R; Li, Cheng

    2006-01-01

    Loss of heterozygosity (LOH) of chromosomal regions bearing tumor suppressors is a key event in the evolution of epithelial and mesenchymal tumors. Identification of these regions usually relies on genotyping tumor and counterpart normal DNA and noting regions where heterozygous alleles in the normal DNA become homozygous in the tumor. However, paired normal samples for tumors and cell lines are often not available. With the advent of oligonucleotide arrays that simultaneously assay thousands of single-nucleotide polymorphism (SNP) markers, genotyping can now be done at high enough resolution to allow identification of LOH events by the absence of heterozygous loci, without comparison to normal controls. Here we describe a hidden Markov model-based method to identify LOH from unpaired tumor samples, taking into account SNP intermarker distances, SNP-specific heterozygosity rates, and the haplotype structure of the human genome. When we applied the method to data genotyped on 100 K arrays, we correctly identified 99% of SNP markers as either retention or loss. We also correctly identified 81% of the regions of LOH, including 98% of regions greater than 3 megabases. By integrating copy number analysis into the method, we were able to distinguish LOH from allelic imbalance. Application of this method to data from a set of prostate samples without paired normals identified known regions of prevalent LOH. We have developed a method for analyzing high-density oligonucleotide SNP array data to accurately identify of regions of LOH and retention in tumors without the need for paired normal samples. PMID:16699594

  16. Chromosome 3p loss of heterozygosity is associated with a unique metabolic network in clear cell renal carcinoma

    PubMed Central

    Gatto, Francesco; Nookaew, Intawat; Nielsen, Jens

    2014-01-01

    Several common oncogenic pathways have been implicated in the emergence of renowned metabolic features in cancer, which in turn are deemed essential for cancer proliferation and survival. However, the extent to which different cancers coordinate their metabolism to meet these requirements is largely unexplored. Here we show that even in the heterogeneity of metabolic regulation a distinct signature encompassed most cancers. On the other hand, clear cell renal cell carcinoma (ccRCC) strongly deviated in terms of metabolic gene expression changes, showing widespread down-regulation. We observed a metabolic shift that associates differential regulation of enzymes in one-carbon metabolism with high tumor stage and poor clinical outcome. A significant yet limited set of metabolic genes that explained the partial divergence of ccRCC metabolism correlated with loss of von Hippel-Lindau tumor suppressor (VHL) and a potential activation of signal transducer and activator of transcription 1. Further network-dependent analyses revealed unique defects in nucleotide, one-carbon, and glycerophospholipid metabolism at the transcript and protein level, which contrasts findings in other tumors. Notably, this behavior is recapitulated by recurrent loss of heterozygosity in multiple metabolic genes adjacent to VHL. This study therefore shows how loss of heterozygosity, hallmarked by VHL deletion in ccRCC, may uniquely shape tumor metabolism. PMID:24550497

  17. Genetic inhibition of autophagy promotes p53 loss-of-heterozygosity and tumorigenesis

    PubMed Central

    Lee, Eunmyong; Wei, Yongjie; Zou, Zhongju; Tucker, Kathryn; Rakheja, Dinesh; Levine, Beth; Amatruda, James F.

    2016-01-01

    Autophagy is an evolutionarily conserved lysosomal degradation pathway that plays an essential role in enabling eukaryotic organisms to adapt to nutrient deprivation and other forms of environmental stress. In metazoan organisms, autophagy is essential for differentiation and normal development; however, whether the autophagy pathway promotes or inhibits tumorigenesis is controversial, and the possible mechanisms linking defective autophagy to cancer remain unclear. To determine if autophagy is important for tumor suppression, we inhibited autophagy in transgenic zebrafish via stable, tissue-specific expression of a dominant-negative autophagy protein Atg5K130R. In heterozygous tp53 mutants, expression of dominant-negative atg5K130R increased tumor incidence and decreased tumor latency compared to non-transgenic heterozygous tp53 mutant controls. In a tp53-deficient background, Tg(mitfa:atg5K130R) mutantsdeveloped malignant peripheral nerve sheath tumors (MPNSTs), neuroendocrine tumors and small-cell tumors. Expression of a Sox10-dependent GFP transgene in the tumors demonstrated their origin from neural crest cells, lending support to a model in which mitfa-expressing cells can arise from sox10+ Schwann cell precursors. Tumors from the transgenic animals exhibited increased DNA damage and loss-of-heterozygosity of tp53. Taken together, our data indicate that genetic inhibition of autophagy promotes tumorigenesis in tp53 mutant zebrafish, and suggest a possible role for autophagy in the regulation of genome stability during oncogenesis. PMID:27655644

  18. Evidence of loss of heterozygosity of the PTCH gene in orthokeratinized odontogenic cyst.

    PubMed

    Diniz, Marina Gonçalves; Galvão, Clarice Ferreira; Macedo, Paula Serelle; Gomes, Carolina Cavaliéri; Gomez, Ricardo Santiago

    2011-03-01

    The orthokeratinized odontogenic cyst (OOC) is an odontogenic cyst of unknown etiology. Clinical, histological, and biological differences are reported between keratocystic odontogenic tumor (KOT) and OOC. PTCH is a tumor suppressor gene related to sonic hedgehog (SHH) pathway important in embryological development. Considering that alterations in this pathway have been described in sporadic and nevoid basal cell syndrome-associated KOT, we tested the hypothesis that OOC is also associated with loss of heterozygosity (LOH) of the PTCH gene. Seven samples of OOC and seven of KOT were included in the study. D9S287, D9S196, and D9S127 microsatellite markers located in the region of PTCH gene, at chromosome 9q, were investigated for LOH. There was loss in at least one locus in 5/7 KOT and in 4/7 OOC samples. The present finding demonstrates that, despite the existence of clinical, morphological, immunohistochemical, and biological behavior differences between OOC and KOT, both harbor similar genetic alterations at 9q.

  19. High-resolution detection of loss of heterozygosity of dinucleotide microsatellite markers.

    PubMed

    Hourihan, R N; O'Sullivan, G C; Morgan, J G

    2001-02-01

    Dinucleotide microsatellite markers are frequently investigated to study inheritance, genetic stability, and allele frequency distribution in a wide variety of genetic disorders. Previous studies have encountered significant problems regarding resolution and detection of dinucleotide, microsatellites. In this study, a useful method to investigate loss of heterozygosity (LOH) of dinucleotide microsatellite markers is described that involves the use of nondenaturing (Spreadex) submerged gel electrophoresis and SYBR Green I nucleic acid staining. This method omits the gel casting step and the use of hazardous radioactive materials frequently used in many microsatellite studies that employ polyacrylamide gel nucleic acid denaturation analysis. Using this method, 62 patients' paired tumor and normal samples were investigated to detect allele deletions in a region of chromosome 7q31.1, which is believed to harbor a tumor suppressor gene. Interpretable results were obtained in all cases. These results were compared to those attained using ABI Prism Genetic Analyzer 310 and Gene-Scan. There were no discrepancies in results obtained between the two assays. The Spreadex system is cheap, does not require larger equipment costs, and may prove to be a useful system for high-throughput investigation of microsatellites. It may have diagnostic significance and also prove useful if applied to population-based genomic screening and linkage analysis.

  20. [Analysis of loss of heterozygosity of the tumor suppressor genes p53 and BRCA1 in ovarial carcinomas].

    PubMed

    Petrović, Bojana; Perović, Milica; Novaković, Ivana; Atanacković, Jasmina; Popović, Branka; Luković, Ljiljana; Petković, Spasoje

    2006-09-01

    Among the genes involved in ovarian carcinogenesis, there has been increased interest in tumor-suppressor genes p53 and BRCA1. Both of the genes make control of cell cycle, DNA repair and apoptosis. The p53 is a "genome guardian" inactivated in more than 50% of human cancers, while BRCA1 mutations are found mostly in breast and ovarian cancer. The aim of this investigation was to establish the frequency of loss of heterozygosity (LOH) in the regions of the genes p53 and BRCA1 in ovarian carcinomas, and to analyze the association of LOH with the disease stage and prognosis. We analyzed 20 patients with a confirmed diagnosis of epithelilal ovarian carcinoma. DNA for molecular-genetic analysis was extracted from the tumor tissue and blood as normal tissue of each person. Microsatellite markers of the regions of genes p53 and BRCA1 were amplified by PCR method. The determination of allelic status of microsatellites and detection of LOH was performed after PAA gel electroforesis. Both of the analyzed microsatellite markers were informative in 13/20 (65%) cases. In the region of gene p53, LOH was established in 4/13 (30.7%) tumors. One of them had histological gradus G1, one had gradus G2, and two of them had gradus G3, while all were with the International Federation of Gynecology and Obstetrics (FIGO) IIIc stage. In the region of gene BRCA1, LOH was detected in 5/13 (38.5%) tumors. Four of them had histological gradus G2, and one had gradus G3, while by the (FIGO) classification one was with stage Ib, one was with stage IIIb, while the three were with stage IlIc. LOH in both of the analyzed regions was detected in one tumor (7.70), with histological gradus G3 and the FIGO IIIc stage. The frequency of LOH in epthelial ovarian carcinomas was 30.7% and 38.5% for p53 and BRCA1 gene regions, respectively. Most of tumors with LOH had histological gradus G2 or G3, and the clinical FIGO stage IIIc, suggesting the association of this occurrence with a later phase of the disease.

  1. Association of loss of heterozygosity with cytogenetic abnormalities in acute myeloid leukemia and myelodysplastic syndrome.

    PubMed

    Pinheiro, R F; Serio, F M; Silva, M R R; Briones, M R S; Chauffaille, M L L F

    2008-07-01

    Deletions on chromosomes 5 and 7 are frequently seen in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). It is assumed that these deletions indicate loss of tumor suppressor genes on these chromosomes and until these tumor suppressor genes are identified, the functional consequences of these deletions and the molecular basis of these myeloid disorders cannot be completely understood. We evaluated loss of heterozygosity (LOH) in 44 patients (18 MDS and 26 AML, diagnosed according to WHO classification criteria) at diagnosis, using a four-microsatellite marker panel: an intragenic marker on the 7th intron of gene IRF-1 of the 5q31.1 region and three markers located inside the 7q31.1 region and correlated the LOH with karyotype abnormalities. The microsatellites chosen corresponded to chromosome regions frequently deleted in MDS/AML. The samples with Q (peak area) less than or equal to 0.50 were indicative of LOH. The percent of informative samples (i.e., heterozygous) for the intragenic microsatellite in gene IRF-1 and in loci D7S486, D7S515 and D7S522 were 66.6, 73.7, 75.5, and 48.8%, respectively. Cytogenetic abnormalities by G-banding were found in 36% (16/44) of the patients (2 of 18 MDS and 14 of 26 AML patients). We found a significantly positive association of the occurrence of LOH with abnormal karyotype (P < 0.05; chi-square test) and there were cases with LOH but the karyotype was normal (by G-banding). These data indicate that LOH in different microsatellite markers is possibly an event previous to chromosomal abnormalities in these myeloid neoplasias.

  2. Loss of heterozygosity (LOH) in tumour suppressor genes in benign and malignant mixed odontogenic tumours.

    PubMed

    Galvão, Clarice F; Gomes, Carolina C; Diniz, Marina G; Vargas, Pablo A; de Paula, Alfredo M B; Mosqueda-Taylor, Adalberto; Loyola, Adriano M; Gomez, Ricardo S

    2012-05-01

    Although molecular alterations are reported in different types of odontogenic tumours, their pathogenesis remains to be established. Loss of heterozygosity (LOH) studies allow the identification of minimal regions of deletions of known or putative tumour suppressor genes, the losses of which may promote neoplastic growth. The purpose of this study was to investigate LOH in a set of odontogenic mixed tumours. Tumour suppressor gene loci on 3p, 9p, 11p, 11q and 17p chromosomes were analysed in five samples of ameloblastic fibroma (AF), three samples of ameloblastic fibro-odontoma (AFO) and three samples of ameloblastic fibrosarcoma (AFS). The most frequently lost genetic loci were p53 (17p13, 62%) and CHRNB1 (17p13, 55%). LOH at the chromosome regions 3p24.3, 9p22 and 9p22-p21 was identified only in AFS. No sample showed LOH at the chromosomal loci 3p21.2 and 11q13.4. For the region 9p22-p13, LOH occurred in one sample of AFO. The fractional allelic loss (FAL) was calculated for each sample. The mean FAL of the benign lesions (i.e. AF and AFO) was 22%, whereas the mean FAL of the malignant lesions (i.e. AFS) was 74.6%. In conclusion, our results show a higher FAL in AFS compared to its benign counterparts and reveal a different pattern of LOH of tumour suppressor genes in AFS, which may regulate changes in tumour behaviour. © 2011 John Wiley & Sons A/S.

  3. Autosomal mutants of proton-exposed kidney cells display frequent loss of heterozygosity on nonselected chromosomes.

    PubMed

    Grygoryev, Dmytro; Dan, Cristian; Gauny, Stacey; Eckelmann, Bradley; Ohlrich, Anna P; Connolly, Marissa; Lasarev, Michael; Grossi, Gianfranco; Kronenberg, Amy; Turker, Mitchell S

    2014-05-01

    High-energy protons found in the space environment can induce mutations and cancer, which are inextricably linked. We hypothesized that some mutants isolated from proton-exposed kidneys arose through a genome-wide incident that causes loss of heterozygosity (LOH)-generating mutations on multiple chromosomes (termed here genomic LOH). To test this hypothesis, we examined 11 pairs of nonselected chromosomes for LOH events in mutant cells isolated from the kidneys of mice exposed to 4 or 5 Gy of 1 GeV protons. The mutant kidney cells were selected for loss of expression of the chromosome 8-encoded Aprt gene. Genomic LOH events were also assessed in Aprt mutants isolated from isogenic cultured kidney epithelial cells exposed to 5 Gy of protons in vitro. Control groups were spontaneous Aprt mutants and clones isolated without selection from the proton-exposed kidneys or cultures. The in vivo results showed significant increases in genomic LOH events in the Aprt mutants from proton-exposed kidneys when compared with spontaneous Aprt mutants and when compared with nonmutant (i.e., nonselected) clones from the proton-exposed kidneys. A bias for LOH events affecting chromosome 14 was observed in the proton-induced Aprt mutants, though LOH for this chromosome did not confer increased radiation resistance. Genomic LOH events were observed in Aprt mutants isolated from proton-exposed cultured kidney cells; however the incidence was fivefold lower than in Aprt mutants isolated from exposed intact kidneys, suggesting a more permissive environment in the intact organ and/or the evolution of kidney clones prior to their isolation from the tissue. We conclude that proton exposure creates a subset of viable cells with LOH events on multiple chromosomes, that these cells form and persist in vivo, and that they can be isolated from an intact tissue by selection for a mutation on a single chromosome.

  4. Genome-Wide Loss of Heterozygosity and DNA Copy Number Aberration in HPV-Negative Oral Squamous Cell Carcinoma and Their Associations with Disease-Specific Survival.

    PubMed

    Chen, Chu; Zhang, Yuzheng; Loomis, Melissa M; Upton, Melissa P; Lohavanichbutr, Pawadee; Houck, John R; Doody, David R; Mendez, Eduardo; Futran, Neal; Schwartz, Stephen M; Wang, Pei

    2015-01-01

    Oral squamous cell cancer of the oral cavity and oropharynx (OSCC) is associated with high case-fatality. For reasons that are largely unknown, patients with the same clinical and pathologic staging have heterogeneous response to treatment and different probability of recurrence and survival, with patients with Human Papillomavirus (HPV)-positive oropharyngeal tumors having the most favorable survival. To gain insight into the complexity of OSCC and to identify potential chromosomal changes that may be associated with OSCC mortality, we used Affymtrix 6.0 SNP arrays to examine paired DNA from peripheral blood and tumor cell populations isolated by laser capture microdissection to assess genome-wide loss of heterozygosity (LOH) and DNA copy number aberration (CNA) and their associations with risk factors, tumor characteristics, and oral cancer-specific mortality among 75 patients with HPV-negative OSCC. We found a highly heterogeneous and complex genomic landscape of HPV-negative tumors, and identified regions in 4q, 8p, 9p and 11q that seem to play an important role in oral cancer biology and survival from this disease. If confirmed, these findings could assist in designing personalized treatment or in the creation of models to predict survival in patients with HPV-negative OSCC.

  5. Evaluation of loss of heterozygosity and microsatellite instability in human pterygium: clinical correlations

    PubMed Central

    Detorakis, E; Sourvinos, G; Tsamparlakis, J; Spandidos, D

    1998-01-01

    AIMS—To evaluate the incidence of loss of heterozygosity (LOH) and microsatellite instability (MI) in pterygia and their possible correlation with clinical variables.
METHODS—50 pterygia, blood, and conjunctival specimens were obtained. A personal and family history was recorded for each patient. Amplification of 15 microsatellite markers at regions 17p, 17q, 13q, 9p, and 9q was performed using the polymerase chain reaction. The electrophoretic pattern of DNA from pterygia was compared with the respective pattern from blood and conjunctiva.
RESULTS—LOH incidence was the highest at 9p (48%), followed by 17q (42%). Only three cases displayed MI. LOH incidence at individual markers was positively correlated with recurrence (D9S59, p=0.11 and D9S270, p=0.16), family history of neoplasia (D13S175, p=0.09), altitude of present residence ( D9S112, p=0.1), duration of the existence of pterygium (D9S144, p=0.06), and inversely correlated with age (D9S59, p=0.09). Concerning chromosome arms, LOH was positively correlated with the altitude of present residence (13q and 17p, p=0.03) and duration of the existence of pterygium (13q and 17p, p=0.09).
CONCLUSIONS—LOH is a common event whereas MI is a very uncommon one at the examined markers in pterygium, indicating the presence of putative tumour suppressor genes implicated in the aetiopathogenesis of the disease. The fact that LOH at 9q31-33 was more frequent in recurrent pterygia and also correlated with known risk factors such as young age and high altitude of residence, implies a possible predictive value of this finding for postoperative recurrence.

 Keywords: heterozygosity; microsatellite instability; pterygium PMID:9924343

  6. Microsatellite instability and loss of heterozygosity in gastric carcinoma in comparison to family history.

    PubMed Central

    Keller, G.; Rudelius, M.; Vogelsang, H.; Grimm, V.; Wilhelm, M. G.; Mueller, J.; Siewert, J. R.; Höfler, H.

    1998-01-01

    We compared 29 gastric carcinomas from patients with a variably strong family history for gastric cancer (group 1) with 36 gastric carcinomas from patients without a family history of this disease (group 2) for microsatellite instability (MSI) and loss of heterozygosity (LOH) with 12 microsatellite markers. Both study groups had similar proportions of histological types and tumor locations. Widespread MSI (alterations at > or = 6 loci) was seen in 5 of 29 (17%) of the tumors belonging to group 1 and in 4 of 36 (11%) group 2 tumors. MSI at a low level (alterations at 1 to 3 loci) was observed in 12 of 29 (41%) of tumors in group 1 and in 10 of 36 (28%) of tumors in group 2, differences that were not statistically significant. A significant difference with respect to low level MSI was observed between the two groups when considering the overall mutation rate of microsatellites. Seventeen of 281 (6%) analyzed microsatellite loci showed alterations in group 1 and 11 of 381 (2.9%) in group 2 (P = 0.046). Comparison of both types of MSI to the clinicopathological parameters in both groups revealed a significant association of low level MSI with advanced tumor stages (P = 0.046) in the group 2, whereas no such association was observed in group 1. In respect to LOH, a significant difference between the two groups was observed at chromosome 17p12, as 13 of 22 (59%) informative cases of group 1 showed LOH in comparison with 7 of 26 (27%) (P = 0.024) in group 2. No correlation of LOH at chromosome 17p12 to the pathological or clinical data was observed either in the two groups or in the study as a whole. Our data show that gastric carcinomas of patients with a positive family history of gastric cancer in group 1 are characterized by a higher mutation rate in respect to low level MSI, particularly at dinucleotide repeats, and by a higher frequency of LOH at chromosome 17p12, indicating that different genetic pathways are involved in the pathogenesis of gastric carcinomas

  7. Allelotyping of acute myelogenous leukemia: loss of heterozygosity at 7q31.1 (D7S486) and q33-34 (D7S498, D7S505).

    PubMed

    Koike, M; Tasaka, T; Spira, S; Tsuruoka, N; Koeffler, H P

    1999-03-01

    Loss of a whole chromosome 7(-7) or a deletion of the long arm of chromosome 7 del(7q) occurs frequently in many types of primary cancers including cases of acute myelogenous leukemia (AML). We analyzed for loss of heterozygosity (LOH) of chromosome arm 7q in 26 AML cases using a set of 15 microsatellite markers in order to begin to determine the location of putative tumor suppressor genes (TSG) important to this disease. Seven samples (27%) showed LOH at one or more loci on chromosome 7q. We identified the smallest commonly deleted regions to be at 7q31.1 (D7S486) and 7q33-34 (D7S498, D7S505) suggesting that alterations of a TSG in each region have an important role in de novo AML.

  8. Phytophthora capsici - Loss of Heterozygosity (LOH): A Widespread Mechanism for Rapid Adaptation ( 7th Annual SFAF Meeting, 2012)

    ScienceCinema

    Mudge, Joanne [NCGR

    2016-07-12

    Joanne Mudge on "Phytophthora capsici - Loss of Heterozygosity (LOH): A Widespread Mechanism for Rapid Mutation" at the 2012 Sequencing, Finishing, Analysis in the Future Meeting held June 5-7, 2012 in Santa Fe, New Mexico.

  9. YMAP: a pipeline for visualization of copy number variation and loss of heterozygosity in eukaryotic pathogens.

    PubMed

    Abbey, Darren A; Funt, Jason; Lurie-Weinberger, Mor N; Thompson, Dawn A; Regev, Aviv; Myers, Chad L; Berman, Judith

    2014-01-01

    The design of effective antimicrobial therapies for serious eukaryotic pathogens requires a clear understanding of their highly variable genomes. To facilitate analysis of copy number variations, single nucleotide polymorphisms and loss of heterozygosity events in these pathogens, we developed a pipeline for analyzing diverse genome-scale datasets from microarray, deep sequencing, and restriction site associated DNA sequence experiments for clinical and laboratory strains of Candida albicans, the most prevalent human fungal pathogen. The YMAP pipeline (http://lovelace.cs.umn.edu/Ymap/) automatically illustrates genome-wide information in a single intuitive figure and is readily modified for the analysis of other pathogens with small genomes.

  10. An integer programming formulation of the parsimonious loss of heterozygosity problem.

    PubMed

    Catanzaro, Daniele; Labbé, Martine; Halldórsson, Bjarni V

    2013-01-01

    A loss of heterozygosity (LOH) event occurs when, by the laws of Mendelian inheritance, an individual should be heterozygote at a given site but, due to a deletion polymorphism, is not. Deletions play an important role in human disease and their detection could provide fundamental insights for the development of new diagnostics and treatments. In this paper, we investigate the parsimonious loss of heterozygosity problem (PLOHP), i.e., the problem of partitioning suspected polymorphisms from a set of individuals into a minimum number of deletion areas. Specifically, we generalize Halldórsson et al.'s work by providing a more general formulation of the PLOHP and by showing how one can incorporate different recombination rates and prior knowledge about the locations of deletions. Moreover, we show that the PLOHP can be formulated as a specific version of the clique partition problem in a particular class of graphs called undirected catch-point interval graphs and we prove its general $({\\cal NP})$-hardness. Finally, we provide a state-of-the-art integer programming (IP) formulation and strengthening valid inequalities to exactly solve real instances of the PLOHP containing up to 9,000 individuals and 3,000 SNPs. Our results give perspectives on the mathematics of the PLOHP and suggest new directions on the development of future efficient exact solution approaches.

  11. Maintenance and loss of heterozygosity in a thelytokous lineage of honey bees (Apis mellifera capensis).

    PubMed

    Goudie, Frances; Allsopp, Michael H; Beekman, Madeleine; Oxley, Peter R; Lim, Julianne; Oldroyd, Benjamin P

    2012-06-01

    An asexual lineage that reproduces by automictic thelytokous parthenogenesis has a problem: rapid loss of heterozygosity resulting in effective inbreeding. Thus, the circumstances under which rare asexual lineages thrive provide insights into the trade-offs that shape the evolution of alternative reproductive strategies across taxa. A socially parasitic lineage of the Cape honey bee, Apis mellifera capensis, provides an example of a thelytokous lineage that has endured for over two decades. It has been proposed that cytological adaptations slow the loss of heterozygosity in this lineage. However, we show that heterozygosity at the complementary sex determining (csd) locus is maintained via selection against homozygous diploid males that arise from recombination. Further, because zygosity is correlated across the genome, it appears that selection against diploid males reduces loss of homozygosity at other loci. Selection against homozygotes at csd results in substantial genetic load, so that if a thelytokous lineage is to endure, unusual ecological circumstances must exist in which asexuality permits such a high degree of fecundity that the genetic load can be tolerated. Without these ecological circumstances, sex will triumph over asexuality. In A. m. capensis, these conditions are provided by the parasitic interaction with its conspecific host, Apis mellifera scutellata.

  12. Loss of heterozygosity in human primary prostate carcinomas: a possible tumor suppressor gene at 7q31.1.

    PubMed

    Zenklusen, J C; Thompson, J C; Troncoso, P; Kagan, J; Conti, C J

    1994-12-15

    We studied loss of heterozygosity (LOH) on human chromosome 7q to determine the location of a putative tumor suppressor gene (TSG) in human primary prostate carcinomas. Samples were obtained from 16 primary prostate carcinomas surgically removed from patients at The University of Texas M. D. Anderson Cancer Center. Paired normal and tumor DNAs were used as template for PCR amplification of a set of 14 CA microsatellite repeats on 7q21-qter. Twelve of 16 cases studied had LOH at one or more loci on 7q. Eighty-three percent LOH (five of six informative cases) was detected with D7S522 at 7q31.1-7q31.2. Percentage of LOH was normally distributed around D7S522. The high incidence of LOH in primary prostate carcinomas suggests that there is a TSG relevant to the development of prostate cancers at 7q31.1-31.2, confirming our previous functional evidence for a TSG at this location. Further research needs to be conducted to establish the identity and function of this putative TSG.

  13. Immune escape from NY-ESO-1-specific T-cell therapy via loss of heterozygosity in the MHC.

    PubMed

    Klippel, Z K; Chou, J; Towlerton, A M; Voong, L N; Robbins, P; Bensinger, W I; Warren, E H

    2014-03-01

    Adoptive immunotherapy of tumors with T cells specific for the cancer-testis antigen NY-ESO-1 has shown great promise in preclinical models and in early stage clinical trials. Tumor persistence or recurrence after NY-ESO-1-specific therapy occurs, however, and the mechanisms of recurrence remain poorly defined. In a murine xenograft model of NY-ESO-1(+) multiple myeloma, we observed tumor recurrence after adoptive transfer of CD8(+) T cells genetically redirected to the prototypic NY-ESO-1157-165 peptide presented by HLA-A*02:01. Analysis of the myeloma cells that had escaped from T-cell control revealed intact expression of NY-ESO-1 and B2M, but selective, complete loss of HLA-A*02:01 expression from the cell surface. Loss of heterozygosity (LOH) in the major histocompatibility complex (MHC) involving the HLA-A locus was identified in the tumor cells, and further analysis revealed selective loss of the allele encoding HLA-A*02:01. Although LOH involving the MHC has not been described in myeloma patients with persistent or recurrent disease after immune therapies such as allogeneic hematopoietic cell transplantation (HCT), it has been described in patients with acute myelogenous leukemia who relapsed after allogeneic HCT. These results suggest that MHC loss should be evaluated in patients with myeloma and other cancers who relapse after adoptive NY-ESO-1-specific T-cell therapy.

  14. Are there any more ovarian tumor suppressor genes? A new perspective using ultra high-resolution copy number and loss of heterozygosity analysis.

    PubMed

    Gorringe, Kylie L; Ramakrishna, Manasa; Williams, Louise H; Sridhar, Anita; Boyle, Samantha E; Bearfoot, Jennifer L; Li, Jason; Anglesio, Michael S; Campbell, Ian G

    2009-10-01

    Ovarian cancer is characterized by complex genetic alterations, including copy number loss and copy number-neutral loss of heterozygosity (LOH). These alterations are assumed to represent the "second hit" of the underlying tumor suppressor gene (TSG), however, relative to the number of LOH hotspots reported, few ovarian TSGs have been identified. We conducted a high-resolution LOH analysis using SNP arrays (500K and SNP6.0) of 106 primary ovarian tumors of various histological subtypes together with matching normal DNA. LOH was detected in at least 35% of samples on chromosomes 17, 19p, 22q, Xp, 13q, 8p, 6q, 4q, 5q, 1p, 16q, and 9q with a median minimal region of overlap of only 300 kb. Subtype-specific differences in LOH frequency were noted, particularly for mucinous cases. We also identified 192 somatic homozygous deletions (HDs). Recurrent HDs targeted known TSGs such as CDKN2A (eight samples), RB1 (five samples), and PTEN (three samples). Additional recurrent HDs targeted 16 candidate TSGs near minimal regions of LOH on chromosomes 17, 13, 8p, 5q, and X. Given the importance of HDs in inactivating known genes, these candidates are highly likely to be ovarian TSGs. Our data suggest that the poor success of previous LOH studies was due to the inability of previous technology to resolve complex genomic alterations and distinguish true LOH from allelic imbalance. This study shows that recurrent regions of LOH and HD frequently align with known TSGs suggesting that LOH analysis remains a valid approach to discovering new candidates.

  15. Comparison of loss of heterozygosity patterns between ovarian tumors of low malignant potential and malignant ovarian tumors

    SciTech Connect

    Crawford, E.C.; Miller, D.M.; Finley, W.H.

    1994-09-01

    Ovarian tumors of low malignant potential (LMP) represent a pathologic subtype of ovarian tumor that possess many features common to malignant tumors including epithelial stratification, increased mitotic activity and atypical cellularity. These tumors, however, do not invade the ovarian stroma and have a much improved patient prognosis. Utilizing dinucleotide repeats, loss of heterozygosity (LOH) studies were performed on a total of 12 ovarian tumors of LMP in 5 regions found to have significant levels of LOH in malignant ovarian tumors. The regions chosen for study were 3p, 6q, 11p, 17p and 17q. LOH could be demonstrated in malignant ovarian tumors in loci from 3p, 11p and both chromosomal arms of 17 when compared to normal tissue from the same patient. Loss in malignant tumors was more common in loci mapped to 3p21 and to 11p15. OH was not noted in any samples for a repeat in the TP53 gene even though flanking markers on 17p were lost in 1 patient with a malignant tumor. Loss was not demonstrated in any of the loci examined from 6q in malignant ovarian tumors. LOH was not demonstrated in any of the 39 loci examined from any of the five chromosomal regions in the ovarian tumors of LMP. Cytogenetic analyses of these LMP tumors were consistent with lack of involvement in these chromosomal regions. These data suggest the mechanism of tumorigenesis is different in tumors of LMP from that in malignant ovarian tumors.

  16. Immune deficiency augments the prevalence of p53 loss of heterozygosity in spontaneous tumors but not bi-directional loss of heterozygosity in bone marrow progenitors.

    PubMed

    Shetzer, Yoav; Napchan, Yael; Kaufman, Tom; Molchadsky, Alina; Tal, Perry; Goldfinger, Naomi; Rotter, Varda

    2017-03-15

    p53 loss of heterozygosity (LOH) is a frequent event in tumors of somatic and Li-Fraumeni syndrome patients harboring p53 mutation. Here, we focused on resolving a possible crosstalk between the immune-system and p53 LOH. Previously, we reported that p53 heterozygous bone-marrow mesenchymal progenitor cells undergo p53 LOH in-vivo. Surprisingly, the loss of either the wild-type p53 allele or mutant p53 allele was detected with a three-to-one ratio in favor of losing the mutant allele. In this study, we examined whether the immune-system can affect the LOH directionality in bone marrow progenitors. We found that mesenchymal progenitor cells derived from immune-deficient mice exhibited the same preference of losing the mutant p53 allele as immune-competent matched cells, nevertheless, these animals showed a significantly shorter tumor-free survival, indicating the possible involvement of immune surveillance in this model. Surprisingly, spontaneous tumors of p53 heterozygous immune-deficient mice exhibited a significantly higher incidence of p53 LOH compared to that observed in tumors derived of p53 heterozygous immune-competent mice. These findings indicate that the immune-system may affect the p53 LOH prevalence in spontaneous tumors. Thus suggesting that the immune-system may recognize and clear cells that underwent p53 LOH, whereas in immune-compromised mice, those cells will form tumors with shorter latency. In individuals with a competent immune-system, p53 LOH independent pathways may induce malignant transformation which requires a longer tumor latency. Moreover, this data may imply that the current immunotherapy treatment aimed at abrogating the inhibition of cellular immune checkpoints may be beneficial for LFS patients.

  17. Chromosome 3p loss of heterozygosity and mutation analysis of the FHIT and beta-cat genes in squamous cell carcinoma of the head and neck.

    PubMed Central

    González, M V; Pello, M F; Ablanedo, P; Suárez, C; Alvarez, V; Coto, E

    1998-01-01

    AIMS: To study the loss of heterozygosity at the short arm of chromosome 3 in primary tumours from patients with squamous cell carcinoma of the head and neck; to determine whether the FHIT gene, mapped to 3p14.2 and the CTNNB1 (beta-cat) gene, mapped to 3p21, are deleted or mutated in these tumours. METHODS: DNA was extracted from fresh tumours. Loss of heterozygosity was assessed by microsatellite analysis of the following markers: D3S1283 and D3S1286 (3p24), D3S966 (3p21), and D3S1300 (3P14.2). Homozygous deletion was determined by radioactive multiplex polymerase chain reaction of exons 5 and 6 of the FHIT gene. The presence of mutations in FHIT exon 5 and beta-cat exon 3 was studied by single strand conformation polymorphism. RESULTS: 50% of informative cases (25/50) showed loss of heterozygosity for at least one of the 3p markers. 3p21 was the region with the highest rate of allelic deletion (63%). No point mutation was found in FHIT exon 5 or beta-cat exon 3. No case showed homozygous deletion for the FHIT (exons 5 and 6) or the beta-cat exon 3. CONCLUSIONS: The short arm of chromosome 3 is often deleted in the head and neck squamous cell carcinomas. In the remaining alleles of the FHIT or beta-cat genes, no evidence was found for point mutations or deletions, documented in other common carcinomas. Inactivation could occur by different mechanisms such as methylation, or other genes (not studied here) could be target of allelic losses in squamous cell carcinoma of the head and neck. Images PMID:9797729

  18. The nonhomologous end joining factor Artemis suppresses multi-tissue tumor formation and prevents loss of heterozygosity.

    PubMed

    Woo, Y; Wright, S M; Maas, S A; Alley, T L; Caddle, L B; Kamdar, S; Affourtit, J; Foreman, O; Akeson, E C; Shaffer, D; Bronson, R T; Morse, H C; Roopenian, D; Mills, K D

    2007-09-06

    Nonhomologous end joining (NHEJ) is a critical DNA repair pathway, with proposed tumor suppression functions in many tissues. Mutations in the NHEJ factor ARTEMIS cause radiation-sensitive severe combined immunodeficiency in humans and may increase susceptibility to lymphoma in some settings. We now report that deficiency for Artemis (encoded by Dclre1c/Art in mouse) accelerates tumorigenesis in several tissues in a Trp53 heterozygous setting, revealing tumor suppression roles for NHEJ in lymphoid and non-lymphoid cells. We also show that B-lineage lymphomas in these mice undergo loss of Trp53 heterozygosity by allele replacement, but arise by mechanisms distinct from those in Art Trp53 double null mice. These findings demonstrate a general tumor suppression function for NHEJ, and reveal that interplay between NHEJ and Trp53 loss of heterozygosity influences the sequence of multi-hit oncogenesis. We present a model where p53 status at the time of tumor initiation is a key determinant of subsequent oncogenic mechanisms. Because Art deficient mice represent a model for radiation-sensitive severe combined immunodeficiency, our findings suggest that these patients may be at risk for both lymphoid and non-lymphoid cancers.

  19. Loss-of-heterozygosity facilitates passage through Haldane's sieve for Saccharomyces cerevisiae undergoing adaptation.

    PubMed

    Gerstein, A C; Kuzmin, A; Otto, S P

    2014-05-07

    Haldane's sieve posits that the majority of beneficial mutations that contribute to adaptation should be dominant, as these are the mutations most likely to establish and spread when rare. It has been argued, however, that if the dominance of mutations in their current and previous environments are correlated, Haldane's sieve could be eliminated. We constructed heterozygous lines of Saccharomyces cerevisiae containing single adaptive mutations obtained during exposure to the fungicide nystatin. Here we show that no clear dominance relationship exists across environments: mutations exhibited a range of dominance levels in a rich medium, yet were exclusively recessive under nystatin stress. Surprisingly, heterozygous replicates exhibited variable-onset rapid growth when exposed to nystatin. Targeted Sanger sequencing demonstrated that loss-of-heterozygosity (LOH) accounted for these growth patterns. Our experiments demonstrate that recessive beneficial mutations can avoid Haldane's sieve in clonal organisms through rapid LOH and thus contribute to rapid evolutionary adaptation.

  20. Expression of PTEN in mycosis fungoides and correlation with loss of heterozygosity.

    PubMed

    Katona, Terrence M; Smoller, Bruce R; Webb, Alden L; Hattab, Eyas M; Khalil, Ahmed; Hiatt, Kim M

    2013-07-01

    Mycosis fungoides (MF) exhibits a variety of underlying molecular defects including aberrations involving the PTEN tumor suppressor gene. Specifically, loss of heterozygosity of PTEN has been previously demonstrated. We hypothesize that abnormalities of PTEN may result in altered immunohistochemical expression of its protein product. Thirty-six MF specimens were stained with monoclonal antibody against PTEN protein. The percentage of nuclei retaining PTEN expression and the staining intensity was recorded. Average percentage of lymphoma cells retaining expression of the PTEN protein was 92% within patch-stage lesions, 81.4% in plaque-stage lesions, and 81.1% in tumor-stage lesions. Average intensity of staining for patch-stage lesions was 2.90, 2.50 for plaque lesions and 2.44 for tumor lesions. Cases lacking loss of heterozygozity at PTEN (n = 6) had an average expression of 81% and an average intensity of staining of 2.42. Whereas, cases with loss of heterozygozity at PTEN (n = 6) had an average expression of 75% of cells with an average staining intensity of 2.33. The percentage of cells retaining PTEN and staining intensity decrease from patch- to plaque-stage lesions, whereas both parameters show mild diminution in tumor lesions compared with plaque lesions. PTEN expression in a small sample seems to correlate with previous demonstration of loss of heterozygosity at the molecular level. Although a trend for loss of PTEN expression exists with histologic progression of MF, the effect is modest and may not represent the pivotal defect in MF pathogenesis.

  1. Loss of heterozygosity at the SS receptor type 5 locus in human GH- and TSH-secreting pituitary adenomas.

    PubMed

    Filopanti, M; Ballarè, E; Lania, A G; Bondioni, S; Verga, U; Locatelli, M; Zavanone, L M; Losa, M; Gelmini, S; Peri, A; Orlando, C; Beck-Peccoz, P; Spada, A

    2004-11-01

    SS receptor types 2 and 5 (sst2 and sst5) are involved in the control of secretion and proliferation of normal and tumoral somatotrophs and thyrotrophs. The mechanisms leading to reduced responsiveness to SS analogues in patients with pituitary tumors are poorly understood. The aim of the study was to verify the possible loss of heterozygosity (LOH) at the sst5 gene locus in somatotroph and thyrotroph adenomas by screening leukocyte and tumor DNA for two single nucleotide polymorphisms, i.e. C1004T leading to P335L change and T-461C in the 5'-upstream region. Among the 13 informative samples, 1 GH- and 1 TSH-secreting adenoma showed LOH at sst5 gene locus with the retention of Leu335 variant. By analyzing other polymorphic markers spanning from telomere to 16p13.3-13.2 boundaries, DNA deletion of at least 1 megabase was found in both tumors. LOH in thyrotroph adenoma was associated with unusual tumor aggressiveness that required a second surgery and resistance to SS analogs, while no obvious phenotype was identified in the case of the somatotroph adenoma. In conclusions, LOH at the sst5 gene locus is a rare phenomenon, occurring in about 10% of pituitary tumors, that seems to be associated with an aggressive phenotype, at least in thyrotroph adenomas. Further studies are required to confirm this association and to identify the genes, in addition to sst5, lost in these tumors.

  2. Combination of Complement-Dependent Cytotoxicity and Relative Fluorescent Quantification of HLA Length Polymorphisms Facilitates the Detection of a Loss of Heterozygosity

    PubMed Central

    Reibke, Roland; Subklewe, Marion; Zahn, Robert; Kauke, Teresa; Spiekermann, Karsten; Spannagl, Michael; Tischer, Johanna; Hiddemann, Wolfgang; Dick, Andrea

    2014-01-01

    Loss of heterozygosity (LOH) is a common event in malignant cells. In this work we introduce a new approach to identify patients with loss of heterozygosity in the HLA region either at first diagnosis or after HLA mismatched allogeneic HSCT. Diagnosis of LOH requires a high purity of recipient target cells. FACS is time consuming and also frequently prevented by rather nonspecific or unknown immune phenotype. The approach for recipient cell enrichment is based on HLA targeted complement-dependent cytotoxicity (CDC). Relative fluorescent quantification (RFQ) analysis of HLA intron length polymorphisms then allows analysis of HLA heterozygosity. The approach is exemplified in recent clinical cases illustrating the detection of an acquired allele loss. As illustrated in one case with DPB1, distinct HLA loci in donor and patient were sufficient for both proof of donor cell removal and evaluation of allele loss in the patient's leukemic cells. Results were confirmed using HLA-B RFQ analysis and leukemia-associated aberrant immunophenotype (LAIP) based cell sort. Both results confirmed suspected loss of HLA heterozygosity. Our approach complements or substitutes for FACS-based cell enrichment; hence it may be further developed as novel routine diagnostic tool. This allows rapid recipient cell purification and testing for loss of HLA heterozygosity before and after allogeneic HSCT in easily accessible peripheral blood samples. PMID:24860670

  3. Loss of heterozygosity of tumor suppressor genes (p16, Rb, E-cadherin, p53) in hypopharynx squamous cell carcinoma.

    PubMed

    Sang-Hyuk Lee, Sang-Hyuk; Lee, Nam-Hoon; Jin, Sung-Min; Rho, Young-Soo; Jo, Sung-Jin

    2011-07-01

    Microsatellite alterations, especially those that cause loss of heterozygosity (LOH), have recently been postulated as a novel mechanism of carcinogenesis and a useful prognostic factor in many kinds of malignant tumors. However, few studies have focused on a specific site, hypopharynx. The aim of this study was to evaluate the relationship between LOH and hypopharyngeal squamous cell carcinoma (HPSCC). Laboratory-based study. Integrated health care system. Matched normal and cancerous tissues from 30 patients with HPSCC were examined for LOH in 4 tumor suppressor genes (TSGs) (p16, Rb, E-cadherin, and p53) at loci 9p21, 13q21, 6q22, and 17p13, respectively, using microsatellite markers amplified by polymerase chain reaction. The results for each loci were compared with clinicopathological features. Among the 30 cases, 26 (86.7%) exhibited LOH, with the most common alteration being LOH at p53 (52.6%). Significantly higher rates of LOH detection were seen in Rb, p53, and the LOH-high group (cases where 2 or more loci with LOH were found) in cases of lymph node metastasis. Compared with stage I and II carcinoma, tumors of stages III and IV had significantly higher frequencies of LOH in Rb, p53, and the LOH-high group. However, the presence of LOH was not significantly correlated with survival. These results suggest that LOH in TSGs such as Rb and p53 may contribute to the development and progression of HPSCC. The presence of LOH in the primary tumor may also be predictive of lymph node metastasis.

  4. Paternal uniparental disomy with segmental loss of heterozygosity of chromosome 11 are hallmark characteristics of syndromic and sporadic embryonal rhabdomyosarcoma.

    PubMed

    Robbins, Katherine M; Stabley, Deborah L; Holbrook, Jennifer; Sahraoui, Rebecca; Sadreameli, Alexa; Conard, Katrina; Baker, Laura; Gripp, Karen W; Sol-Church, Katia

    2016-12-01

    Costello syndrome (CS) arises from a typically paternally derived germline mutation in the proto-oncogene HRAS, and is considered a rasopathy. CS results in failure-to-thrive, intellectual disabilities, short stature, coarse facial features, skeletal abnormalities, congenital heart disease, and a predisposition for cancer, most commonly embryonal rhabdomyosarcoma (ERMS). The goal of this study was to characterize CS ERMS at the molecular level and to determine how divergent it is from sporadic ERMS. We characterized eleven ERMS tumors from eight unrelated CS patients, carrying paternally derived HRAS c.34G>A (p.Gly12Ser; 6) or c.35G>C (p.Gly12Ala; 2) mutations. Loss of heterozygosity (LOH) was evaluated in all CS ERMS by microarray and/or short tandem repeat (STR) markers spanning the entire chromosome 11. Eight CS ERMS tumors displayed complete paternal uniparental disomy of chromosome 11 (pUPD11), whereas two displayed UPD only at 11p and a second primary ERMS tumor showed UPD limited to 11p15.5, the classical hallmark for ERMS. Three sporadic ERMS cell lines (RD, Rh36, Rh18) and eight formalin fixed paraffin embedded (FFPE) ERMS tumors were also analyzed for RAS mutations and LOH status. We found a higher than anticipated frequency of RAS mutations (HRAS or NRAS; 50%) in sporadic ERMS cell lines/tumors. Unexpectedly, complete uniparental disomy (UPD11) was observed in five specimens, while the other six showed LOH extending across the p and q arms of chromosome 11. In this study, we are able to clearly demonstrate complete UPD11 in both syndromic and sporadic ERMS. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  5. Paternal Uniparental Disomy with Segmental Loss of Heterozygosity of Chromosome 11 are Hallmark Characteristics of Syndromic and Sporadic Embryonal Rhabdomyosarcoma

    PubMed Central

    Robbins, Katherine M.; Stabley, Deborah L.; Holbrook, Jennifer; Sahraoui, Rebecca; Sadreameli, Alexa; Conard, Katrina; Baker, Laura; Gripp, Karen W.; Sol-Church, Katia

    2016-01-01

    Costello syndrome (CS) arises from a typically paternally derived germline mutation in the proto-oncogene HRAS, and is considered a rasopathy. CS results in failure-to-thrive, intellectual disabilities, short stature, coarse facial features, skeletal abnormalities, congenital heart disease, and a predisposition for cancer, most commonly embryonal rhabdomyosarcoma (ERMS). The goal of this study was to characterize CS ERMS at the molecular level and to determine how divergent it is from sporadic ERMS. We characterized eleven ERMS tumors from eight unrelated CS patients, carrying paternally derived HRAS c.34G>A (p.Gly12Ser; 6) or c.35G>C (p.Gly12Ala; 2) mutations. Loss of heterozygosity (LOH) was evaluated in all CS ERMS by microarray and/or short tandem repeat (STR) markers spanning the entire chromosome 11. Eight CS ERMS tumors displayed complete paternal uniparental disomy of chromosome 11 (pUPD11), whereas two displayed UPD only at 11p and a second primary ERMS tumor showed UPD limited to 11p15.5, the classical hallmark for ERMS. Three sporadic ERMS cell lines (RD, Rh36, Rh18) and eight formalin fixed paraffin embedded (FFPE) ERMS tumors were also analyzed for RAS mutations and LOH status. We found a higher than anticipated frequency of RAS mutations (HRAS or NRAS; 50%) in sporadic ERMS cell lines/tumors. Unexpectedly, complete uniparental disomy (UPD11) was observed in five specimens, while the other six showed LOH extending across the p and q arms of chromosome 11. In this study, we are able to clearly demonstrate complete UPD11 in both syndromic and sporadic ERMS. PMID:27589201

  6. Mosaicism due to myeloid lineage restricted loss of heterozygosity as cause of spontaneous Rh phenotype splitting.

    PubMed

    Körmöczi, Günther F; Dauber, Eva-Maria; Haas, Oskar A; Legler, Tobias J; Clausen, Frederik B; Fritsch, Gerhard; Raderer, Markus; Buchta, Christoph; Petzer, Andreas L; Schönitzer, Diether; Mayr, Wolfgang R; Gassner, Christoph

    2007-09-15

    Spontaneous Rh phenotype alteration interferes with pretransfusion and prenatal blood group examinations and may potentially indicate hematologic disease. In this study, the molecular background of this biologic phenomenon was investigated. In 9 patients (3 with hematologic disease), routine RhD typing showed a mixture of D-positive and D-negative red cells not attributable to transfusion or hematopoietic stem-cell transplantation. In all patients, congenital and acquired chimerism was excluded by microsatellite analysis. In contrast to D-positive red cells, D-negative subpopulations were also negative for C or E in patients genotyped CcDdee or ccDdEe, respectively, which suggested the presence of erythrocyte precursors with an apparent homozygous cde/cde or hemizygous cde/- genotype. Except for one patient with additional Fy(b) antigen anomaly, no other blood group systems were affected. RH genotyping of single erythropoietic burst-forming units, combined with microsatellite analysis of blood, different tissues, sorted blood cell subsets, and erythropoietic burst-forming units, indicated myeloid lineage-restricted loss of heterozygosity (LOH) of variable chromosome 1 stretches encompassing the RHD/RHCE gene loci. Fluorescent in situ hybridization studies indicated that LOH was caused by either somatic recombination or deletion. Therefore, most cases of spontaneous Rh phenotype splitting appear to be due to hematopoietic mosaicism based on LOH on chromosome 1.

  7. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms

    PubMed Central

    Jankowska, Anna M.; Szpurka, Hadrian; Tiu, Ramon V.; Makishima, Hideki; Afable, Manuel; Huh, Jungwon; O'Keefe, Christine L.; Ganetzky, Rebecca; McDevitt, Michael A.

    2009-01-01

    Chromosomal abnormalities are frequent in myeloid malignancies, but in most cases of myelodysplasia (MDS) and myeloproliferative neoplasms (MPN), underlying pathogenic molecular lesions are unknown. We identified recurrent areas of somatic copy number–neutral loss of heterozygosity (LOH) and deletions of chromosome 4q24 in a large cohort of patients with myeloid malignancies including MDS and related mixed MDS/MPN syndromes using single nucleotide polymorphism arrays. We then investigated genes in the commonly affected area for mutations. When we sequenced TET2, we found homozygous and hemizygous mutations. Heterozygous and compound heterozygous mutations were found in patients with similar clinical phenotypes without LOH4q24. Clinical analysis showed most TET2 mutations were present in patients with MDS/MPN (58%), including CMML (6/17) or sAML (32%) evolved from MDS/MPN and typical MDS (10%), suggesting they may play a ubiquitous role in malignant evolution. TET2 mutations affected conserved domains and the N terminus. TET2 is widely expressed in hematopoietic cells but its function is unknown, and it lacks homology to other known genes. The frequency of mutations in this candidate myeloid regulatory gene suggests an important role in the pathogenesis of poor prognosis MDS/MPN and sAML and may act as a disease gene marker for these often cytogenetically normal disorders. PMID:19372255

  8. Human pituitary adenomas show no loss of heterozygosity at the retinoblastoma gene locus

    SciTech Connect

    Zhu, J.; Leon, S.P.; Beggs, A.H.; Busque, L.; Gilliland, D.G.; Black, P.M.

    1994-04-01

    The retinoblastoma tumor suppressor gene (RB1) is inactivated in hereditary and sporadic forms of retinoblastoma as well as in a number of other sporadic tumors. The majority of human pituitary tumors have been shown to be monoclonal neoplasms, suggesting that 1 or more somatic mutations are involved in the clonal expansion of a single progenitor cell. Recently, a high percentage of transgenic mice containing a disrupted RB1 allele have been shown to develop pituitary tumors. To investigate whether RB1 inactivation contributes to the development of human pituitary adenomas, the authors searched for loss of heterozygosity (LOH) within the RB1 gene locus in a variety of human pituitary adenomas. They screened 34 adenomas for LOH using a polymerase chain reaction (PCR)-based microsatellite polymorphic marker at the RB1 gene locus. In addition, a variable number of tandem repeat markers from within the RB1 gene was also used to search for LOH in 14 tumors. They found no LOH or microsatellite instability at the RB1 locus in any of the informative cases (30 of 34). Additionally, they showed that 4 representative adenomas from female patients are monoclonal in origin using a PCR-based clonality analysis assay. They conclude that the RB1 gene shows no LOH in a variety of human pituitary adenomas and that PCR-based microsatellite markers can serve as a useful tool for LOH analysis in human pituitary tumors. 42 refs., 3 figs., 1 tab.

  9. Dissecting Loss of Heterozygosity (LOH) in Neurofibromatosis Type 1-Associated Neurofibromas: Importance of Copy Neutral LOH

    PubMed Central

    Garcia-Linares, Carles; Fernández-Rodríguez, Juana; Terribas, Ernest; Mercadé, Jaume; Pros, Eva; Benito, Llúcia; Benavente, Yolanda; Capellà, Gabriel; Ravella, Anna; Blanco, Ignacio; Kehrer-Sawatzki, Hildegard; Lázaro, Conxi; Serra, Eduard

    2011-01-01

    Dermal neurofibromas (dNFs) are benign tumors of the peripheral nervous system typically associated with Neurofibromatosis type 1 (NF1) patients. Genes controlling the integrity of the DNA are likely to influence the number of neurofibromas developed because dNFs are caused by somatic mutational inactivation of the NF1 gene, frequently evidenced by loss of heterozygosity (LOH). We performed a comprehensive analysis of the prevalence and mechanisms of LOH in dNFs. Our study included 518 dNFs from 113 patients. LOH was detected in 25% of the dNFs (N = 129). The most frequent mechanism causing LOH was mitotic recombination, which was observed in 62% of LOH-tumors (N = 80), and which does not reduce the number of NF1 gene copies. All events were generated by a single crossover located between the centromere and the NF1 gene, resulting in isodisomy of 17q. LOH due to the loss of the NF1 gene accounted for a 38% of dNFs with LOH (N = 49), with deletions ranging in size from ∼80 kb to ∼8 Mb within 17q. In one tumor we identified the first example of a neurofibroma-associated second-hit type-2 NF1 deletion. Analysis of the prevalence of mechanisms causing LOH in dNFs in individual patients (possibly under genetic control) will elucidate whether there exist interindividual variation. Hum Mutat 32:78–90, 2011. © 2010 Wiley-Liss, Inc. PMID:21031597

  10. [Clinicopathologic significance of β-catenin protein and loss of heterozygosity on 10q in medulloblastoma].

    PubMed

    Li, Jun-zhi; Wang, Cheng-hui; Zhou, Fu-an; Miao, Na; Abulajang, Gulinaer; Zhang, Wei

    2012-12-01

    To study the expression of β-catenin protein and the status of loss of heterozygosity (LOH) on chromsome 10q in medulloblastoma, with clinical correlation. Immunohistochemical study for β-catenin protein was carried out in 50 cases of medulloblastoma encountered in the First Affiliated Hospital of Xinjiang Medical University during the period from 2002 to 2011, including 32 cases of classic medulloblastoma, 13 cases of desmoplastic medulloblastoma and 5 cases of medulloblastoma with extensive nodularity. The status of LOH on 10q was also detected by fluorescence in-situ hybridization. The clinicopathologic characteristics and prognostic parameters were studied by Kaplan-Meien and Cox analysis. The rates of expression of β-catenin protein in classic medulloblastoma, desmoplastic medulloblastoma and medulloblastoma with extensive nodularity were 53.1% (17/32), 4/13 and 1/5, respectively. The rate of LOH on 10q was 33.3% (8/24) in classic medulloblastoma and 2/11 in desmoplastic medulloblastoma. There was no statistically significant difference between the two tumor types. Univariate analysis showed that the expression of β-catenin protein (P = 0.022), lack of LOH on 10q (P = 0.020), extensiveness of tumor resection (P < 0.01), radiotherapy (P = 0.002) and chemotherapy (P < 0.01) represented important prognostic factors. Medulloblastoma with expression of β-catenin protein and without LOH on 10q carries a better prognosis. Assessment of these parameters is helpful in evaluating prognosis and subsequent patient management.

  11. Pleomorphic carcinoma of the lung associated with loss of heterozygosity of p53 gene.

    PubMed

    Arita, Norimasa; Mikami, Yoshiki; Yoshida, Minako; Konishi, Ichiro; Horiike, Norio; Miyauchi, Katsutoshi; Miyazaki, Tatsuhiko; Nose, Masato; Ono, Masao

    2005-06-01

    We report a case with pleomorphic carcinoma of the lung in a 70-year-old man. Pleomorphic carcinoma is characterized by a heterogenous composition that includes epithelial and mesechymal malignancies. In the present case, the tumor was composed of a mixture of unequivocal squamous cell carcinoma and spindle cell components resembling sarcomatous overgrowth. The spindle component did not include a heterologous mesenchymal element characterized by overt differentiation for bone, cartilage, neuron or muscle tissue. To evaluate a state of differentiation of the spindle cell component, we immunohistochemically examined expression of the antigens including vimentin, cytokeratin, sarcomeric actin, alpha-smooth muscle actin, S-100 protein, CD34, Factor VIII, and CD68. The results showed sole expression of vimentin in the spindle cell component, suggesting an immature state of the mesenchymal lineage. Furthermore, the spindle cell component of this case was genetically characterized by loss of heterozygosity (LOH) at a codon 234 of exon 7 of the p53 gene. This mutation causes an amino-acid replacement (Tyr to Cys), which was previously proven to attenuate p53 function. The present case may suggest a relation between somatic alteration of the p53 gene and histogenesis of pleomorphic carcinoma.

  12. Different mechanisms of radiation-induced loss of heterozygosity in two human lymphoid cell lines from a single donor

    NASA Technical Reports Server (NTRS)

    Wiese, C.; Gauny, S. S.; Liu, W. C.; Cherbonnel-Lasserre, C. L.; Kronenberg, A.

    2001-01-01

    Allelic loss is an important mutational mechanism in human carcinogenesis. Loss of heterozygosity (LOH) at an autosomal locus is one outcome of the repair of DNA double-strand breaks (DSBs) and can occur by deletion or by mitotic recombination. We report that mitotic recombination between homologous chromosomes occurred in human lymphoid cells exposed to densely ionizing radiation. We used cells derived from the same donor that express either normal TP53 (TK6 cells) or homozygous mutant TP53 (WTK1 cells) to assess the influence of TP53 on radiation-induced mutagenesis. Expression of mutant TP53 (Met 237 Ile) was associated with a small increase in mutation frequencies at the hemizygous HPRT (hypoxanthine phosphoribosyl transferase) locus, but the mutation spectra were unaffected at this locus. In contrast, WTK1 cells (mutant TP53) were 30-fold more susceptible than TK6 cells (wild-type TP53) to radiation-induced mutagenesis at the TK1 (thymidine kinase) locus. Gene dosage analysis combined with microsatellite marker analysis showed that the increase in TK1 mutagenesis in WTK1 cells could be attributed, in part, to mitotic recombination. The microsatellite marker analysis over a 64-cM region on chromosome 17q indicated that the recombinational events could initiate at different positions between the TK1 locus and the centromere. Virtually all of the recombinational LOH events extended beyond the TK1 locus to the most telomeric marker. In general, longer LOH tracts were observed in mutants from WTK1 cells than in mutants from TK6 cells. Taken together, the results demonstrate that the incidence of radi-ation-induced mutations is dependent on the genetic background of the cell at risk, on the locus examined, and on the mechanisms for mutation available at the locus of interest.

  13. Loss of heterozygosity of the MEN1 gene in a large series of TSH-secreting pituitary adenomas.

    PubMed

    Asteria, C; Anagni, M; Persani, L; Beck-Peccoz, P

    2001-11-01

    Thyrotropin-secreting pituitary adenomas (TSH-omas) are rare tumors (0.5% of all pituitary adenomas) showing an invasive behavior and usually sporadic, although a few cases are associated with multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant inherited syndrome. This disorder is linked to loss of heterozygosity (LOH) on 11q13 and inactivating mutations of MEN1 gene, which is located in the same chromosomal region. As other types of anterior pituitary adenomas, TSH-omas are the result of a monoclonal outgrowth where the intrinsic genetic defects involving oncogenes or tumor suppressor genes occur in a progenitor cell. However, so far no activating mutations of particular oncogenes or inactivating mutations of tumor suppressor genes have been identified. Starting from the observation that 3-30% of sporadic pituitary adenomas show LOH on 11q13, and that allelic losses on the long arms of chromosome 11, beside 10 and 13, are significantly associated with the transition from the non-invasive to the invasive phenotype, we decided to investigate LOH on 11q13 and mutations of menin in a large series of TSH-omas. Thirteen tumors were evaluated. DNA was extracted from tumors by standard methods and genomic DNA from peripheral blood leukocytes was used as control. LOH was screened by using 3 polymorphic markers on 11q13: D11S956, PYGM, INT-2. In 3 out of 15 cases we could demonstrate LOH on 11q13, but none of the tumors showed menin mutation after sequence analysis. These data strongly suggest that menin does not play a causative role in the development of TSH-omas, and are in agreement with other studies demonstrating a limited role of menin in pituitary sporadic tumorigenesis.

  14. Different mechanisms of radiation-induced loss of heterozygosity in two human lymphoid cell lines from a single donor

    NASA Technical Reports Server (NTRS)

    Wiese, C.; Gauny, S. S.; Liu, W. C.; Cherbonnel-Lasserre, C. L.; Kronenberg, A.

    2001-01-01

    Allelic loss is an important mutational mechanism in human carcinogenesis. Loss of heterozygosity (LOH) at an autosomal locus is one outcome of the repair of DNA double-strand breaks (DSBs) and can occur by deletion or by mitotic recombination. We report that mitotic recombination between homologous chromosomes occurred in human lymphoid cells exposed to densely ionizing radiation. We used cells derived from the same donor that express either normal TP53 (TK6 cells) or homozygous mutant TP53 (WTK1 cells) to assess the influence of TP53 on radiation-induced mutagenesis. Expression of mutant TP53 (Met 237 Ile) was associated with a small increase in mutation frequencies at the hemizygous HPRT (hypoxanthine phosphoribosyl transferase) locus, but the mutation spectra were unaffected at this locus. In contrast, WTK1 cells (mutant TP53) were 30-fold more susceptible than TK6 cells (wild-type TP53) to radiation-induced mutagenesis at the TK1 (thymidine kinase) locus. Gene dosage analysis combined with microsatellite marker analysis showed that the increase in TK1 mutagenesis in WTK1 cells could be attributed, in part, to mitotic recombination. The microsatellite marker analysis over a 64-cM region on chromosome 17q indicated that the recombinational events could initiate at different positions between the TK1 locus and the centromere. Virtually all of the recombinational LOH events extended beyond the TK1 locus to the most telomeric marker. In general, longer LOH tracts were observed in mutants from WTK1 cells than in mutants from TK6 cells. Taken together, the results demonstrate that the incidence of radi-ation-induced mutations is dependent on the genetic background of the cell at risk, on the locus examined, and on the mechanisms for mutation available at the locus of interest.

  15. Copy number neutral loss of heterozygosity at 17p and homozygous mutations of TP53 are associated with complex chromosomal aberrations in patients newly diagnosed with myelodysplastic syndromes.

    PubMed

    Svobodova, Karla; Zemanova, Zuzana; Lhotska, Halka; Novakova, Milena; Podskalska, Lucie; Belickova, Monika; Brezinova, Jana; Sarova, Iveta; Izakova, Silvia; Lizcova, Libuse; Berkova, Adela; Siskova, Magda; Jonasova, Anna; Cermak, Jaroslav; Michalova, Kyra

    2016-03-01

    Complex karyotypes are seen in approximately 20% of patients with myelodysplastic syndromes (MDS) and are associated with a high risk of transformation to acute myeloid leukemia and poor outcomes in patients. Copy number neutral loss of heterozygosity (CN-LOH, i.e., both copies of a chromosomal pair or their parts originate from one parent) might contribute to increased genomic instability in the bone-marrow cells of patients with MDS. The pathological potential of CN-LOH, which arises as a clonal aberration in a proportion of somatic cells, consists of tumor suppressor gene and oncogene homozygous mutations. The aim of our study was to evaluate the frequency of CN-LOH at 17p in bone-marrow cells of newly diagnosed MDS patients with complex chromosomal aberrations and to assess its correlation with mutations in the TP53 gene (17p13.1). CN-LOH was detected in 40 chromosomal regions in 21 (29%) of 72 patients analyzed. The changes in 27 of the 40 regions identified were sporadic. The most common finding was CN-LOH of the short arm of chromosome 17, which was detected in 13 (18%) of 72 patients. A mutational analysis confirmed the homozygous mutation of TP53 in all CN-LOH 17p patients, among which two frameshift mutations are not registered in the International Agency for Research on Cancer TP53 Database. CN-LOH 17p correlated with aggressive disease (median overall survival 4 months) and was strongly associated with a complex karyotype in the cohort studied, which might cause rapid disease progression in high-risk MDS. No other CN-LOH region previously recorded in MDS or AML patients (1p, 4q, 7q, 11q, 13q, 19q, 21q) was detected in our cohort of patients with complex karyotype examined at the diagnosis of MDS. The LOH region appeared to be balanced (i.e., with no DNA copy number change) when examined with conventional and molecular cytogenetic methods. Therefore, a microarray that detects single-nucleotide polymorphisms is an ideal method with which to identify and

  16. Loss of heterozygosity at chromosomes 1p35-pter, 4q, and 18q and protein expression differences between adenocarcinomas of the distal stomach and gastric cardia.

    PubMed

    Xu, Yan; Man, Xiaohui; Lv, Zhi; Li, Deming; Sun, Zhe; Chen, Hong; Wang, Zhenning; Luo, Yang; Xu, Huimian

    2012-12-01

    Loss of heterozygosity of 1p35-pter, 4q, and 18q is frequent in gastric carcinoma, suggesting that these regions harbor tumor suppressor genes. However, the differences in these genetic alterations between adenocarcinoma of the gastric cardia and adenocarcinoma of the distal stomach remain unclear. In this study, loss of heterozygosity at chromosomes 1p35-pter, 4q, and 18q were analyzed in adenocarcinoma of the gastric cardia and adenocarcinoma of the distal stomach samples acquired by laser capture microdissection. The expression of several tumor suppressor gene proteins, runt-related transcription factor 3 (1p36), annexin A10 (4q33), SMAD family member 4 (18q21.1), and deleted in colorectal carcinoma (18q21.3), was evaluated immunohistochemically. The adenocarcinoma of the distal stomach and adenocarcinoma of the gastric cardia lesions had a similar trend in total deletion frequency for chromosomes 1p35-pter (36.5% for adenocarcinoma of the distal stomach and 32.5% for adenocarcinoma of the gastric cardia), 4q (42.3% for adenocarcinoma of the distal stomach and 47.5% for adenocarcinoma of the gastric cardia), and 18q (38.5% for adenocarcinoma of the distal stomach and 45% for adenocarcinoma of the gastric cardia). However, loss of heterozygosity patterns were clearly different in the 2 adenocarcinomas. Deletion mapping indicated that 4q32.2-4q34.3, 18q21.2-21.31, 18q22.3-23, and 1p35.2-1p36.13 were involved in adenocarcinoma of the distal stomach, whereas 4q13.3-4q22.3, 4q31.21-4q32.2, 18q21.31-18q22.1, and 1p35.2-1p36.13 were involved in adenocarcinoma of the gastric cardia. Expression of ANXA10 (P = .038), SMAD family member 4 (P = .028), and deleted in colorectal carcinoma (P = .004) was less common in adenocarcinoma of the distal stomach than in adenocarcinoma of the gastric cardia. Expression of runt-related transcription factor 3 (P = .795) showed no significant difference in the 2 tumors. The tumors differed in the profile of genetic alterations and

  17. Frequent loss of heterozygosity in human primary squamous cell and colon carcinomas at 7q31.1: evidence for a broad range tumor suppressor gene.

    PubMed

    Zenklusen, J C; Thompson, J C; Klein-Szanto, A J; Conti, C J

    1995-03-15

    Consistent deletions and loss of heterozygosity (LOH) in polymorphic markers in a determinate chromosomal fragment are known to be indicative of a closely mapping tumor suppressor gene. Deletion of the long arm of chromosome 7 is a frequent trait in many kinds of human primary tumors. We studied LOH of 14 markers on chromosome 7q in order to determine the location of a putative tumor suppressor gene in human primary squamous cell carcinoma of the head and neck and in human primary colon carcinomas. Samples were obtained from 18 primary squamous cell carcinomas of the head and neck and 18 primary colon carcinomas surgically removed from patients at the Fox Chase Cancer Center. Loss of heterozygosity was studied performing PCR amplifications of a set of 14 CA microsatellite repeats encompassing 7q21-qter. Of 18 squamous cell carcinomas of the head and neck cases studied, 12 had LOH at one or more loci on 7q. Fifty-three percent of 15 informative cases had LOH of the CA microsatellite dinucleotide repeat marker D7S522 at 7q31.1-7q31.2. Eleven of 18 colon carcinoma cases had LOH of one or more markers assayed, and the maximum LOH (80% of 10 informative cases) was at D7S522. Distributions of percentage of LOH in both tumor types were normally distributed around microsatellite D7S522. The high incidence of LOH in both tumor types studied suggests that a tumor suppressor gene relevant to the development of epithelial cancers is present on the 7q31.1-31.2, confirming our previous functional evidence for a tumor suppressor gene on chromosome 7.

  18. Hydrogen peroxide induced loss of heterozygosity correlates with replicative lifespan and mitotic asymmetry in Saccharomyces cerevisiae.

    PubMed

    Güven, Emine; Parnell, Lindsay A; Jackson, Erin D; Parker, Meighan C; Gupta, Nilin; Rodrigues, Jenny; Qin, Hong

    2016-01-01

    Cellular aging in Saccharomyces cerevisiae can lead to genomic instability and impaired mitotic asymmetry. To investigate the role of oxidative stress in cellular aging, we examined the effect of exogenous hydrogen peroxide on genomic instability and mitotic asymmetry in a collection of yeast strains with diverse backgrounds. We treated yeast cells with hydrogen peroxide and monitored the changes of viability and the frequencies of loss of heterozygosity (LOH) in response to hydrogen peroxide doses. The mid-transition points of viability and LOH were quantified using sigmoid mathematical functions. We found that the increase of hydrogen peroxide dependent genomic instability often occurs before a drop in viability. We previously observed that elevation of genomic instability generally lags behind the drop in viability during chronological aging. Hence, onset of genomic instability induced by exogenous hydrogen peroxide treatment is opposite to that induced by endogenous oxidative stress during chronological aging, with regards to the midpoint of viability. This contrast argues that the effect of endogenous oxidative stress on genome integrity is well suppressed up to the dying-off phase during chronological aging. We found that the leadoff of exogenous hydrogen peroxide induced genomic instability to viability significantly correlated with replicative lifespan (RLS), indicating that yeast cells' ability to counter oxidative stress contributes to their replicative longevity. Surprisingly, this leadoff is positively correlated with an inverse measure of endogenous mitotic asymmetry, indicating a trade-off between mitotic asymmetry and cell's ability to fend off hydrogen peroxide induced oxidative stress. Overall, our results demonstrate strong associations of oxidative stress to genomic instability and mitotic asymmetry at the population level of budding yeast.

  19. NF1 gene mutations and loss of heterozygosity in constitutional and tumor tissues

    SciTech Connect

    Abernathy, C.R.; Colman, S.D.; Ho, V.T.

    1994-09-01

    Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder characterized by neurofibromas, cafe-au-lait spots, and Lisch nodules. NF1 patients are at increased risk for certain types of malignancies such as brain tumors, sarcomas, and leukemias. NF1 is caused by disrupting mutations of the NF1 gene (17q11.2), with half of cases caused by new mutation. Less than 50 constitutional mutations have thus far been reported, with only one recurring. We are pursuing mutation analysis in germline and tumor tissues from NF1 patients (and non-NF1 tumors) by heteroduplex analysis (HDA) and SSCP, simultaneously testing for large deletions by Southern blots and loss-of-heterozygosity (LOH) studies. HDA has so far identified 18 exon mutations/variants in 110 unrelated patients (3/4 of exons tested), including splice mutations, insertions, deletions, and point changes. RT-PCR analysis in our four clearly-inactivating mutations showed that all four mutant alleles are expressed. This suggests that aberrant forms of the protein (neurofibromin) may be produced, which may shed light on yet-unknown functions. In a study of 10 new-mutations parent-child sets, one very mildly-affected patient showed LOH of an entire NF1 allele, in contrast to other patients reported who have similar deletions and a severe phenotype. This mutation is materally-derived, which is unusual given that over 90% of new mutations are thought to be of paternal origin. Preliminary LOH studies in one new-mutation patient indicate large independent somatic deletions involving the maternal NF1 allele in several neurofibromas, implicating the two-hit tumor suppressor system in neurofibroma formation. no other losses on chromosome 17 are evident, and blood and tumor karyotypes are normal. We are attempting to identify the germline mutation, confirm the somatic findings, and find the boundaries of the deletions.

  20. Hydrogen peroxide induced loss of heterozygosity correlates with replicative lifespan and mitotic asymmetry in Saccharomyces cerevisiae

    PubMed Central

    Jackson, Erin D.; Parker, Meighan C.; Gupta, Nilin; Rodrigues, Jenny

    2016-01-01

    Cellular aging in Saccharomyces cerevisiae can lead to genomic instability and impaired mitotic asymmetry. To investigate the role of oxidative stress in cellular aging, we examined the effect of exogenous hydrogen peroxide on genomic instability and mitotic asymmetry in a collection of yeast strains with diverse backgrounds. We treated yeast cells with hydrogen peroxide and monitored the changes of viability and the frequencies of loss of heterozygosity (LOH) in response to hydrogen peroxide doses. The mid-transition points of viability and LOH were quantified using sigmoid mathematical functions. We found that the increase of hydrogen peroxide dependent genomic instability often occurs before a drop in viability. We previously observed that elevation of genomic instability generally lags behind the drop in viability during chronological aging. Hence, onset of genomic instability induced by exogenous hydrogen peroxide treatment is opposite to that induced by endogenous oxidative stress during chronological aging, with regards to the midpoint of viability. This contrast argues that the effect of endogenous oxidative stress on genome integrity is well suppressed up to the dying-off phase during chronological aging. We found that the leadoff of exogenous hydrogen peroxide induced genomic instability to viability significantly correlated with replicative lifespan (RLS), indicating that yeast cells’ ability to counter oxidative stress contributes to their replicative longevity. Surprisingly, this leadoff is positively correlated with an inverse measure of endogenous mitotic asymmetry, indicating a trade-off between mitotic asymmetry and cell’s ability to fend off hydrogen peroxide induced oxidative stress. Overall, our results demonstrate strong associations of oxidative stress to genomic instability and mitotic asymmetry at the population level of budding yeast. PMID:27833823

  1. Recurrent 1; 17 translocations in human neuroblastoma reveal nonhomologous mitotic recombination during the S/G2 phase as a novel mechanism for loss of heterozygosity

    SciTech Connect

    Caron, H.; Sluis, P. van; Westerveld, A.; Slater, R.; Versteeg, R.; Kraker, J. de; Voute, P.A. ); Roy, N. van; Speleman, F.

    1994-08-01

    Neuroblastomas often show loss of heterozygosity of the chromosomal region 1p36 (LOH 1p), probably reflecting loss of a tumor-suppressor gene. Here the authors describe three neuroblastoma tumors and two cell lines in which LOH 1p results from an unbalanced translocation between the p arm of chromosome 1 and the q arm of chromosome 17. Southern blot and cytogenetic analyses show that in all cases the chromosome 17 homologue from which the 1;17 translocation was derived is still present and intact. This suggests a model in which a translocation between the short arm of chromosome 1 and the long arm of chromosome 17 takes place in the S/G2 phase of the cell cycle and results in LOH 1p. Nonhomologous mitotic recombination in the S/G2 phase is a novel mechanism of LOH. 24 refs., 5 figs., 1 tab.

  2. Loss of heterozygosity at the FLCN locus in early renal cystic lesions in dogs with renal cystadenocarcinoma and nodular dermatofibrosis.

    PubMed

    Bønsdorff, Tina B; Jansen, Johan H; Thomassen, Ragnar F; Lingaas, Frode

    2009-05-01

    Small, macroscopically visible cysts on the surface of the kidneys were observed in eight 6-8-week-old puppies diagnosed with renal cystadenocarcinoma and nodular dermatofibrosis (RCND). Histologic examination of the renal cortices in these puppies reveals numerous small cystic tubular changes. Hyperplastic change of the epithelial lining of cysts is frequently observed. By laser-capture microdissection we have sampled epithelial cells from such early renal cystic lesions in eight paternal half-sibs diagnosed with RCND. DNA was obtained from the laser-captured material, and all coding exons of the germline-mutated FLCN gene were sequenced to detect putative second hits. Samples from 31 independent hyperplastic epithelial cell sections of tubular microcysts of the RCND siblings were examined as well as normal control samples of the tissue sections. Loss of heterozygosity was detected in 35% of the transformed samples. The frequently observed loss of heterozygosity at the FLCN locus in atypical epithelial cells lining the cysts suggests that loss of heterozygosity/function of the FLCN gene may contribute to neoplastic transformation of renal epithelial cells at a very early age of RCND-affected dogs. The transformed renal epithelial cells seem to grow slowly in young puppies, which indicates that other mutational events are required for the development of tumors in adult dogs.

  3. Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma.

    PubMed

    Kakar, Sanjay; Deng, Guoren; Smyrk, Thomas C; Cun, Lisa; Sahai, Vaibhav; Kim, Young S

    2012-07-01

    The relationship of molecular abnormalities with clinicopathologic features and survival in colorectal signet ring cell carcinoma, and its comparison with mucinous and conventional adenocarcinomas, has not been well studied. High-level microsatellite instability, loss of heterozygosity (LOH) at four loci, CpG island methylation phenotype based on seven loci, BRAF V600E mutation and KRAS mutation in signet ring cell carcinoma were compared with mucinous and conventional adenocarcinomas. The relationship of these molecular features in signet ring cell carcinoma with clinicopathologic features and survival was examined. LOH was observed in 93% of signet ring cell carcinomas compared with 62 and 70% of mucinous and conventional adenocarcinomas. Also, 80% of signet ring cell carcinomas with high-level microsatellite instability showed LOH compared with 14% each of mucinous and conventional adenocarcinomas. High-level microsatellite instability, CpG island methylation phenotype-positive status and BRAF V600E mutation were more often seen in signet ring cell carcinoma and mucinous adenocarcinoma compared with conventional adenocarcinoma. BRAF V600E mutation was significantly associated with CpG island methylation phenotype-positive status. Stage and BRAF V600E mutation in microsatellite-stable cases were the only variables with an affect on survival. In conclusion, chromosomal instability manifested by LOH is nearly a universal finding in signet ring cell carcinoma, including cases with high-level microsatellite instability. This may explain the aggressive behavior of signet ring cell carcinoma irrespective of high-level microsatellite-instability status. BRAF V600E mutation and CpG island methylation phenotype-positive status are similar in signet ring cell carcinoma and mucinous adenocarcinoma but more frequent when compared with conventional adenocarcinoma. In signet ring cell carcinoma, BRAF V600E mutation adversely affects survival in microsatellite-stable tumors

  4. Mitotic crossover promotes leukemogenesis in children born with TEL-AML1 via the generation of loss of heterozygosity at 12p.

    PubMed

    Ivanovski, Ivan; Garavelli, Livia; Djurić, Olivera; Ćirović, Aleksandar; Škorić, Dejan; Ivanovski, Petar I

    2015-06-30

    TEL-AML1 (ETV6-RUNX1) fusion gene which is formed prenatally in 1% of the newborns, is a common genetic abnormality in childhood Bcell precursor acute lymphoblastic leukemia. But only one child out of a hundred children born with this fusion gene develops leukemia (bottleneck phenomenon) later in its life, if contracts the second mutation. In other words, out of a hundred children born with TEL-AML1 only one child is at risk for leukemia development, which means that TEL-AML1 fusion gene is not sufficient for overt leukemia. There is a stringent requirement for a second genetic abnormality for leukemia development and this is the real or the ultimate cause of the leukemia bottleneck phenomenon. In most cases of TEL-AML1+ leukemia, the translocation t(12;21) is complemented with the loss of the normal TEL gene, not involved in the translocation, on the contralateral 12p. The loss of the normal TEL gene, i.e. loss of heterozygosity at 12p, occurs postnatally during the mitotic proliferation of TEL-AML1+ cell in the mitotic crossing over process. Mitotic crossing over is a very rare event with a frequency rate of 10-6 in a 10 kb region. The exploration and identification of the environmental exposure(s) that cause(s) proliferation of the TELAML1+ cell in which approximately 106 mitoses are generated to cause 12p loss of heterozygosity, i.e. TEL gene deletion, may contribute to the introduction of preventive measures for leukemia.

  5. Loss of heterozygosity at chromosome 9p21 is a frequent finding in enteropathy-type T-cell lymphoma.

    PubMed

    Obermann, E C; Diss, T C; Hamoudi, R A; Munson, P; Wilkins, B S; Camozzi, M L P; Isaacson, P G; Du, M Q; Dogan, A

    2004-02-01

    Enteropathy-type T-cell lymphoma (ETL) and ulcerative jejunitis (UJ) are rare disorders often occurring in patients with coeliac disease. The genetic events associated with the accumulation of intraepithelial lymphocytes in coeliac disease and tumour development are largely unknown. Deletions at chromosome 9p21, which harbours the tumour suppressor genes p14/ARF, p15/INK4b, and p16/INK4a, and 17p13, where p53 is located, are associated with the development and progression of lymphomas. To examine whether deletions at 9p21 and 17p13 play a role in ETL, 22 cases of ETL and seven cases of UJ were screened for loss of heterozygosity (LOH) by tissue microdissection and polymerase chain reaction (PCR) analysis for microsatellite markers. Furthermore, p53 and p16 protein expression was examined by immunohistochemistry. In addition, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis for detection of mutations in exons 5-8 of the p53 gene was performed in five cases of ETL and three cases of UJ. LOH was found in at least one microsatellite marker at the 9p21 locus in 8 of 22 (36%) ETLs, but not in UJ. Five of nine (56%) tumours composed of large cells showed LOH at 9p21, as opposed to two of eight (25%) tumours with small- or medium-sized cell morphology. The region spanning the p14/p15/p16 gene locus was most frequently affected (five cases); LOH at these markers coincided with loss of p16 protein expression in all of these cases. p53 overexpression was demonstrated in all ETLs examined and in four of seven cases of UJ. However, no alterations of the p53 gene were detected by LOH or PCR-SSCP analysis. The results of this study show that LOH at chromosome 9p21 is frequent in ETL, especially in tumours with large cell morphology; this finding suggests that gene loss at this locus may play a role in the development of ETL.

  6. GPHMM: an integrated hidden Markov model for identification of copy number alteration and loss of heterozygosity in complex tumor samples using whole genome SNP arrays

    PubMed Central

    Li, Ao; Liu, Zongzhi; Lezon-Geyda, Kimberly; Sarkar, Sudipa; Lannin, Donald; Schulz, Vincent; Krop, Ian; Winer, Eric; Harris, Lyndsay; Tuck, David

    2011-01-01

    There is an increasing interest in using single nucleotide polymorphism (SNP) genotyping arrays for profiling chromosomal rearrangements in tumors, as they allow simultaneous detection of copy number and loss of heterozygosity with high resolution. Critical issues such as signal baseline shift due to aneuploidy, normal cell contamination, and the presence of GC content bias have been reported to dramatically alter SNP array signals and complicate accurate identification of aberrations in cancer genomes. To address these issues, we propose a novel Global Parameter Hidden Markov Model (GPHMM) to unravel tangled genotyping data generated from tumor samples. In contrast to other HMM methods, a distinct feature of GPHMM is that the issues mentioned above are quantitatively modeled by global parameters and integrated within the statistical framework. We developed an efficient EM algorithm for parameter estimation. We evaluated performance on three data sets and show that GPHMM can correctly identify chromosomal aberrations in tumor samples containing as few as 10% cancer cells. Furthermore, we demonstrated that the estimation of global parameters in GPHMM provides information about the biological characteristics of tumor samples and the quality of genotyping signal from SNP array experiments, which is helpful for data quality control and outlier detection in cohort studies. PMID:21398628

  7. Length and loss of heterozygosity of an intron 1 polymorphic sequence of egfr is related to cytogenetic alterations and epithelial growth factor receptor expression.

    PubMed

    Buerger, H; Gebhardt, F; Schmidt, H; Beckmann, A; Hutmacher, K; Simon, R; Lelle, R; Boecker, W; Brandt, B

    2000-02-15

    Overexpression of epithelial growth factor receptor (EGFR) is correlated with a poor prognosis and reduced steroid receptor expression. Recently, it was demonstrated that the length of a CA repeat in the intron 1 of EGFR correlated with the expression of EGFR in vitro. We investigated 112 cases of cancerous and noncancerous breast tumor samples for loss of heterozygosity (LOH) in intron 1 of the egfr gene and determined the intratumoral EGFR content and genetic alterations by comparative genomic hybridization. Heterozygous tumors with short CA repeats showed elevated EGFR expression in contrast to tumors with longer CA repeats. Tumors with LOH in intron 1 of egfr revealed higher EGFR expression when the longer allele was lost compared with loss of the shorter allele. Additionally, tumors with a loss of the long allele showed more chromosomal alterations, especially a higher frequency of amplifications. We conclude that the CA repeat status in intron 1 of the egfr gene also modulates the intratumoral EGFR content in vivo. Furthermore, LOH at the CA repeat is associated with genetically advanced tumors. Therefore, allele-specific gene expression due to LOH of the CA repeat could be assumed to be an important event in invasive breast cancer development.

  8. Distinctive clinical presentation of a NF-1 patient with loss of heterozygosity of PTCH in his epithelial tumors.

    PubMed

    Jacobson, Elizabeth; Toms, Catherine; Huang, Conway; Skelton, Henry; Smith, Kathleen

    2005-10-01

    Although patients with neurofibromatosis (NF) have an increased incidence of tumors, there is only one study that suggests that NF1 patients may have an increased risk for epithelial malignancies. We present a patient with known NF1 who had developed multiple epithelial tumors since early in his life. All but one of these tumors were morphologically most consistent with trichoepitheliomas. Loss of heterozygosity (LOH) for Patched 1 gene (PTCH) was demonstrated within two of the trichoepitheloma-like tumors and one tumor diagnosed as basal cell carcinoma, and the patient was show to have a PTCH gene deletion. To our knowledge, a patient presenting with both NF1 and multiple trichoepitheliomas (MTE) has not previously been reported. The dysregulation in cellular proliferation and signaling induced by decreased NF1 along with the PTCH gene mutation may explain the pattern of immunohistochemical staining within these tumors, and the rare association of NF1 with epithelial neoplasms.

  9. False homozygous HLA genotyping results due to copy number neutral loss of heterozygosity in acquired aplastic anaemia.

    PubMed

    Heyrman, Bert; De Becker, Ann; Verheyden, Sonja; Demanet, Christian

    2017-03-02

    The aim of this case report is to draw attention on possible false human leucocyte antigen (HLA) genotyping in acquired aplastic anaemia prior to allogeneic haematopoietic stem cell transplantation. In acquired aplastic anaemia loss of heterozygosity (LOH) of chromosome 6p is known to occur in around 12%. We report false HLA genotyping results due to LOH and a coinciding steep rise in neutrophils following filgrastim stimulation in a patient with very severe aplastic anaemia. At diagnosis we obtained heterozygous results on peripheral blood. Failing to reach a partial response at 6 months with immune-suppressive therapy we repeated HLA genotyping, obtaining homozygous results. Repeated testing confirmed loss of HLA genotype heterozygosity. HLA genotyping on cells obtained by a buccal swab confirmed the previous HLA heterozygosity. A second course of filgrastim at the time of homozygous HLA genotyping resulted in a steep rise in neutrophils. Stopping filgrastim resulted in an equally steep drop.

  10. Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity

    PubMed Central

    Baker, Darren J.; Jin, Fang; Jeganathan, Karthik B.; van Deursen, Jan M.

    2010-01-01

    Summary Genetic alterations that promote chromosome missegregation have been proposed to drive tumorigenesis through loss of whole chromosomes containing key tumor suppressor genes. To test this unproven idea, we bred Bub1 mutant mice that inaccurately segregate their chromosomes onto p53+/−, ApcMin/+, Rb+/− or Pten+/− backgrounds. Bub1 insufficiency predisposed p53+/− mice to thymic lymphomas and ApcMin/+ mice to colonic tumors. These tumors consistently lacked the non-mutated tumor suppressor allele, but had gained a copy of the mutant allele. In contrast, Bub1 insufficiency had no impact on tumorigenesis in Rb+/− mice and inhibited prostatic intraepithelial neoplasia formation in Pten+/− mice. Thus, Bub1 insufficiency can drive tumor formation through tumor suppressor gene loss of heterozygosity, but only in restricted genetic and cellular contexts. PMID:19962666

  11. Detection of loss of heterozygosity in formalin-fixed paraffin-embedded tumor specimens by the polymerase chain reaction.

    PubMed Central

    Bianchi, A. B.; Navone, N. M.; Conti, C. J.

    1991-01-01

    A polymerase chain reaction-based procedure was used for the detection of DNA length polymorphisms generated by naturally occurring genetic deletions or insertions of known sequence. This method consists of a simple one-step assay that does not require any restriction enzyme analysis or Southern blot hybridization, allowing identification in ethidium bromide-stained gels. The procedure described here was used to detect loss of heterozygosity at various loci, including the Hbb beta-globin gene cluster, in chemically induced mouse skin tumors, using a variety of tissue preparations, including microdissection of formalin-fixed, paraffin-embedded specimens, short-term cultures, and fluorescence-activated cell sorting of epithelial populations. This approach may be useful in detecting tumor-specific reduction to homozygosity at polymorphic chromosomal loci, allowing the mapping of putative tumor-suppressor loci involved in carcinogenesis. Images Figure 2 Figure 3 Figure 4 Figure 5 PMID:1992758

  12. High-Resolution Genome-Wide Analysis of Irradiated (UV and γ-Rays) Diploid Yeast Cells Reveals a High Frequency of Genomic Loss of Heterozygosity (LOH) Events

    PubMed Central

    St. Charles, Jordan; Hazkani-Covo, Einat; Yin, Yi; Andersen, Sabrina L.; Dietrich, Fred S.; Greenwell, Patricia W.; Malc, Ewa; Mieczkowski, Piotr; Petes, Thomas D.

    2012-01-01

    In diploid eukaryotes, repair of double-stranded DNA breaks by homologous recombination often leads to loss of heterozygosity (LOH). Most previous studies of mitotic recombination in Saccharomyces cerevisiae have focused on a single chromosome or a single region of one chromosome at which LOH events can be selected. In this study, we used two techniques (single-nucleotide polymorphism microarrays and high-throughput DNA sequencing) to examine genome-wide LOH in a diploid yeast strain at a resolution averaging 1 kb. We examined both selected LOH events on chromosome V and unselected events throughout the genome in untreated cells and in cells treated with either γ-radiation or ultraviolet (UV) radiation. Our analysis shows the following: (1) spontaneous and damage-induced mitotic gene conversion tracts are more than three times larger than meiotic conversion tracts, and conversion tracts associated with crossovers are usually longer and more complex than those unassociated with crossovers; (2) most of the crossovers and conversions reflect the repair of two sister chromatids broken at the same position; and (3) both UV and γ-radiation efficiently induce LOH at doses of radiation that cause no significant loss of viability. Using high-throughput DNA sequencing, we also detected new mutations induced by γ-rays and UV. To our knowledge, our study represents the first high-resolution genome-wide analysis of DNA damage-induced LOH events performed in any eukaryote. PMID:22267500

  13. Large proportion of low frequency microsatellite-instability and loss of heterozygosity in pheochromocytoma and endocrine tumors detected with an extended marker panel.

    PubMed

    Kupka, Susan; Haack, Birgit; Zdichavsky, Marty; Mlinar, Tanja; Kienzle, Christine; Bock, Thomas; Kandolf, Reinhard; Kroeber, Stefan-Martin; Königsrainer, Alfred

    2008-04-01

    Pheochromocytoma (PCC) is a usually benign tumor originated in the majority of patients from the adrenal medulla. Regarding sporadic forms of PCC, mechanisms of pathogenesis are largely unknown. Recently, microsatellite-instability (MSI) was discussed as genetic factor contributing to PCC development. Since microsatellite markers used for MSI detection have only been recommended for colorectal carcinoma (CRC), we established an extended marker set for MSI detection in PCC. Twenty-two PCC patients were analyzed applying 11 microsatellite markers. Our marker set comprised the reference panel for CRC and six additional markers, which have already been described to detect MSI in tumors other than CRC. Moreover, 23 endocrine tumors with gastrointestinal origin were examined in order to test the applicability of this marker panel. Microsatellite-instability was detected in 41% of PCCs. Twenty-seven percent showed loss of heterozygosity (LOH) events affecting different chromosomal regions. Among the 23 patients with endocrine tumors, only three (one pancreatic endocrine tumor, one duodenal neuro-endocrine tumor, one hepatic metastasis of a primary tumor with unknown origin) demonstrated MSI. The extended microsatellite panel is qualified to detect MSI in PCC. Nine percent of MSI-positive cases would have not been noticed by the use of the reference panel alone. PCCs are characterized by low frequency MSI pointing to failures in factors involved in DNA replication.

  14. Recurrent loss of heterozygosity in 1p36 associated with TNFRSF14 mutations in IRF4 translocation negative pediatric follicular lymphomas.

    PubMed

    Martin-Guerrero, Idoia; Salaverria, Itziar; Burkhardt, Birgit; Szczepanowski, Monika; Baudis, Michael; Bens, Susanne; de Leval, Laurence; Garcia-Orad, Africa; Horn, Heike; Lisfeld, Jasmin; Pellissery, Shoji; Klapper, Wolfram; Oschlies, Ilske; Siebert, Reiner

    2013-08-01

    Pediatric follicular lymphoma is a rare disease that differs genetically and clinically from its adult counterpart. With the exception of pediatric follicular lymphoma with IRF4-translocation, the genetic events associated with these lymphomas have not yet been defined. We applied array-comparative genomic hybridization and molecular inversion probe assay analyses to formalin-fixed paraffin-embedded tissues from 18 patients aged 18 years and under with IRF4 translocation negative follicular lymphoma. All evaluable cases lacked t(14;18). Only 6 of 16 evaluable cases displayed chromosomal imbalances with gains or amplifications of 6pter-p24.3 (including IRF4) and deletion and copy number neutral-loss of heterozygosity in 1p36 (including TNFRSF14) being most frequent. Sequencing of TNFRSF14 located in the minimal region of loss in 1p36.32 showed nine mutations in 7 cases from our series. Two subsets of pediatric follicular lymphoma were delineated according to the presence of molecular alterations, one with genomic aberrations associated with higher grade and/or diffuse large B-cell lymphoma component and more widespread disease, and another one lacking genetic alterations associated with more limited disease.

  15. High-resolution genome-wide analysis of irradiated (UV and γ-rays) diploid yeast cells reveals a high frequency of genomic loss of heterozygosity (LOH) events.

    PubMed

    St Charles, Jordan; Hazkani-Covo, Einat; Yin, Yi; Andersen, Sabrina L; Dietrich, Fred S; Greenwell, Patricia W; Malc, Ewa; Mieczkowski, Piotr; Petes, Thomas D

    2012-04-01

    In diploid eukaryotes, repair of double-stranded DNA breaks by homologous recombination often leads to loss of heterozygosity (LOH). Most previous studies of mitotic recombination in Saccharomyces cerevisiae have focused on a single chromosome or a single region of one chromosome at which LOH events can be selected. In this study, we used two techniques (single-nucleotide polymorphism microarrays and high-throughput DNA sequencing) to examine genome-wide LOH in a diploid yeast strain at a resolution averaging 1 kb. We examined both selected LOH events on chromosome V and unselected events throughout the genome in untreated cells and in cells treated with either γ-radiation or ultraviolet (UV) radiation. Our analysis shows the following: (1) spontaneous and damage-induced mitotic gene conversion tracts are more than three times larger than meiotic conversion tracts, and conversion tracts associated with crossovers are usually longer and more complex than those unassociated with crossovers; (2) most of the crossovers and conversions reflect the repair of two sister chromatids broken at the same position; and (3) both UV and γ-radiation efficiently induce LOH at doses of radiation that cause no significant loss of viability. Using high-throughput DNA sequencing, we also detected new mutations induced by γ-rays and UV. To our knowledge, our study represents the first high-resolution genome-wide analysis of DNA damage-induced LOH events performed in any eukaryote.

  16. Hamartomas from patients with tuberous sclerosis show loss of heterozygosity for chromosome 9q34

    SciTech Connect

    Green, A.J.; Sepp, T.; Yates, J.R.W. |

    1994-09-01

    We have previously shown allele loss in hamartomas from cases of tuberous sclerosis (TSC) for markers in the region of the recently characterized TSC2 gene on chromosome 16p13.3. Germline deletions in the TSC2 gene have been shown in 5% of patients with TSC. These data strongly suggest that the TSC2 gene acts as a tumor suppressor gene. We hypothesised that hamartomas from patients with TSC can also show allele loss for markers on chromosome 9q34 in the region of the TSC1 gene. We studied 7 hamartomas (3 renal angiomyolipomas, 3 giant cell astrocytomas, and a cardiac rhabdomyoma) from 7 cases of TSC, none of which showed allele loss for markers on chromosome 16p13.3. Eight microsatellite markers were analyzed, comprising from centromeric to telomeric, ASS - D9S64 - D9S149 -D9S150 - DBH - D9S66 - D9S114 - D9S67. Two hamartomas (one renal angiomyolipoma and one giant cell astrocytoma) showed allele loss for at least two markers. The region of allele loss involved the TSC1 locus, but did not include D9S149 or D9S67. We have shown allele loss in two of seven TSC hamartomas in the region of the TSC1 gene on 9q34. Based on this deletion mapping, we suggest that the TSC1 gene on 9a34, like the TSC2 gene, acts as a tumor suppressor gene.

  17. p53 loss-of-heterozygosity is a necessary prerequisite for mutant p53 stabilization and gain-of-function in vivo.

    PubMed

    Alexandrova, Evguenia M; Mirza, Safia A; Xu, Sulan; Schulz-Heddergott, Ramona; Marchenko, Natalia D; Moll, Ute M

    2017-03-09

    Missense mutations in TP53 comprise >75% of all p53 alterations in cancer, resulting in highly stabilized mutant p53 proteins that not only lose their tumor-suppressor activity, but often acquire oncogenic gain-of-functions (GOFs). GOF manifests itself in accelerated tumor onset, increased metastasis, increased drug resistance and shortened survival in patients and mice. A known prerequisite for GOF is mutant p53 protein stabilization, which itself is linked to aberrant protein conformation. However, additional determinants for mutant p53 stabilization likely exist. Here we show that in initially heterozygous mouse tumors carrying the hotspot GOF allele R248Q (p53Q/+), another necessary prerequisite for mutant p53 stabilization and GOF in vivo is loss of the remaining wild-type p53 allele, termed loss-of-heterozygosity (LOH). Thus, in mouse tumors with high frequency of p53 LOH (osteosarcomas and fibrosarcomas), we find that mutant p53 protein is stabilized (16/17 cases, 94%) and tumor onset is significantly accelerated compared with p53+/- tumors (GOF). In contrast, in mouse tumors with low frequency of p53 LOH (MMTV-Neu breast carcinomas), mutant p53 protein is not stabilized (16/20 cases, 80%) and GOF is not observed. Of note, human genomic databases (TCGA, METABRIC etc.) show a high degree of p53 LOH in all examined tumor types that carry missense p53 mutations, including sarcomas and breast carcinomas (with and without HER2 amplification). These data - while cautioning that not all genetic mouse models faithfully represent the human situation - demonstrate for the first time that p53 LOH is a critical prerequisite for missense mutant p53 stabilization and GOF in vivo.

  18. Comprehensive SNP array study of frequently used neuroblastoma cell lines; copy neutral loss of heterozygosity is common in the cell lines but uncommon in primary tumors

    PubMed Central

    2011-01-01

    Background Copy neutral loss of heterozygosity (CN-LOH) refers to a special case of LOH occurring without any resulting loss in copy number. These alterations is sometimes seen in tumors as a way to inactivate a tumor suppressor gene and have been found to be important in several types of cancer. Results We have used high density single nucleotide polymorphism arrays in order to investigate the frequency and distribution of CN-LOH and other allelic imbalances in neuroblastoma (NB) tumors and cell lines. Our results show that the frequency of these near-CN-LOH events is significantly higher in the cell lines compared to the primary tumors and that the types of CN-LOH differ between the groups. We also show that the low-risk neuroblastomas that are generally considered to have a "triploid karyotype" often present with a complex numerical karyotype (no segmental changes) with 2-5 copies of each chromosome. Furthermore a comparison has been made between the three related cell lines SK-N-SH, SH-EP and SH-SY5Y with respect to overall genetic aberrations, and several aberrations unique to each of the cell lines has been found. Conclusions We have shown that the NB tumors analyzed contain several interesting allelic imbalances that would either go unnoticed or be misinterpreted using other genome-wide techniques. These findings indicate that the genetics underlying NB might be even more complex than previously known and that SNP arrays are important analysis tools. We have also showed that these near-CN-LOH events are more frequently seen in NB cell lines compared to NB tumors and that a set of highly related cell lines have continued to evolve secondary to the subcloning event. Taken together our analysis highlights that cell lines in many cases differ substantially from the primary tumors they are thought to represent, and that caution should be taken when drawing conclusions from cell line-based studies. PMID:21899760

  19. Genome Sequencing and Mapping Reveal Loss of Heterozygosity as a Mechanism for Rapid Adaptation in the Vegetable Pathogen Phytophthora capsici

    SciTech Connect

    Lamour, Kurt H.; Mudge, Joann; Gobena, Daniel; Hurtado-Gonzales, Oscar P.; Schmutz, Jeremy; Kuo, Alan; Miller, Neil A.; Rice, Brandon J.; Raffaele, Sylvain; Cano, Liliana M.; Bharti, Arvind K.; Donahoo, Ryan S.; Finely, Sabra; Huitema, Edgar; Hulvey, Jon; Platt, Darren; Salamov, Asaf; Savidor, Alon; Sharma, Rahul; Stam, Remco; Sotrey, Dylan; Thines, Marco; Win, Joe; Haas, Brian J.; Dinwiddie, Darrell L.; Jenkins, Jerry; Knight, James R.; Affourtit, Jason P.; Han, Cliff S.; Chertkov, Olga; Lindquist, Erika A.; Detter, Chris; Grigoriev, Igor V.; Kamoun, Sophien; Kingsmore, Stephen F.

    2012-02-07

    The oomycete vegetable pathogen Phytophthora capsici has shown remarkable adaptation to fungicides and new hosts. Like other members of this destructive genus, P. capsici has an explosive epidemiology, rapidly producing massive numbers of asexual spores on infected hosts. In addition, P. capsici can remain dormant for years as sexually recombined oospores, making it difficult to produce crops at infested sites, and allowing outcrossing populations to maintain significant genetic variation. Genome sequencing, development of a high-density genetic map, and integrative genomic or genetic characterization of P. capsici field isolates and intercross progeny revealed significant mitotic loss of heterozygosity (LOH) in diverse isolates. LOH was detected in clonally propagated field isolates and sexual progeny, cumulatively affecting >30percent of the genome. LOH altered genotypes for more than 11,000 single-nucleotide variant sites and showed a strong association with changes in mating type and pathogenicity. Overall, it appears that LOH may provide a rapid mechanism for fixing alleles and may be an important component of adaptability for P. capsici.

  20. Genome sequencing and mapping reveal loss of heterozygosity as a mechanism for rapid adaptation in the vegetable pathogen Phytophthora capsici.

    PubMed

    Lamour, Kurt H; Mudge, Joann; Gobena, Daniel; Hurtado-Gonzales, Oscar P; Schmutz, Jeremy; Kuo, Alan; Miller, Neil A; Rice, Brandon J; Raffaele, Sylvain; Cano, Liliana M; Bharti, Arvind K; Donahoo, Ryan S; Finley, Sabra; Huitema, Edgar; Hulvey, Jon; Platt, Darren; Salamov, Asaf; Savidor, Alon; Sharma, Rahul; Stam, Remco; Storey, Dylan; Thines, Marco; Win, Joe; Haas, Brian J; Dinwiddie, Darrell L; Jenkins, Jerry; Knight, James R; Affourtit, Jason P; Han, Cliff S; Chertkov, Olga; Lindquist, Erika A; Detter, Chris; Grigoriev, Igor V; Kamoun, Sophien; Kingsmore, Stephen F

    2012-10-01

    The oomycete vegetable pathogen Phytophthora capsici has shown remarkable adaptation to fungicides and new hosts. Like other members of this destructive genus, P. capsici has an explosive epidemiology, rapidly producing massive numbers of asexual spores on infected hosts. In addition, P. capsici can remain dormant for years as sexually recombined oospores, making it difficult to produce crops at infested sites, and allowing outcrossing populations to maintain significant genetic variation. Genome sequencing, development of a high-density genetic map, and integrative genomic or genetic characterization of P. capsici field isolates and intercross progeny revealed significant mitotic loss of heterozygosity (LOH) in diverse isolates. LOH was detected in clonally propagated field isolates and sexual progeny, cumulatively affecting >30% of the genome. LOH altered genotypes for more than 11,000 single-nucleotide variant sites and showed a strong association with changes in mating type and pathogenicity. Overall, it appears that LOH may provide a rapid mechanism for fixing alleles and may be an important component of adaptability for P. capsici.

  1. Population polymorphism of nuclear mitochondrial DNA insertions reveals widespread diploidy associated with loss of heterozygosity in Debaryomyces hansenii.

    PubMed

    Jacques, Noémie; Sacerdot, Christine; Derkaoui, Meriem; Dujon, Bernard; Ozier-Kalogeropoulos, Odile; Casaregola, Serge

    2010-03-01

    Debaryomyces hansenii, a yeast that participates in the elaboration of foodstuff, displays important genetic diversity. Our recent phylogenetic classification of this species led to the subdivision of the species into three distinct clades. D. hansenii harbors the highest number of nuclear mitochondrial DNA (NUMT) insertions known so far for hemiascomycetous yeasts. Here we assessed the intraspecific variability of the NUMTs in this species by testing their presence/absence first in 28 strains, with 21 loci previously detected in the completely sequenced strain CBS 767(T), and second in a larger panel of 77 strains, with 8 most informative loci. We were able for the first time to structure populations in D. hansenii, although we observed little NUMT insertion variability within the clades. We determined the chronology of the NUMT insertions, which turned out to correlate with the previously defined taxonomy and provided additional evidence that colonization of nuclear genomes by mitochondrial DNA is a dynamic process in yeast. In combination with flow cytometry experiments, the NUMT analysis revealed the existence of both haploid and diploid strains, the latter being heterozygous and resulting from at least four crosses among strains from the various clades. As in the diploid pathogen Candida albicans, to which D. hansenii is phylogenetically related, we observed a differential loss of heterozygosity in the diploid strains, which can explain some of the large genetic diversity found in D. hansenii over the years.

  2. Population Polymorphism of Nuclear Mitochondrial DNA Insertions Reveals Widespread Diploidy Associated with Loss of Heterozygosity in Debaryomyces hansenii ▿ †

    PubMed Central

    Jacques, Noémie; Sacerdot, Christine; Derkaoui, Meriem; Dujon, Bernard; Ozier-Kalogeropoulos, Odile; Casaregola, Serge

    2010-01-01

    Debaryomyces hansenii, a yeast that participates in the elaboration of foodstuff, displays important genetic diversity. Our recent phylogenetic classification of this species led to the subdivision of the species into three distinct clades. D. hansenii harbors the highest number of nuclear mitochondrial DNA (NUMT) insertions known so far for hemiascomycetous yeasts. Here we assessed the intraspecific variability of the NUMTs in this species by testing their presence/absence first in 28 strains, with 21 loci previously detected in the completely sequenced strain CBS 767T, and second in a larger panel of 77 strains, with 8 most informative loci. We were able for the first time to structure populations in D. hansenii, although we observed little NUMT insertion variability within the clades. We determined the chronology of the NUMT insertions, which turned out to correlate with the previously defined taxonomy and provided additional evidence that colonization of nuclear genomes by mitochondrial DNA is a dynamic process in yeast. In combination with flow cytometry experiments, the NUMT analysis revealed the existence of both haploid and diploid strains, the latter being heterozygous and resulting from at least four crosses among strains from the various clades. As in the diploid pathogen Candida albicans, to which D. hansenii is phylogenetically related, we observed a differential loss of heterozygosity in the diploid strains, which can explain some of the large genetic diversity found in D. hansenii over the years. PMID:20048048

  3. Genome sequencing and mapping reveal loss of heterozygosity as a mechanism for rapid adaptation in the vegetable pathogen Phytophthora capsici

    PubMed Central

    Lamour, Kurt H.; Mudge, Joann; Gobena, Daniel; Hurtado-Gonzales, Oscar P.; Schmutz, Jeremy; Kuo, Alan; Miller, Neil A.; Rice, Brandon J.; Raffaele, Sylvain; Cano, Liliana M.; Bharti, Arvind K.; Donahoo, Ryan S.; Finley, Sabra; Huitema, Edgar; Hulvey, Jon; Platt, Darren; Salamov, Asaf; Savidor, Alon; Sharma, Rahul; Stam, Remco; Storey, Dylan; Thines, Marco; Win, Joe; Haas, Brian J.; Dinwiddie, Darrell L.; Jenkins, Jerry; Knight, James R.; Affourtit, Jason P.; Han, Cliff S.; Chertkov, Olga; Lindquist, Erika A.; Detter, Chris; Grigoriev, Igor V.; Kamoun, Sophien; Kingsmore, Stephen F.

    2013-01-01

    The oomycete vegetable pathogen Phytophthora capsici has shown remarkable adaptation to fungicides and new hosts. Like other members of this destructive genus, P. capsici has an explosive epidemiology, rapidly producing massive numbers of asexual spores on infected hosts. In addition, P. capsici can remain dormant for years as sexually-recombined oospores, making it difficult to produce crops at infested sites, and allowing outcrossing populations to maintain significant genetic variation. Genome sequencing, development of a high-density genetic map, and integrative genomic/genetic characterization of P. capsici field isolates and intercross progeny revealed significant mitotic loss of heterozygosity (LOH) and higher levels of SNVs than those reported for humans, plants, and P. infestans. LOH was detected in clonally propagated field isolates and sexual progeny, cumulatively affecting >30% of the genome. LOH altered genotypes for more than 11,000 single nucleotide variant (SNV) sites and showed a strong association with changes in mating type and pathogenicity. Overall, it appears that LOH may provide a rapid mechanism for fixing alleles and may be an important component of adaptability for P. capsici. PMID:22712506

  4. Evidence that lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangiomyomatosis.

    PubMed Central

    Smolarek, T A; Wessner, L L; McCormack, F X; Mylet, J C; Menon, A G; Henske, E P

    1998-01-01

    Lymphangiomyomatosis (LAM) is a rare disease, of unknown etiology, affecting women almost exclusively. Lung transplantation is the only consistently effective therapy for LAM. Microscopically, LAM consists of a diffuse proliferation of smooth muscle cells. LAM can occur without evidence of other disease (referred to as "sporadic LAM") or in association with tuberous sclerosis complex (TSC). TSC is an autosomal dominant tumor suppressor gene syndrome characterized by seizures, mental retardation, and tumors in the brain, heart, skin, and kidney. Renal angiomyolipomas occur in approximately 50% of sporadic LAM patients and in 70% of TSC patients. Loss of heterozygosity (LOH) in the chromosomal region for the TSC2 gene occurs in 60% of TSC-associated angiomyolipomas. Because of the similar pulmonary and renal manifestations of TSC and sporadic LAM, we hypothesized that LAM and TSC have a common genetic basis. We analyzed renal angiomyolipomas, from 13 women with sporadic LAM, for LOH in the regions of the TSC1 (chromosome 9q34) and TSC2 (chromosome 16p13) genes. TSC2 LOH was detected in seven (54%) of the angiomyolipomas. We also found TSC2 LOH in four lymph nodes from a woman with retroperitoneal LAM. No TSC1 LOH was found. Our findings indicate that the TSC2 gene may be involved in the pathogenesis of sporadic LAM. However, genetic transmission of LAM has not been reported. Women with LAM may have low-penetrance germ-line TSC2 mutations, or they may be mosaic, with TSC2 mutations in the lung and the kidney but not in other organs. PMID:9529362

  5. Loss of Heterozygosity and Copy Number Abnormality in Clear Cell Renal Cell Carcinoma Discovered by High-Density Affymetrix 10K Single Nucleotide Polymorphism Mapping Array1

    PubMed Central

    Toma, Marieta I; Grosser, Marianne; Herr, Alexander; Aust, Daniela E; Meye, Axel; Hoefling, Christian; Fuessel, Susanne; Wuttig, Daniela; Wirth, Manfred P; Baretton, Gustavo B

    2008-01-01

    Genetic aberrations are crucial in renal tumor progression. In this study, we describe loss of heterozygosity (LOH) and DNA-copy number abnormalities in clear cell renal cell carcinoma (cc-RCC) discovered by genome-wide single nucleotide polymorphism (SNP) arrays. Genomic DNA from tumor and normal tissue of 22 human cc-RCCs was analyzed on the Affymetrix GeneChip Human Mapping 10K Array. The array data were validated by quantitative polymerase chain reaction and immunohistochemistry. Reduced DNA copy numbers were detected on chromosomal arm 3p in 91%, on chromosome 9 in 32%, and on chromosomal arm 14q in 36% of the tumors. Gains were detected on chromosomal arm 5q in 45% and on chromosome 7 in 32% of the tumors. Copy number abnormalities were found not only in FHIT and VHL loci, known to be involved in renal carcinogenesis, but also in regions containing putative new tumor suppressor genes or oncogenes. In addition, microdeletions were detected on chromosomes 1 and 6 in genes with unknown impact on renal carcinogenesis. In validation experiments, abnormal protein expression of FOXP1 (on 3p) was found in 90% of tumors (concordance with SNP array data in 85%). As assessed by quantitative polymerase chain reaction, PARK2 and PACRG were down-regulated in 57% and 100%, respectively, and CSF1R was up-regulated in 69% of the cc-RCC cases (concordance with SNP array data in 57%, 33%, and 38%). Genome-wide SNP array analysis not only confirmed previously described large chromosomal aberrations but also detected novel microdeletions in genes potentially involved in tumor genesis of cc-RCC. PMID:18592004

  6. Allelic loss of chromosomes 16q and 10q in human prostate cancer

    SciTech Connect

    Carter, B.S.; Ewing, C.M.; Ward, W.S.; Treiger, B.F.; Isaacs, W.B.; Epstein, J.I. ); Aalders, T.W.; Schalken, J.A. )

    1990-11-01

    Recent advances in understanding the molecular genetics of common adult tumors have indicated that multiple genetic alterations including the activation of oncogenes and the inactivation of tumor suppressor genes are important in the pathogenesis of these tumors. Loss of heterozygosity is a hallmark of tumor suppressor gene inactivation and has been used to identify chromosomal regions that contain these genes. The authors have examines allelic loss in the most common tumor in men, prostate cancer. Twenty-eight prostate cancer specimens have been examined for loss of heterozygosity at 11 different chromosomal arms including 3p, 7q, 9q, 10p, 10q, 11p, 13q, 16p, 17p, and 18q. Fifty-four percent (13/24) of clinically localized tumors and 4 of 4 metastatic tumors showed loss of heterozygosity on at least one chromosome. Chromosomes 16q and 10q exhibited the highest frequency of loss of heterozygosity with 30% of tumors showing loss at these chromosomes. These data demonstrate that allelic loss is a common event in prostate cancer and suggest that chromosomes 16q and 10q may contain the sites of tumor suppressor genes important in the pathogenesis of human prostate cancer.

  7. Loss of heterozygosity on chromosome 22 in sporadic schwannoma and its relation to the proliferation of tumor cells.

    PubMed

    Bian, Liu-guan; Sun, Qing-fang; Tirakotai, Wuttipong; Zhao, Wei-guo; Shen, Jian-kang; Luo, Qi-zhong; Bertalanffy, Helmut

    2005-09-20

    Schwannoma is the tumor arising mainly from the cranial and spinal nerves. Bilateral vestibular schwannoma is the hallmark of neurofibromatosis type 2 (NF2). The NF2 gene has been cloned with comprehensive analysis of its mutations in schwannoma. However, most studies focused on vestibular schwannoma. There are differences in proliferation of tumor cell and ultrastructure between vestibular and spinal schwannomas. It is unknown whether genetic alterations in vestibular schwannoma are different from those in non-vestibular schwannoma. We analyzed the loss of heterozygosity (LOH) on chromosome 22 in patients with sporadic schwannoma including vestibular and spinal schwannomas and correlated this genetic alteration with tumor proliferation. In 54 unrelated patients without clinical NF1 or NF2, 36 patients had sporadic vestibular schwannoma, and 18 dorsal spinal root schwannoma. Four highly polymorphic linkage to NF2 gene microsatellite DNA markers (D22S264, D22S268, D22S280, CRYB2) were used to analyze LOH. The proliferative index was evaluated by Ki-67 and proliferative cell nuclear antigen (PCNA) immunostaining. Student's t test was used to analyze the difference of the proliferative index between schwannoma with LOH and that without LOH. The difference of the frequency of LOH in vestibular and spinal schwannomas was investigated by the chi-square test. Twenty-three schwannomas (42.6%, 23/54) showed allele loss. The frequency of LOH in vestibular schwannoma was significantly higher than that in spinal schwannoma (chi2 = 5.14, P < 0.05). The proliferative index of schwannoma with LOH was significantly higher than that without LOH (tki-67 = 2.97, P = 0.0045; tPCNA = 2.93, P = 0.0051). LOH on chromosome 22 is a frequent event in the tumorigenesis of sporadic schwannoma. And, there is a correlation between LOH on chromosome 22 and proliferative activity in schwannoma. The frequency of LOH in vestibular schwannoma is significantly different from that in spinal schwannoma.

  8. Single Nucleotide Polymorphism (SNP)-Based Loss of Heterozygosity (LOH) Testing by Real Time PCR in Patients Suspect of Myeloproliferative Disease

    PubMed Central

    Huijsmans, Cornelis J. J.; Poodt, Jeroen; Damen, Jan; van der Linden, Johannes C.; Savelkoul, Paul H. M.; Pruijt, Johannes F. M.; Hilbink, Mirrian; Hermans, Mirjam H. A.

    2012-01-01

    During tumor development, loss of heterozygosity (LOH) often occurs. When LOH is preceded by an oncogene activating mutation, the mutant allele may be further potentiated if the wild-type allele is lost or inactivated. In myeloproliferative neoplasms (MPN) somatic acquisition of JAK2V617F may be followed by LOH resulting in loss of the wild type allele. The occurrence of LOH in MPN and other proliferative diseases may lead to a further potentiating the mutant allele and thereby increasing morbidity. A real time PCR based SNP profiling assay was developed and validated for LOH detection of the JAK2 region (JAK2LOH). Blood of a cohort of 12 JAK2V617F-positive patients (n = 6 25–50% and n = 6>50% JAK2V617F) and a cohort of 81 patients suspected of MPN was stored with EDTA and subsequently used for validation. To generate germ-line profiles, non-neoplastic formalin-fixed paraffin-embedded tissue from each patient was analyzed. Results of the SNP assay were compared to those of an established Short Tandem Repeat (STR) assay. Both assays revealed JAK2LOH in 1/6 patients with 25–50% JAK2V617F. In patients with >50% JAK2V617F, JAK2LOH was detected in 6/6 by the SNP assay and 5/6 patients by the STR assay. Of the 81 patients suspected of MPN, 18 patients carried JAK2V617F. Both the SNP and STR assay demonstrated the occurrence of JAK2LOH in 5 of them. In the 63 JAK2V617F-negative patients, no JAK2LOH was observed by SNP and STR analyses. The presented SNP assay reliably detects JAK2LOH and is a fast and easy to perform alternative for STR analyses. We therefore anticipate the SNP approach as a proof of principle for the development of LOH SNP-assays for other clinically relevant LOH loci. PMID:22768290

  9. Single nucleotide polymorphism (SNP)-based loss of heterozygosity (LOH) testing by real time PCR in patients suspect of myeloproliferative disease.

    PubMed

    Huijsmans, Cornelis J J; Poodt, Jeroen; Damen, Jan; van der Linden, Johannes C; Savelkoul, Paul H M; Pruijt, Johannes F M; Hilbink, Mirrian; Hermans, Mirjam H A

    2012-01-01

    During tumor development, loss of heterozygosity (LOH) often occurs. When LOH is preceded by an oncogene activating mutation, the mutant allele may be further potentiated if the wild-type allele is lost or inactivated. In myeloproliferative neoplasms (MPN) somatic acquisition of JAK2V617F may be followed by LOH resulting in loss of the wild type allele. The occurrence of LOH in MPN and other proliferative diseases may lead to a further potentiating the mutant allele and thereby increasing morbidity. A real time PCR based SNP profiling assay was developed and validated for LOH detection of the JAK2 region (JAK2LOH). Blood of a cohort of 12 JAK2V617F-positive patients (n=6 25-50% and n=6>50% JAK2V617F) and a cohort of 81 patients suspected of MPN was stored with EDTA and subsequently used for validation. To generate germ-line profiles, non-neoplastic formalin-fixed paraffin-embedded tissue from each patient was analyzed. Results of the SNP assay were compared to those of an established Short Tandem Repeat (STR) assay. Both assays revealed JAK2LOH in 1/6 patients with 25-50% JAK2V617F. In patients with >50% JAK2V617F, JAK2LOH was detected in 6/6 by the SNP assay and 5/6 patients by the STR assay. Of the 81 patients suspected of MPN, 18 patients carried JAK2V617F. Both the SNP and STR assay demonstrated the occurrence of JAK2LOH in 5 of them. In the 63 JAK2V617F-negative patients, no JAK2LOH was observed by SNP and STR analyses. The presented SNP assay reliably detects JAK2LOH and is a fast and easy to perform alternative for STR analyses. We therefore anticipate the SNP approach as a proof of principle for the development of LOH SNP-assays for other clinically relevant LOH loci.

  10. Genome-wide analysis of loss of heterozygosity in breast infiltrating ductal carcinoma distant normal tissue highlights arm specific enrichment and expansion across tumor stages.

    PubMed

    Ruan, Xiaoyang; Liu, Hongfang; Boardman, Lisa; Kocher, Jean-Pierre A

    2014-01-01

    Studies have shown concurrent loss of heterozygosity (LOH) in breast infiltrating ductal carcinoma (IDC) and adjacent or distant normal tissue. However, the overall extent of LOH in normal tissue and their significance to tumorigenesis remain unknown, as existing studies are largely based on selected microsatellite markers. Here we present the first autosome-wide study of LOH in IDC and distant normal tissue using informative loci deduced from SNP array-based and sequencing-based techniques. We show a consistently high LOH concurrence rate in IDC (mean = 24%) and distant normal tissue (m = 54%), suggesting for most patients (31/33) histologically normal tissue contains genomic instability that can be a potential marker of increased IDC risk. Concurrent LOH is more frequent in fragile site related genes like WWOX (9/31), NTRK2 (10/31), and FHIT (7/31) than traditional genetic markers like BRCA1 (0/23), BRCA2 (2/29) and TP53 (1/13). Analysis at arm level shows distant normal tissue has low level but non-random enrichment of LOH (topped by 8p and 16q) significantly correlated with matched IDC (Pearson r = 0.66, p = 3.5E-6) (topped by 8p, 11q, 13q, 16q, 17p, and 17q). The arm-specific LOH enrichment was independently observed in tumor samples from 548 IDC patients when stratified by tumor size based T stages. Fine LOH structure from sequencing data indicates LOH in low order tissues non-randomly overlap (∼67%) with LOH that usually has longer tract length (the length of genomic region affected by LOH) in high order tissues. The consistent observations from multiple datasets suggest progressive LOH in the development of IDC potentially through arm-specific pile up effect with discernible signature in normal tissue. Our finding also suggests that LOH detected in IDC by comparing to paired adjacent or distant normal tissue are more likely underestimated.

  11. Loss of heterozygosity on chromosome 22 in ovarian carcinoma is distal to and is not accompanied by mutations in NF2 at 22q12.

    PubMed Central

    Englefield, P.; Foulkes, W. D.; Campbell, I. G.

    1994-01-01

    Frequent loss of heterozygosity (LOH) has been reported on 22q in ovarian carcinoma, implying the presence of a tumour-suppressor gene. The neurofibromatosis type 2 gene (NF2) at 22q12 is a plausible candidate. Analysis of 9 of the 17 exons of NF2 by single-strand conformational polymorphism (SSCP) in 67 ovarian carcinomas did not detect any somatic mutations, suggesting that NF2 is not involved in the pathogenesis of ovarian carcinoma. LOH data support this conclusion and that the putative tumour-suppressor gene lies distal to NF2, beyond D22S283. Images Figure 1 PMID:7947096

  12. Allele Imbalance or Loss of Heterozygosity, in Normal Appearing Breast Epithelium as a Novel Biomarker to Predict Future Breast Cancer

    DTIC Science & Technology

    2011-07-10

    from present genomic study Summary 24 cases were rejected after tissue blocks were cut and the H& E stains were examined ( i.e., too few TDLUs...manner in which the tissue was preserved ( i.e., cassettes couldn’t fit into microtome) DNA analyzd but reject Tissue cut and rejected after H& E ...control study. The NHS-BBD study consists of a subset of women enrolled in the NHS. Cases are wom en with breast ca ncer diagnosed by June 1, 1995

  13. Prognostic Significance of Loss-of-Heterozygosity of the CUTL1 Putative Tumor Suppressor Gene in Breast Cancers

    DTIC Science & Technology

    1999-07-01

    Nam Sung Moona, Nathalie Martin-Soudanta, Ginette B1rub~a, Lam Leduya, and Alain Nepveua,c,* aMolecular Oncology Group, Departments of Medicine...was pre- pared and used in RNase mapping analysis using 30 pg of total RNA from human placenta as well as Hel , 293 and HeLa cell lines. The same amount

  14. Prognostic Significance of Loss-of-Heterozygosity of the CUTL1 Putative Tumor Suppressor Gene in Breast Cancers

    DTIC Science & Technology

    2000-08-01

    the CUTLI gene Wendy Rong Zeng a Erinn Soucie a, 1, Nam Sung Moon a, Nathalie Martin-Soudant a, Ginette B rub6 a, Lam Leduy a, Alain Nepveu a,b...prepared and used in RNase mapping analysis using 30 jg of total RNA from human placenta as well as Hel , 293 and HeLa cell lines. The same amount of

  15. Clinical significance of previously cryptic copy number alterations and loss of heterozygosity in pediatric acute myeloid leukemia and myelodysplastic syndrome determined using combined array comparative genomic hybridization plus single-nucleotide polymorphism microarray analyses.

    PubMed

    Koh, Kyung-Nam; Lee, Jin Ok; Seo, Eul Ju; Lee, Seong Wook; Suh, Jin Kyung; Im, Ho Joon; Seo, Jong Jin

    2014-07-01

    The combined array comparative genomic hybridization plus single-nucleotide polymorphism microarray (CGH+SNP microarray) platform can simultaneously detect copy number alterations (CNA) and copy-neutral loss of heterozygosity (LOH). Eighteen children with acute myeloid leukemia (AML) (n=15) or myelodysplastic syndrome (MDS) (n=3) were studied using CGH+SNP microarray to evaluate the clinical significance of submicroscopic chromosomal aberrations. CGH+SNP microarray revealed CNAs at 14 regions in 9 patients, while metaphase cytogenetic (MC) analysis detected CNAs in 11 regions in 8 patients. Using CGH+SNP microarray, LOHs>10 Mb involving terminal regions or the whole chromosome were detected in 3 of 18 patients (17%). CGH+SNP microarray revealed cryptic LOHs with or without CNAs in 3 of 5 patients with normal karyotypes. CGH+SNP microarray detected additional cryptic CNAs (n=2) and LOHs (n=5) in 6 of 13 patients with abnormal MC. In total, 9 patients demonstrated additional aberrations, including CNAs (n=3) and/or LOHs (n=8). Three of 15 patients with AML and terminal LOH>10 Mb demonstrated a significantly inferior relapse-free survival rate (P=0.041). This study demonstrates that CGH+SNP microarray can simultaneously detect previously cryptic CNAs and LOH, which may demonstrate prognostic implications.

  16. Loss of heterozygosity on chromosome 11q13 in two families with acromegaly/gigantism is independent of mutations of the multiple endocrine neoplasia type I gene.

    PubMed

    Gadelha, M R; Prezant, T R; Une, K N; Glick, R P; Moskal, S F; Vaisman, M; Melmed, S; Kineman, R D; Frohman, L A

    1999-01-01

    Familial acromegaly/gigantism occurring in the absence of multiple endocrine neoplasia type I (MEN-1) or the Carney complex has been reported in 18 families since the biochemical diagnosis of GH excess became available, and the genetic defect is unknown. In the present study we examined 2 unrelated families with isolated acromegaly/gigantism. In family A, 3 of 4 siblings were affected, with ages at diagnosis of 19, 21, and 23 yr. In family B, 5 of 13 siblings exhibited the phenotype and were diagnosed at 13, 15, 17, 17, and 24 yr of age. All 8 affected patients had elevated basal GH levels associated with high insulin-like growth factor I levels and/or nonsuppressible serum GH levels during an oral glucose tolerance test. GHRH levels were normal in affected members of family A. An invasive macroadenoma was found in 6 subjects, and a microadenoma was found in 1 subject from family B. The sequence of the GHRH receptor complementary DNA in 1 tumor from family A was normal. There was no history of consanguinity in either family, and the past medical history and laboratory results excluded MEN-1 and the Carney complex in all affected and unaffected screened subjects. Five of 8 subjects have undergone pituitary surgery to date, and paraffin-embedded pituitary blocks were available for analysis. Loss of heterozygosity on chromosome 11q13 was studied by comparing microsatellite polymorphisms of leukocyte and tumor DNA using PYGM (centromeric) and D11S527 (telomeric), markers closely linked to the MEN-1 tumor suppressor gene. All tumors exhibited a loss of heterozygosity at both markers. Sequencing of the MEN-1 gene revealed no germline mutations in either family, nor was a somatic mutation found in tumor DNA from one subject in family A. The integrity of the MEN-1 gene in this subject was further supported by demonstration of the presence of MEN-1 messenger ribonucleic acid, as assessed by RT-PCR. These data indicate that loss of heterozygosity in these affected family

  17. High frequency of loss of heterozygosity at 11p15 and IGF2 overexpression are not related to clinical outcome in childhood adrenocortical tumors positive for the R337H TP53 mutation.

    PubMed

    Rosati, Roberto; Cerrato, Flavia; Doghman, Mabrouka; Pianovski, Mara A D; Parise, Guilherme A; Custódio, Gislaine; Zambetti, Gerard P; Ribeiro, Raul C; Riccio, Andrea; Figueiredo, Bonald C; Lalli, Enzo

    2008-10-01

    A germline TP53 R337H mutation is present in childhood adrenocortical tumors (ACT) from southern Brazil. Other genetic alterations are also frequently found in these tumors. This study was designed to assess whether alterations of the 11p15 region exist in childhood ACT, accounting for IGF2 overexpression in these tumors, and how they are related to clinical outcome. Tumor DNA of 12 children with ACT (4 adenomas and 8 carcinomas) and from the blood of their parents was analyzed. All patients showed 11p15 loss of heterozygosity (LOH) in the tumor. In contrast to the single case of paternal LOH, IGF2 was overexpressed in tumors with maternal allele loss. Our data show that 11p15 LOH is a widespread finding in childhood ACT not related with malignancy, contrary to adult ACT. Alterations in the expression of other genes in the same region (e.g., CDKN1C) may contribute to ACT tumorigenesis. (c)2008 Elsevier Inc. All rights reserved.

  18. Using promoter replacement and selection for loss of heterozygosity to generate an industrially applicable sake yeast strain that homozygously overproduces isoamyl acetate.

    PubMed

    Sahara, Hiroshi; Kotaka, Atsushi; Kondo, Akihiko; Ueda, Mitsuyoshi; Hata, Yoji

    2009-11-01

    By application of the high-efficiency loss of heterozygosity (HELOH) method for disrupting genes in diploid sake yeast (Kotaka et al., Appl. Microbiol. Biotechnol., 82, 387-395 (2009)), we constructed, from a heterozygous integrant, a homozygous diploid that overexpresses the alcohol acetyltransferase gene ATF2 from the SED1 promoter, without the need for sporulation and mating. Under the conditions of sake brewing, the homozygous integrant produced 1.4 times more isoamyl acetate than the parental, heterozygous strain. Furthermore, the homozygous integrant was more genetically stable than the heterozygous recombinant. Thus, the HELOH method can produce homozygous, recombinant sake yeast that is ready to be grown on an industrial scale using the well-established procedures of sake brewing. The HELOH method, therefore, facilitates genetic modification of this rarely sporulating diploid yeast strain while maintaining those characteristics required for industrial applications.

  19. Somatic loss of heterozygosity, but not haploinsufficiency alone, leads to full-blown autoimmune lymphoproliferative syndrome in 1 of 12 family members with FAS start codon mutation.

    PubMed

    Hauck, Fabian; Magerus-Chatinet, Aude; Vicca, Stephanie; Rensing-Ehl, Anne; Roesen-Wolff, Angela; Roesler, Joachim; Rieux-Laucat, Frédéric

    2013-04-01

    We describe a family with 12 members carrying a heterozygous germline FAS c.3G>T start codon mutation leading to FAS haploinsufficiency. One patient had autoimmune lymphoproliferative syndrome (ALPS), one had recovered from ALPS, and ten mutation-positive relatives (MPRs) were healthy. FAS-mediated apoptosis and surface expression of FAS in single-positive T cells were lower for MPRs but did not discriminate between them and the ALPS patient. However, double-negative (DN) T cells of the ALPS patient had no FAS expression due to somatic loss of heterozygosity. Our results in this kindred suggest that FAS haploinsufficiency does not cause ALPS-FAS, but that modifying genetic events are crucial for its pathogenesis. FAS surface expression on DN T cells should be assessed routinely and FAS haploinsufficient patients should be followed as its potential for lymphomagenesis is not well defined and a second hit might occur later on.

  20. Loss of heterozygosity and mutation analysis of the p16 (9p21) and p53 (17p13) genes in squamous cell carcinoma of the head and neck.

    PubMed

    González, M V; Pello, M F; López-Larrea, C; Suárez, C; Menéndez, M J; Coto, E

    1995-09-01

    We analyzed allelic loss at the p53 gene (17p13) and at chromosome region 9p21 in 35 primary head and neck squamous cell carcinomas. Loss of heterozygosity (LOH) at p53 and 9p21 was found in 50 and 75% of informative cases, respectively. LOH at the p53 gene did not increase significantly with tumor stage, but was more frequent in moderately and poorly differentiated tumors than in well-differentiated tumors. LOH plus mutation or homozygous deletion of p53 was limited to advanced stage and poorly differentiated tumors. Allelic loss at 9p21 is frequent in early stage head and neck squamous cell carcinoma and is not significantly associated with LOH at p53. The second exon of the p16/MTS1/CDKN2 gene was found to be homozygously deleted in 1 of 19 cases showing LOH at 9p21, but direct sequencing did not show mutations in the remaining 18 cases. This suggests that p16 plays a limited role in the development of head and neck squamous cell carcinoma.

  1. Microsatellite Instability and Loss of Heterozygosity at Chromosomal Location 18q: Prospective Evaluation of Biomarkers for Stages II and III Colon Cancer—A Study of CALGB 9581 and 89803

    PubMed Central

    Bertagnolli, Monica M.; Redston, Mark; Compton, Carolyn C.; Niedzwiecki, Donna; Mayer, Robert J.; Goldberg, Richard M.; Colacchio, Thomas A.; Saltz, Leonard B.; Warren, Robert S.

    2011-01-01

    Purpose Colorectal cancer (CRC) develops as a result of a series of accumulated genomic changes that produce oncogene activation and tumor suppressor gene loss. These characteristics may classify CRC into subsets of distinct clinical behaviors. Patients and Methods We studied two of these genomic defects—mismatch repair deficiency (MMR-D) and loss of heterozygosity at chromosomal location 18q (18qLOH)—in patients enrolled onto two phase III cooperative group trials for treatment of potentially curable colon cancer. These trials included prospective secondary analyses to determine the relationship between these markers and treatment outcome. A total of 1,852 patients were tested for MMR status and 955 (excluding patients with MMR-D tumors) for 18qLOH. Results Compared with stage III, more stage II tumors were MMR-D (21.3% v 14.4%; P < .001) and were intact at 18q (24.2% v 15.1%; P = .001). For the combined cohort, patients with MMR-D tumors had better 5-year disease-free survival (DFS; 0.76 v 0.67; P < .001) and overall survival (OS; 0.81 v 0.78; P = .029) than those with MMR intact (MMR-I) tumors. Among patients with MMR-I tumors, the status of 18q did not affect outcome, with 5-year values for patients with 18q intact versus 18qLOH tumors of 0.74 versus 0.65 (P = .18) for DFS and 0.81 versus 0.77 (P = .18) for OS. Conclusion We conclude that MMR-D tumor status, but not the presence of 18qLOH, has prognostic value for stages II and III colon cancer. PMID:21747089

  2. Three tumor-suppressor regions on chromosome 11p identified by high-resolution deletion mapping in human non-small-cell lung cancer

    SciTech Connect

    Bepler, G.; Garcia-Blanco, A. )

    1994-06-07

    Non-small-cell lung cancer is the leading cause of cancer death for men and women in the industrialized nations. Identification of regions for genes involved in its pathogenesis has been difficult. Data presented here show three distinct regions identified on chromosome 11p. Two regions on 11p13 distal to the Wilms tumor gene WT1 and on 11p15.5 between the markers HBB and D11S860 are described. The third region on the telomere of 11p15.5 has been previously described and is further delineated in this communication. By high-resolution mapping the size of each of these regions was estimated to be 2-3 megabases. The frequency of somatic loss of genetic information in these regions (57%, 71%, and 45%, respectively) was comparable to that seen in heritable tumors such as Wilms tumor (55%) and retinoblastoma (70%) and suggests their involvement in pathogenesis of non-small-cell lung cancer. Gene dosage analyses revealed duplication of the remaining allele in the majority of cases in the 11p13 and the proximal 11p15.5 region but rarely in the distal 11p15.5 region. In tumors with loss of heterozygosity in all three regions any combination of duplication or simple deletion was observed, suggesting that loss of heterozygosity occurs independently and perhaps at different points in time. These results provide a basis for studies directed at cloning potential tumor-suppressor genes in these regions and for assessing their biological and clinical significance in non-small-cell lung cancer.

  3. Cost-Effectiveness Analysis of Using Loss of Heterozygosity to Manage Premalignant Oral Dysplasia in British Columbia, Canada.

    PubMed

    Cromwell, Ian; Regier, Dean A; Peacock, Stuart J; Poh, Catherine F

    2016-09-01

    Management of low-grade oral dysplasias (LGDs) is complicated, as only a small percentage of lesions will progress to invasive disease. The current standard of care requires patients to undergo regular monitoring of their lesions, with intervention occurring as a response to meaningful clinical changes. Recent improvements in molecular technologies and understanding of the biology of LGDs may allow clinicians to manage lesions based on their genome-guided risk. We used a decision-analytic Markov model to estimate the cost-effectiveness of risk-stratified care using a genomic assay. In the experimental arm, patients with LGDs were managed according to their risk profile using the assay, with low- and intermediate-risk patients given longer screening intervals and high-risk patients immediately treated with surgery. Patients in the comparator arm had standard care (biannual follow-up appointments at an oral cancer clinic). Incremental costs and outcomes in life-years gained (LYG) and quality-adjusted life-years (QALY) were calculated based on the results in each arm. The mean cost of assay-guided management was $8,123 (95% confidence interval [CI] $2,973 to $23,062 in 2013 Canadian dollars) less than the cost of standard care. This difference was driven largely by reductions in resource use among people who did not develop cancer. Mean incremental effectiveness was 0.18 LYG (95% CI 0.08 to 0.39) or 0.64 QALY (95% CI 0.46 to 0.89). Sensitivity analysis suggests that these findings are robust to both expected and extreme variation in all parameter values. Use of the assay-guided management strategy costs less and is more effective than standard management of LGDs. The findings of this study strongly suggest that the use of a risk-stratification method such as a genomic assay can result in improved quality-adjusted survival outcomes for patients with low-grade oral dysplasia (LGD). The use of such an assay in this study provides "precision medicine," allowing for a

  4. Cost-Effectiveness Analysis of Using Loss of Heterozygosity to Manage Premalignant Oral Dysplasia in British Columbia, Canada

    PubMed Central

    Regier, Dean A.; Peacock, Stuart J.; Poh, Catherine F.

    2016-01-01

    Background. Management of low-grade oral dysplasias (LGDs) is complicated, as only a small percentage of lesions will progress to invasive disease. The current standard of care requires patients to undergo regular monitoring of their lesions, with intervention occurring as a response to meaningful clinical changes. Recent improvements in molecular technologies and understanding of the biology of LGDs may allow clinicians to manage lesions based on their genome-guided risk. Methods. We used a decision-analytic Markov model to estimate the cost-effectiveness of risk-stratified care using a genomic assay. In the experimental arm, patients with LGDs were managed according to their risk profile using the assay, with low- and intermediate-risk patients given longer screening intervals and high-risk patients immediately treated with surgery. Patients in the comparator arm had standard care (biannual follow-up appointments at an oral cancer clinic). Incremental costs and outcomes in life-years gained (LYG) and quality-adjusted life-years (QALY) were calculated based on the results in each arm. Results. The mean cost of assay-guided management was $8,123 (95% confidence interval [CI] $2,973 to $23,062 in 2013 Canadian dollars) less than the cost of standard care. This difference was driven largely by reductions in resource use among people who did not develop cancer. Mean incremental effectiveness was 0.18 LYG (95% CI 0.08 to 0.39) or 0.64 QALY (95% CI 0.46 to 0.89). Sensitivity analysis suggests that these findings are robust to both expected and extreme variation in all parameter values. Conclusion. Use of the assay-guided management strategy costs less and is more effective than standard management of LGDs. Implications for Practice: The findings of this study strongly suggest that the use of a risk-stratification method such as a genomic assay can result in improved quality-adjusted survival outcomes for patients with low-grade oral dysplasia (LGD). The use of such an

  5. Loss of heterozygosity for the NF2 gene in retinal and optic nerve lesions of patients with neurofibromatosis 2

    PubMed Central

    Chan, Chi-Chao; Koch, Christian A; Kaiser-Kupfer, Muriel I; Parry, Dilys M; Gutmann, David H; Zhuang, Zhengping; Vortmeyer, Alexander O

    2008-01-01

    Individuals affected with the neurofibromatosis 2 (NF2) cancer predisposition syndrome develop specific ocular lesions. To determine whether these lesions result from altered NF2 gene expression, microdissection and PCR were used to investigate 40 ocular lesions from seven eyes of four NF2 patients for LOH, with markers that flank the NF2 gene on chromosome 22q. NF2 protein (merlin) expression was also evaluated in these lesions, using immunohistochemistry. Retinal hamartoma was observed in all seven eyes, including one with combined pigment epithelial and retinal hamartoma (CPERH). Retinal tufts were present in four eyes (three patients), retinal dysplasia in two eyes (two patients), optic nerve neurofibroma in one eye, iris naevoid hyperplasia in two eyes (two patients) and pseudophakia in all eyes. Markers were informative in three patients (six eyes from three unrelated families). One patient was non-informative due to prolonged decalcification. All retinal and optic nerve, but not iris lesions, demonstrated consistent LOH for the NF2 gene. Merlin was not expressed in the retina, optic nerve, or iris lesions. These results suggest that inactivation of the NF2 gene is associated with the formation of a variety of retinal and optic nerve lesions in NF2 patients. PMID:12210058

  6. The Clark Phase-able Sample Size Problem: Long-Range Phasing and Loss of Heterozygosity in GWAS

    NASA Astrophysics Data System (ADS)

    Halldórsson, Bjarni V.; Aguiar, Derek; Tarpine, Ryan; Istrail, Sorin

    A phase transition is taking place today. The amount of data generated by genome resequencing technologies is so large that in some cases it is now less expensive to repeat the experiment than to store the information generated by the experiment. In the next few years it is quite possible that millions of Americans will have been genotyped. The question then arises of how to make the best use of this information and jointly estimate the haplotypes of all these individuals. The premise of the paper is that long shared genomic regions (or tracts) are unlikely unless the haplotypes are identical by descent (IBD), in contrast to short shared tracts which may be identical by state (IBS). Here we estimate for populations, using the US as a model, what sample size of genotyped individuals would be necessary to have sufficiently long shared haplotype regions (tracts) that are identical by descent (IBD), at a statistically significant level. These tracts can then be used as input for a Clark-like phasing method to obtain a complete phasing solution of the sample. We estimate in this paper that for a population like the US and about 1% of the people genotyped (approximately 2 million), tracts of about 200 SNPs long are shared between pairs of individuals IBD with high probability which assures the Clark method phasing success. We show on simulated data that the algorithm will get an almost perfect solution if the number of individuals being SNP arrayed is large enough and the correctness of the algorithm grows with the number of individuals being genotyped.

  7. Loss of p53 in esophageal squamous cell carcinoma and the correlation with survival: analyses of gene mutations, protein expression, and loss of heterozygosity in Japanese patients.

    PubMed

    Egashira, Akinori; Morita, Masaru; Yoshida, Rintaro; Saeki, Hiroshi; Oki, Eiji; Sadanaga, Noriaki; Kakeji, Yoshihiro; Tsujitani, Shun-Ichi; Maehara, Yoshihiko

    2011-08-01

    A high frequency of p53 protein expression or gene mutation has been reported in the early stages of esophageal squamous cell carcinoma (ESCC), and thus loss of p53 function is thought to be very important in esophageal carcinogenesis. However, there is controversy surrounding the correlation between p53 dysfunction and ESCC tumor progression. The complexity arises from the different modalities, such as mutation analysis, immunohistochemistry, and the detection of loss of heterozygosity (LOH) at the p53 genomic locus. In this study, we comprehensively analyzed p53 gene mutation, p53 protein expression, and LOH at 17p13 in 94 surgically resected Japanese cases of ESCC. The frequency of p53 gene mutation was 60.6%. The rate of positive p53 protein expression was 56.4%. The frequency of LOH at 17p13 was 67.5%. There was a statistically significant correlation between the presence of a gene mutation and LOH, whereas, there was no significant correlation between gene mutation and protein expression. Despite the importance of loss of p53 function in esophageal carcinogenesis, none of the examined parameters, either singly or combined, correlated with overall survival. Taken together, p53 function is a primary target for esophageal carcinogenesis but there is no apparent correlation with the malignant phenotype in ESCC. Copyright © 2011 Wiley-Liss, Inc.

  8. Correlation of histomorphologic prognostic markers and proliferative index with loss of heterozygosity 1p/19q and MGMT status in diffusely infiltrating gliomas.

    PubMed

    Deb, Prabal; Mani, N S; Sudumbrekar, S M; Taneja, Nitin; Patrikar, Seema

    2013-07-01

    Loss of heterozygosity (LOH)1p/19q, and epigenetic silencing of O(6)-methylguanine-DNAmethyltransferase (MGMT) gene, displayed promising role as predictive and prognostic markers in brain tumours. The present study correlated both with conventional histomorphologic prognostic markers and proliferative index in diffusely infiltrating gliomas (DIG). Tissues from 45 patients were evaluated for LOH1p/19q using polymerase chain reaction based microsatellite analysis; and for MGMT using immunohistochemistry. Results were correlated with age, histologic type, WHO grade, and proliferation index. Mean MIB-1 LI showed significant correlation with tumour grade. MGMT-staining in grade II and IV tumours were 31.1% and 16.8%, respectively, while in DA and GBM it was 88.2% and 19.0%, respectively, which were statistically significant. Sixteen cases showed LOH 1p and/or 19q of which 10 (5 oligodendroglial, 3 GBM, AA, DA) had combined LOH; while three each showed 1p (all GBM) and 19q (2 DA and GBM) loss. In the MIB-1LI ≤ 5% and >5% groups LOH 1p and/or 19q was encountered in 6 and 10 cases, respectively. A significant inverse association was noted between LOH with MGMT. LOH1p/19q and MGMT shows good correlation with conventional histomorphologic and proliferation markers, and should constitute part of the optimal diagnostic workup of DIG.

  9. Acquired copy-neutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPL-mutated myeloproliferative neoplasms.

    PubMed

    Rumi, Elisa; Pietra, Daniela; Guglielmelli, Paola; Bordoni, Roberta; Casetti, Ilaria; Milanesi, Chiara; Sant'Antonio, Emanuela; Ferretti, Virginia; Pancrazzi, Alessandro; Rotunno, Giada; Severgnini, Marco; Pietrelli, Alessandro; Astori, Cesare; Fugazza, Elena; Pascutto, Cristiana; Boveri, Emanuela; Passamonti, Francesco; De Bellis, Gianluca; Vannucchi, Alessandro; Cazzola, Mario

    2013-05-23

    We studied mutations of MPL exon 10 in patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF), first investigating a cohort of 892 consecutive patients. MPL mutation scanning was performed on granulocyte genomic DNA by using a high-resolution melt assay, and the mutant allele burden was evaluated by using deep sequencing. Somatic mutations of MPL, all but one involving codon W515, were detected in 26/661 (4%) patients with ET, 10/187 (5%) with PMF, and 7/44 (16%) patients with post-ET myelofibrosis. Comparison of JAK2 (V617F)-mutated and MPL-mutated patients showed only minor phenotypic differences. In an extended group of 62 MPL-mutated patients, the granulocyte mutant allele burden ranged from 1% to 95% and was significantly higher in patients with PMF or post-ET myelofibrosis compared with those with ET. Patients with higher mutation burdens had evidence of acquired copy-neutral loss of heterozygosity (CN-LOH) of chromosome 1p in granulocytes, consistent with a transition from heterozygosity to homozygosity for the MPL mutation in clonal cells. A significant association was found between MPL-mutant allele burden greater than 50% and marrow fibrosis. These observations suggest that acquired CN-LOH of chromosome 1p involving the MPL location may represent a molecular mechanism of fibrotic transformation in MPL-mutated myeloproliferative neoplasms.

  10. Acquired copy-neutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPL-mutated myeloproliferative neoplasms

    PubMed Central

    Pietra, Daniela; Guglielmelli, Paola; Bordoni, Roberta; Casetti, Ilaria; Milanesi, Chiara; Sant’Antonio, Emanuela; Ferretti, Virginia; Pancrazzi, Alessandro; Rotunno, Giada; Severgnini, Marco; Pietrelli, Alessandro; Astori, Cesare; Fugazza, Elena; Pascutto, Cristiana; Boveri, Emanuela; Passamonti, Francesco; De Bellis, Gianluca; Vannucchi, Alessandro; Cazzola, Mario

    2013-01-01

    We studied mutations of MPL exon 10 in patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF), first investigating a cohort of 892 consecutive patients. MPL mutation scanning was performed on granulocyte genomic DNA by using a high-resolution melt assay, and the mutant allele burden was evaluated by using deep sequencing. Somatic mutations of MPL, all but one involving codon W515, were detected in 26/661 (4%) patients with ET, 10/187 (5%) with PMF, and 7/44 (16%) patients with post-ET myelofibrosis. Comparison of JAK2 (V617F)–mutated and MPL-mutated patients showed only minor phenotypic differences. In an extended group of 62 MPL-mutated patients, the granulocyte mutant allele burden ranged from 1% to 95% and was significantly higher in patients with PMF or post-ET myelofibrosis compared with those with ET. Patients with higher mutation burdens had evidence of acquired copy-neutral loss of heterozygosity (CN-LOH) of chromosome 1p in granulocytes, consistent with a transition from heterozygosity to homozygosity for the MPL mutation in clonal cells. A significant association was found between MPL-mutant allele burden greater than 50% and marrow fibrosis. These observations suggest that acquired CN-LOH of chromosome 1p involving the MPL location may represent a molecular mechanism of fibrotic transformation in MPL-mutated myeloproliferative neoplasms. PMID:23575445

  11. Screening for RB1 mutations in tumor tissue using denaturing high performance liquid chromatography, multiplex ligation-dependent probe amplification, and loss of heterozygosity analysis.

    PubMed

    Sellner, Loryn N; Edkins, Edward; Smith, Nicholas

    2006-01-01

    Retinoblastoma is a malignant retinal neoplasm arising in infancy as a result of inactivating mutations in both alleles of the retinoblastoma susceptibility gene, RB1. Identification of the causative RB1 mutations in a patient assists in the clinical management of the affected patient and risk assessment of family members, principally on the basis of whether there is a germline mutation. In this paper, we describe our experience with molecular analysis of RB1 mutations in tumor and nontumor samples from 18 retinoblastoma patients, using multiplex ligation dependent probe amplification (MLPA) to detect large deletions or duplications, microsatellite analysis to detect loss of heterozygosity (LOH), and denaturing high performance liquid chromatography (D-HPLC) analysis to detect point mutations and small insertions or deletions. We found LOH in 71% of all cases, and 83% of these were due to acquired isodisomy rather than chromosomal deletions. Small mutations identified by D-HPLC accounted for 78% of the non-LOH mutations, and large deletions/duplications detected by MLPA accounted for the remaining 22%. We give the first report of a large, multiexon duplication in RB1 of exons 8 to 18.

  12. Collision of extensive exocrine and neuroendocrine neoplasms in multiple endocrine neoplasia type 1 revealed by cytogenetic analysis of loss of heterozygosity: a case report.

    PubMed

    Moriyoshi, Koki; Minamiguchi, Sachiko; Miyagawa-Hayashino, Aya; Fujimoto, Masakazu; Kawaguchi, Michiya; Haga, Hironori

    2013-09-01

    The combination of exocrine and neuroendocrine neoplasms is rarely found in the pancreas. These combined lesions vary from a clonal tumor with mixed differentiation to the incidental co-existence of two or more independent tumors, but the differential diagnosis is sometimes difficult. Here we report a case of multiple endocrine neoplasia type 1 (MEN1) with extensive ductal and neuroendocrine neoplastic changes. These two types of tumors admixed markedly in some parts, which made it difficult to determine the pathological diagnosis based on histological findings. Cytogenetic analysis showed that loss of heterozygosity (LOH) of the MEN1 locus exists in neuroendocrine but not in exocrine neoplasms, indicating that independent mechanisms of tumorigenesis may occur in these two types of tumors. This case shows the usefulness of cytogenetic analysis for the diagnosis of combined tumors of the pancreas. Extensive exocrine neoplastic change, including pancreatic intraepithelial neoplasia (PanIN) in virtually all pancreatic ducts and a focus of intraductal papillary mucinous neoplasm (IPMN) with focal invasion, was a distinguishing feature of the present case. The possible association of ductal tumorigenesis and a MEN1 background is discussed.

  13. Concurrence of B-lymphoblastic leukemia and myeloproliferative neoplasm with copy neutral loss of heterozygosity at chromosome 1p harboring a MPL W515S mutation.

    PubMed

    Tao, Jiangchuan; Zhang, Xiaohui; Lancet, Jeffrey; Bennett, John M; Cai, Li; Papenhausen, Peter; Moscinski, Lynn; Zhang, Ling

    2014-01-01

    B-lymphoblastic leukemia (B-ALL) is a neoplasm of precursors committed to B-cell lineage, whereas myeloproliferative neoplasm (MPN) is a clonal proliferation derived from myeloid stem cells. Concurrent B-ALL with MPN is uncommon except in the presence of abnormalities of the PDGFRA, PDGFRB, or FGFR1 genes or the BCR-ABL1 fusion gene. Herein, we describe a rare concurrence, B-ALL with MPN without the aforementioned genetic aberrations, in a 64-year-old male patient. The patient was initially diagnosed with B-ALL with normal karyotype and responded well to aggressive chemotherapy but had sustained leukocytosis and splenomegaly. The posttreatment restaging bone marrow was free of B-ALL but remained hypercellular with myeloid predominance. Using a single nucleotide polymorphism microarray study, we identified a copy neutral loss of heterozygosity at the terminus of 1p in the bone marrow samples taken at diagnosis and again at remission, 49% and 100%, respectively. Several additional genetic abnormalities were present in the initial marrow sample but not in the remission marrow samples. Retrospective molecular studies detected a MPL W515S homozygous mutation in both the initial and remission marrows for B-ALL, at 30-40% and 80% dosage effect, respectively. In summary, we present a case of concurrent B-ALL and MPN and demonstrate a stepwise cytogenetic and molecular approach to the final diagnosis.

  14. Chromosome 1q loss of heterozygosity frequently occurs in sporadic insulinomas and is associated with tumor malignancy.

    PubMed

    Yang, Ying-Mai; Liu, Tong-Hua; Chen, Yuan-Jia; Jiang, Wei-Jun; Qian, Jia-Ming; Lu, Xin; Gao, Jie; Wu, Sha-Fei; Sang, Xin-Ting; Chen, Jie

    2005-11-01

    The pathogenesis of sporadic insulinomas is not clear, and there are no reliable genetic determinants that are useful to distinguish malignant and benign forms of this tumor. It was reported that 1q LOH might contribute to pathogenesis in gastrinomas and was correlated with tumor progression. However, little data are available on 1q LOH in sporadic insulinomas. In our study, we determine whether 1q LOH occurs in sporadic insulinomas and is associated with tumor malignancy by performing 1q allelotyping with 17 markers in 40 tumors and pair normal DNA. Thirty-five (88%) insulinomas had 1q LOH. Of the 35 insulinomas with 1q LOH, 14 (40%) had 1q21.3-23.2 LOH over a 7.5 cM region (SRO-1), whereas LOH in 21 tumors (60%) occurred at 1q31.3 over an 11.4 cM area (SRO-2). Of 24 tumors without MEN1 LOH, 20 had either SRO-1 or SRO-2 LOH (83%), whereas in 16 tumors with MEN1 LOH, 9 were shown to have LOH at either SRO-1 or SRO-2 (56%) (p = 0.065). This result suggests that LOH at 2 SRO might be MEN1 gene independent and may contribute to the pathogenesis in a subset of insulinomas without MEN1 gene LOH. The presence of 1q21.3-23.2 LOH is significantly associated with malignancy of insulinomas (p = 0.014). The high frequency of LOH at 1q 21.3-23.2 and 1q31.3 suggests these 2 areas may harbor putative tumor suppressor genes that may play an important role in the tumorigenesis of a subset of insulinomas. LOH at 1q21.3-23.2, which was associated with tumor malignancy, could be one of the genetic markers for identifying malignancy in sporadic insulinomas.

  15. Genomic landscape of copy number variation and copy neutral loss of heterozygosity events in equine sarcoids reveals increased instability of the sarcoid genome.

    PubMed

    Pawlina-Tyszko, Klaudia; Gurgul, Artur; Szmatoła, Tomasz; Ropka-Molik, Katarzyna; Semik-Gurgul, Ewelina; Klukowska-Rötzler, Jolanta; Koch, Christoph; Mählmann, Kathrin; Bugno-Poniewierska, Monika

    2017-09-01

    Although they are the most common neoplasms in equids, sarcoids are not fully characterized at the molecular level. Therefore, the objective of this study was to characterize the landscape of structural rearrangements, such as copy number variation (CNV) and copy neutral loss of heterozygosity (cnLOH), in the genomes of sarcoid tumor cells. This information will not only broaden our understanding of the characteristics of this genome but will also improve the general knowledge of this tumor and the mechanisms involved in its generation. To this end, Equine SNP64K Illumina microarrays were applied along with bioinformatics tools dedicated for signal intensity analysis. The analysis revealed increased instability of the genome of sarcoid cells compared with unaltered skin tissue samples, which was manifested by the prevalence of CNV and cnLOH events. Many of the identified CNVs overlapped with the other research results, but the simultaneously observed variability in the number and sizes of detected aberrations indicated a need for further studies and the development of more reliable bioinformatics algorithms. The functional analysis of genes co-localized with the identified aberrations revealed that these genes are engaged in vital cellular processes. In addition, a number of these genes directly contribute to neoplastic transformation. Furthermore, large numbers of cnLOH events identified in the sarcoids suggested that they may play no less significant roles than CNVs in the carcinogenesis of this tumor. Thus, our results indicate the importance of cnLOH and CNV in equine sarcoid oncogenesis and present a direction of future research. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  16. Bromate induces loss of heterozygosity in the thymidine kinase gene of L5178Y/Tk(+/-)-3.7.2C mouse lymphoma cells.

    PubMed

    Harrington-Brock, Karen; Collard, Deborah D; Chen, Tao

    2003-05-09

    Potassium bromate (KBrO(3)) induces DNA damage and tumors in mice and rats, but is a relatively weak mutagen in microbial assays and the in vitro mammalian Hprt assay. Concern that there may be a human health risk associated with bromate, a disinfectant by-product of ozonation, has accompanied the increasing use of ozonation as an alternative to chlorination for treatment of drinking water. In this study, we have evaluated the mutagenicity of KBrO(3) and sodium bromate (NaBrO(3)) in the Tk gene of mouse lymphoma cells. In contrast to the weak mutagenic activity seen in the previous studies, bromate induced a mutant frequency of over 100 x 10(-6) at 0.6mM with minimal cytotoxicity (70-80% survival) and over 1300 x 10(-6) at 3mM ( approximately 10% survival). The increase in the Tk mutant frequency was primarily due to the induction of small colony of Tk mutants. Loss of heterozygosity (LOH) analysis of 384 mutants from control and 2.7 mM KBrO(3)-treated cells showed that almost all (99%) bromate-induced mutants resulted from LOH, whereas in the control cultures 77% of the Tk mutants were LOH. Our results suggest that bromate is a potent mutagen in the Tk gene of mouse lymphoma cells, and the mechanism of action primarily involves LOH. The ability of the mouse lymphoma assay to detect a wider array of mutational events than the microbial or V79 Hprt assays may account for the potent mutagenic response.

  17. Alpha-1,3-galactosyltransferase-deficient miniature pigs produced by serial cloning using neonatal skin fibroblasts with loss of heterozygosity

    PubMed Central

    Kim, Young June; Ahn, Kwang Sung; Kim, Minjeong; Kim, Min Ju; Ahn, Jin Seop; Ryu, Junghyun; Heo, Soon Young; Park, Sang-Min; Kang, Jee Hyun; Choi, You Jung; Shim, Hosup

    2017-01-01

    Objective Production of alpha-1,3-galactosyltransferase (αGT)-deficient pigs is essential to overcome xenograft rejection in pig-to-human xenotransplantation. However, the production of such pigs requires a great deal of cost, time, and labor. Heterozygous αGT knockout pigs should be bred at least for two generations to ultimately obtain homozygote progenies. The present study was conducted to produce αGT-deficient miniature pigs in much reduced time using mitotic recombination in neonatal ear skin fibroblasts. Methods Miniature pig fibroblasts were transfected with αGT gene-targeting vector. Resulting gene-targeted fibroblasts were used for nuclear transfer (NT) to produce heterozygous αGT gene-targeted piglets. Fibroblasts isolated from ear skin biopsies of these piglets were cultured for 6 to 8 passages to induce loss of heterozygosity (LOH) and treated with biotin-conjugated IB4 that binds to galactose-α-1,3-galactose, an epitope produced by αGT. Using magnetic activated cell sorting, cells with monoallelic disruption of αGT were removed. Remaining cells with LOH carrying biallelic disruption of αGT were used for the second round NT to produce homozygous αGT gene-targeted piglets. Results Monoallelic mutation of αGT gene was confirmed by polymerase chain reaction in fibroblasts. Using these cells as nuclear donors, three heterozygous αGT gene-targeted piglets were produced by NT. Fibroblasts were collected from ear skin biopsies of these piglets, and homozygosity was induced by LOH. The second round NT using these fibroblasts resulted in production of three homozygous αGT knockout piglets. Conclusion The present study demonstrates that the time required for the production of αGT-deficient miniature pigs could be reduced significantly by postnatal skin biopsies and subsequent selection of mitotic recombinants. Such procedure may be beneficial for the production of homozygote knockout animals, especially in species, such as pigs, that require a

  18. Loss of heterozygosity at 9q32-33 (DBC1 locus) in primary non-invasive papillary urothelial neoplasm of low malignant potential and low-grade urothelial carcinoma of the bladder and their associated normal urothelium.

    PubMed

    Lopez-Beltran, A; Alvarez-Kindelan, J; Luque, R J; Blanca, A; Quintero, A; Montironi, R; Cheng, L; Gonzalez-Campora, R; Requena, M J

    2008-07-01

    Tumour recurrence has a major impact on patients with non-invasive papillary urothelial tumours of the bladder. To explore the role of DBC1 (deleted in bladder cancer 1 locus), a candidate tumour suppressor gene located at 9q32-33, as prognostic marker we have performed loss of heterozygosity (LOH) testing in 49 patients with primary papillary urothelial tumours and associated normal urothelium. Data from the 38 tumours and 11 specimens of normal urothelium that were informative in the LOH study (D9S195 marker) showed that LOH in urothelium (45.4%) but not in non-invasive tumours (60.5%) was associated with tumour recurrence (p = 0.026) but not to grade or progression. Also, tumours whose normal urothelium had LOH were larger (p = 0.020) and showed cyclin D1 over-expression (p = 0.032). Non-significant increased expression of p53, p21Waf1, apoptotic index and tumour proliferation, and decreased expression of p27Kip1 or cyclin D3 also characterized tumours whose normal urothelium had LOH. The expression of these G1-S modulators, apoptotic index and tumour proliferation was more heterogeneous in papillary urothelial tumours, irrespective of having retained heterozygosity or LOH. Also, Bax expression decreased in papillary urothelial tumours having LOH (p = 0.0473), but Bcl-2 was unrelated to LOH status. In addition, FGFR3 protein expression decreased in LOH tumours (p = 0.036) and in those having LOH in their normal urothelium (p = 0.022). FGFR3 immunohistochemical expression was validated by western blot in selected cases. The survival analysis selected LOH in normal urothelium as a marker of disease-free survival (log-rank 5.32, p = 0.021), progression-free survival (log-rank 3.97, p = 0.046) and overall survival (log-rank 4.26, p = 0.038); LOH in tumours was significant in progression-free survival (log-rank 3.83, p = 0.042). It is concluded that LOH at the DBC1 locus in normal urothelium seems to be relevant in the prognosis of non-invasive papillary tumours of

  19. Pathogenesis and Consequences of Uniparental Disomy in Cancer

    PubMed Central

    Makishima, Hideki; Maciejewski, Jaroslaw P.

    2012-01-01

    Systematic application of new genome-wide single nucleotide polymorphism arrays has demonstrated that somatically acquired regions of loss of heterozygosity (LOH) without changes in copy number frequently occur in many types of cancer. Until recently, the ubiquity of this type of chromosomal defect had remained unrecognized as it cannot be detected using routine cytogenetic technologies. Random and recurrent patterns of copy-neutral LOH, also referred to as uniparental disomy (UPD), can be found in specific cancer types and probably contribute to clonal outgrowth owing to various mechanisms. In this review we explore the types, topography, genesis, pathophysiological consequences and clinical implications of UPD. PMID:21518781

  20. The Risk and Clinical/Molecular Characteristics of Breast Cancer in Women with Neurofibromatosis Type 1

    DTIC Science & Technology

    2016-03-01

    genotype-breast cancer correlation . WES was attempted to identify breast cancer predisposition in addition to the NF1 gene mutation. Aim 3 is to...pathways was performed on archived tumor blocks. Genome-wide copy number and loss of heterozygosity (LOH) analysis were performed on these tumor...WES); loss of heterozygosity (LOH); copy number variation (CNV); NF1 knockdown cells; senescence, Ras 6 3. ACCOMPLISHMENTS Aim 1: To confirm the

  1. Defining the region(s) of deletion at 6q16-q22 in human prostate cancer.

    PubMed

    Hyytinen, Eija-Riitta; Saadut, Rega; Chen, Ceshi; Paull, Lindsay; Koivisto, Pasi A; Vessella, Robert L; Frierson, Henry F; Dong, Jin-Tang

    2002-07-01

    Deletion of the long arm of chromosome 6 (6q) frequently occurs in many neoplasms, including carcinomas of the prostate and breast and melanoma, suggesting the location of a tumor-suppressor gene or genes at 6q. At present, however, the region of deletion has not been well defined, and the target gene of deletion remains to be identified. In this study, we analyzed 44 primary prostate cancers with 16 polymorphic markers for loss of heterozygosity (LOH) by using PCR-based techniques. We also examined 23 cell lines/xenografts of prostate cancer with 38 markers for LOH by the method of homozygosity mapping of deletion. LOH at 6q16 - q22 was detected in 21 of 44 (48%) primary tumors and in 12 of 23 (52%) cell lines/xenografts. Two regions of LOH were defined. One was 7.5 cM at 6q16 - q21 between markers D6S1716 and D6S1580, and the other was 4.3 cM at 6q22 between D6S261 and D6S1702. Whereas no correlation was found between LOH at 6q16-q22 and patient age at diagnosis or Gleason score, tumors at higher stage appear to have more frequent LOH. These findings suggest that deletion of 6q16 - q22 is a frequent event in prostate cancer, and that the deletion originates from two distinct regions. These results should be useful in identifying the target gene(s) of deletion at 6q.

  2. Submicroscopic deletion of 5q involving tumor suppressor genes (CTNNA1, HSPA9) and copy neutral loss of heterozygosity associated with TET2 and EZH2 mutations in a case of MDS with normal chromosome and FISH results

    PubMed Central

    2014-01-01

    Advances in genome-wide molecular cytogenetics allow identification of novel submicroscopic DNA copy number alterations (aCNAs) and copy-neutral loss of heterozygosity (cnLOH) resulting in homozygosity for known gene mutations in myeloid neoplasms. We describe the use of an oligo-SNP array for genomic profiling of aCNA and cnLOH, together with sequence analysis of recurrently mutated genes, in a patient with myelodysplastic syndrome (MDS) presenting with normal karyotype and FISH results. Oligo-SNP array analysis revealed a hemizygous deletion of 896 kb at chromosome 5q31.2, representing the smallest 5q deletion reported to date. The deletion involved multiple genes, including two tumor suppressor candidate genes (CTNNA1 and HSPA9) that are associated with MDS/AML. The SNP-array study also detected 3 segments of somatic cnLOH: one involved the entire long arm of chromosome 4; the second involved the distal half of the long arm of chromosome 7, and the third encompassed the entire chromosome 22 (UPD 22). Sequence analysis revealed mutations in TET2 (4q), EZH2 (7q), ASXL1 (20q11.21), and RUNX1 (21q22.3). Coincidently, TET2 and EZH2 were located at segments of cnLOH resulting in their homozygosity. Loss of heterozygosity affecting these two chromosomes and mutations in TET2 and EZH2 are indicative of a myelodysplastic syndrome with a poor prognosis. Deletion of the tumor suppressor genes CTNNA1 and HSPA9 is also likely to contribute to a poor prognosis. Furthermore, the original cnLOHs in multiple chromosomes and additional cnLOH 14q in the follow-up study suggest genetic evolution of the disease and poor prognosis. This study attests to the fact that some patients with a myelodysplastic syndrome who exhibit a normal karyotype may have underlying genetic abnormalities detectable by chromosomal microarray and/or targeted mutation analyses. PMID:25177364

  3. Regional cancer pain syndromes.

    PubMed

    Chang, Victor T; Janjan, Nora; Jain, Subash; Chau, Chi

    2006-12-01

    Cancer pain often presents in a body region. This review summarizes articles from 1999-2004 relevant to cancer pain syndromes in the head and neck, chest, back, abdomen, pelvis, and limbs. Although the evidence is limited, progress is being made in further development of the evidence base to support and guide current practice.

  4. Three independently deleted regions at chromosome arm 16q in human prostate cancer: allelic loss at 16q24.1–q24.2 is associated with aggressive behaviour of the disease, recurrent growth, poor differentiation of the tumour and poor prognosis for the patient

    PubMed Central

    Elo, J P; Härkönen, P; Kyllönen, A P; Lukkarinen, O; Vihko, P

    1999-01-01

    Loss of heterozygosity at chromosome arm 16q is a frequent event in human prostate cancer. In this study, loss of heterozygosity at 16q was studied in 44 prostate cancer patients exhibiting various clinical features. Fifteen polymorphic polymerase chain reaction (PCR) markers were used to identify the separately deleted areas and the findings were compared with clinicopathological variables and 5-year survival of the patients. The results indicated that there are at least three independently deleted regions at 16q. Allelic losses at the central and distal areas were associated significantly with aggressive behaviour of the disease (16q24.1–q24.2, P< 0.01, and 16q24.3–qter, P< 0.05), and the central area of deletion was further significantly associated with poorly differentiated tumour cells (P< 0.05) and with recurrent (P< 0.01) growth of the tumour. During the follow-up period, 28% of the patients initially with M0 disease developed distant metastases. Of the patients showing allelic loss at 16q24.1–q24.2, distant metastasis were found in 45% during the 5-year follow-up period, and 31% of the patients showing loss at 16q21.1 also developed distant metastases. After the 5-year follow-up period, 14 (32%) of the patients remained alive, whereas 19 (43%) had died because of their prostate cancer. The overall survival rate of the patients showing allelic loss at 16q21.1 or 16q24.1–q24.2 was significantly lower than that of the patients with retained heterozygosity. © 1999 Cancer Research Campaign PMID:10408707

  5. Transformed aggressive γδ-variant T-cell large granular lymphocytic leukemia with acquired copy neutral loss of heterozygosity at 17q11.2q25.3 and additional aberrations.

    PubMed

    Zhang, Ling; Ramchandren, Radhakrishnan; Papenhausen, Peter; Loughran, Thomas P; Sokol, Lubomir

    2014-09-01

    T-cell large granular lymphocytic leukemia (T-LGLL) is a rare indolent lymphoproliferative disorder characterized by cytopenias, splenomegaly, and various degrees of T-cell lymphocytosis, due to a clonal expansion of CD8-positive cytotoxic T-cells. Phenotypic variants of T-LGLL include CD4(+) /CD8(-) T-cells, with dual CD4(-) /CD8(-) /γδ(+) T-cells being even rarer. Cytogenetic abnormalities in T-LGLL have rarely been reported, and there is scientific debate regarding the existence of aggressive or transformed variants of T-LGLL. We report a patient with T-LGLL, γδ variant, with nearly 20-year-long duration of cytopenias before transformation to an unusual clinical scenario, manifesting with marked lymphocytosis >100 × 10(9) /L and infiltration of lymph nodes, tonsils, and subcutaneous tissue. Single-nucleotide polymorphism assays revealed acquired copy neutral loss of heterozygosity at 17q and deletion of 3p21.31, in addition to trisomy 5, monosomy X, and monosomy 21. These genetic abnormalities provided a better understanding of the molecular nature and the potentiality of disease transformation.

  6. NDST4 Is a Novel Candidate Tumor Suppressor Gene at Chromosome 4q26 and Its Genetic Loss Predicts Adverse Prognosis in Colorectal Cancer

    PubMed Central

    Tzeng, Sheng-Tai; Tsai, Ming-Hong; Chen, Chi-Long; Lee, Jing-Xing; Jao, Tzu-Ming; Yu, Sung-Liang; Yen, Sou-Jhy; Yang, Ya-Chien

    2013-01-01

    Background Genomic deletion at tumor suppressor loci is a common genetic aberration in human cancers. The study aimed to explore candidate tumor suppressor genes at chromosome 4q25-q28.2 and to delineate novel prognostic biomarkers associated with colorectal cancer (CRC). Methods Deletion mapping of chromosome 4q25-q28.2 was conducted in 114 sporadic CRC by loss of heterozygosity study with 11 microsatellite markers. A novel candidate tumor suppressor gene, namely NDST4, was identified at 4q26. Gene expression of NDST4 was investigated in 52 pairs of primary CRC tissues by quantitative reverse transcription-polymerase chain reaction. Allelic loss of NDST4 gene was further determined in 174 colorectal carcinomas by loss of heterozygosity analysis, and then was assessed for clinical relevance. Results One minimal deletion region was delineated between D4S2297 and D4S2303 loci at 4q26, where NDST4 was the only gene that had markedly been downregulated in CRC tumors. By laser capture microdissection, NDST4 RNA expression was demonstrated in colonic epithelial cells, but was undetectable in tumor cells. In total, 30 (57.7%) of 52 colorectal carcinomas showed a dramatic reduction in NDST4 gene expression compared with matched normal mucosae. The genetic loss of NDST4 was significantly associated with advanced pathological stage (P = 0.039) and poorer overall survival of patients (P = 0.036). Conclusions NDST4 gene is a novel candidate tumor suppressor gene in human cancer, and the loss of its function might be involved in CRC progression. In addition, the loss of heterozygosity assay, which was established to determine the allelic loss of NDST4 gene, could be a cost-effective tool for providing a useful biomarker of adverse prognosis in CRC. PMID:23825612

  7. Advances in cancer research. Volume 54

    SciTech Connect

    Vande Woude, G.F. ); Klein, G. )

    1990-01-01

    This book contains articles pertaining to Advances in Cancer Research. Included are the following groups: (1) The Role of DNA Methylation in Cancer, (2) Genetic and Epigenetic Losses of Heterozygosity in Cancer Predisposition and Progression, (3) Genetic and Molecular Studies of Cellular Immortalization.

  8. Is loss of heterozygosity at 9q22.3 (PTCH gene) and 19p13.3 (STK11 gene) involved in the pathogenesis of ovarian stromal tumors?

    PubMed

    Tsuji, Takahiro; Catasus, Lluis; Prat, Jaime

    2005-07-01

    Some ovarian fibromas and rare fibrosarcomas are associated with Gorlin syndrome, which is caused by mutation in the human homologue of Drosophila patched gene (PTCH), localized on chromosome 9q22.3. The relationship between PTCH gene and sporadic ovarian tumors in the thecoma-fibroma group has not been well characterized. On the other hand, we have recently described loss of heterozygosity (LOH) at 19p13.3 in 2 sporadic fibromas with sex-cord elements. We have analyzed DNA from 8 fibromas, 6 cellular fibromas, 2 fibrothecomas, 9 luteinized thecomas, and 2 fibrosarcomas of the ovary for LOH at 9q22.3 and 19p13.3, using polymerase chain reaction amplification for 10 microsatellite markers. LOH at 9q22.3 was detected in 4 (67%) of 6 cellular fibromas, with the highest frequency at microsatellite marker D9S15, which localizes proximal to the PTCH gene. Of 9 luteinized thecomas, 2 (22%) also exhibited LOH at 9q22.3 with 3 microsatellite markers other than D9S15. Allelic losses were not detected in any fibroma, fibrothecoma, or fibrosarcoma. LOH at 19p13.3 was found in 2 (25%) of 8 fibromas, 3 (50%) of 6 cellular fibromas, and 1 (11%) of 9 luteinized thecomas. None of the 2 fibrothecomas or 2 fibrosarcomas showed LOH at 19p13.3. LOH at both 9p22.3 and 19p13.3 was observed in 3 (50%) of 6 cellular fibromas, but not in luteinized thecomas. The results indicate that (1) LOH at both PTCH gene and STK11 gene is relatively frequent in cellular fibromas; (2) approximately a quarter of luteinized thecomas exhibited LOH of the PTCH gene; in both neoplasms, cellular fibromas and luteinized thecomas, LOH may play a role in their pathogenesis; and (3) sporadic cellular fibromas may arise through similar genetic pathways as cases of Gorlin syndrome.

  9. Genetics, Cytogenetics, and Epigenetics of Colorectal Cancer

    PubMed Central

    Migliore, Lucia; Migheli, Francesca; Spisni, Roberto; Coppedè, Fabio

    2011-01-01

    Most of the colorectal cancer (CRC) cases are sporadic, only 25% of the patients have a family history of the disease, and major genes causing syndromes predisposing to CRC only account for 5-6% of the total cases. The following subtypes can be recognized: MIN (microsatellite instability), CIN (chromosomal instability), and CIMP (CpG island methylator phenotype). CIN occurs in 80–85% of CRC. Chromosomal instability proceeds through two major mechanisms, missegregation that results in aneuploidy through the gain or loss of whole chromosomes, and unbalanced structural rearrangements that lead to the loss and/or gain of chromosomal regions. The loss of heterozygosity that occur in the first phases of the CRC cancerogenesis (in particular for the genes on 18q) as well as the alteration of methylation pattern of multiple key genes can drive the development of colorectal cancer by facilitating the acquisition of multiple tumor-associated mutations and the instability phenotype. PMID:21490705

  10. Mutation analysis of the CHK2 gene in breast carcinoma and other cancers.

    PubMed

    Ingvarsson, Sigurdur; Sigbjornsdottir, Bjarnveig I; Huiping, Chen; Hafsteinsdottir, Sigridur H; Ragnarsson, Gisli; Barkardottir, Rosa B; Arason, Adalgeir; Egilsson, Valgardur; Bergthorsson, Jon T H

    2002-01-01

    Mutations in the CHK2 gene at chromosome 22q12.1 have been reported in families with Li-Fraumeni syndrome. Chk2 is an effector kinase that is activated in response to DNA damage and is involved in cell-cycle pathways and p53 pathways. We screened 139 breast tumors for loss of heterozygosity at chromosome 22q, using seven microsatellite markers, and screened 119 breast tumors with single-strand conformation polymorphism and DNA sequencing for mutations in the CHK2 gene. Seventy-four of 139 sporadic breast tumors (53%) show loss of heterozygosity with at least one marker. These samples and 45 tumors from individuals carrying the BRCA2 999del5 mutation were screened for mutations in the CHK2 gene. In addition to putative polymorphic regions in short mononucleotide repeats in a non-coding exon and intron 2, a germ line variant (T59K) in the first coding exon was detected. On screening 1172 cancer patients for the T59K sequence variant, it was detected in a total of four breast-cancer patients, two colon-cancer patients, one stomach-cancer patient and one ovary-cancer patient, but not in 452 healthy individuals. A tumor-specific 5' splice site mutation at site +3 in intron 8 (TTgt [a --> c]atg) was also detected. We conclude that somatic CHK2 mutations are rare in breast cancer, but our results suggest a tumor suppressor function for CHK2 in a small proportion of breast tumors. Furthermore, our results suggest that the T59K CHK2 sequence variant is a low-penetrance allele with respect to tumor growth.

  11. Mutation analysis of the CHK2 gene in breast carcinoma and other cancers

    PubMed Central

    Ingvarsson, Sigurdur; Sigbjornsdottir, Bjarnveig I; Huiping, Chen; Hafsteinsdottir, Sigridur H; Ragnarsson, Gisli; Barkardottir, Rosa B; Arason, Adalgeir; Egilsson, Valgardur; Bergthorsson, Jon TH

    2002-01-01

    Background Mutations in the CHK2 gene at chromosome 22q12.1 have been reported in families with Li-Fraumeni syndrome. Chk2 is an effector kinase that is activated in response to DNA damage and is involved in cell-cycle pathways and p53 pathways. Methods We screened 139 breast tumors for loss of heterozygosity at chromosome 22q, using seven microsatellite markers, and screened 119 breast tumors with single-strand conformation polymorphism and DNA sequencing for mutations in the CHK2 gene. Results Seventy-four of 139 sporadic breast tumors (53%) show loss of heterozygosity with at least one marker. These samples and 45 tumors from individuals carrying the BRCA2 999del5 mutation were screened for mutations in the CHK2 gene. In addition to putative polymorphic regions in short mononucleotide repeats in a non-coding exon and intron 2, a germ line variant (T59K) in the first coding exon was detected. On screening 1172 cancer patients for the T59K sequence variant, it was detected in a total of four breast-cancer patients, two colon-cancer patients, one stomach-cancer patient and one ovary-cancer patient, but not in 452 healthy individuals. A tumor-specific 5' splice site mutation at site +3 in intron 8 (TTgt [a → c]atg) was also detected. Conclusion We conclude that somatic CHK2 mutations are rare in breast cancer, but our results suggest a tumor suppressor function for CHK2 in a small proportion of breast tumors. Furthermore, our results suggest that the T59K CHK2 sequence variant is a low-penetrance allele with respect to tumor growth. PMID:12052256

  12. Refined-mapping of the novel TSG within the 17q24.3 chromosomal region in non-small cell lung cancer samples

    PubMed Central

    Huang, Wayren; Wang, Yiching; Chu, Woeichyn; Tseng, Ruochia

    2016-01-01

    Lung cancer is a leading cause of cancer mortality in Taiwan. It has been previously demonstrated that alterations to tumor suppressor genes (TSGs) are involved in the multi-step carcinogenesis process that results in the development of human cancer, including lung cancer. Both copies of the TSG must be inactivated for their function to be lost. As a result, it is important to search for the genomic regions that potentially contain TSGs and to investigate the etiological association of lung cancer with the allelic deletion of various candidate TSGs. Previous genome-wide loss of heterozygosity (LOH) data has demonstrated that the chromosome region at 17q24.3 was a novel and frequent LOH region that was associated with non-small-cell lung cancer (NSCLC). In the present study, refined mapping using 9 additional microsatellite markers was performed targeting chromosome 17q24.3 by polymerase chain reaction (PCR)-LOH analysis. The allelic loss pattern across 48 available tumors indicates that the minimal deletion region was located between markers D17S1882 and D17S2193 and spanned a distance of approximately 2.7 Mb, reaching 65% LOH at locus D17S1816. A putative gene, LOC51321 (AMZ2), was postulated to be the deletion target on 17q24.3 based on the findings from these NSCLC samples. Reverse transcription-PCR (RT-PCR) expression analysis indicated reduced expression of LOC51321 in 54% (7/13) of the NSCLC cell lines tested and 36% (19/53) of the NSCLC tumor tissue samples analyzed. In CL1-5-F4 cells, low mRNA and protein expression of LOC51321 were associated with the promoter hypermethylation, as determined by RT-PCR, western blotting and methylation-specific PCR assays. In addition, treatment with 5-Aza-deoxycytosine successfully restored mRNA expression by de-methylating the putative promoter region in CL1-5-F4 cells that lacked LOC51321 expression, but did harbor the relevant methylated promoter. These findings indicate that LOC51321 may be involved in lung

  13. Strong evidence that the common variant S384F in BRCA2 has no pathogenic relevance in hereditary breast cancer

    PubMed Central

    Wappenschmidt, B; Fimmers, R; Rhiem, K; Brosig, M; Wardelmann, E; Meindl, A; Arnold, N; Mallmann, P; Schmutzler, RK

    2005-01-01

    Introduction Unclassified variants (UVs) of unknown clinical significance are frequently detected in the BRCA2 gene. In this study, we have investigated the potential pathogenic relevance of the recurrent UV S384F (BRCA2, exon 10). Methods For co-segregation, four women from a large kindred (BN326) suffering from breast cancer were analysed. Moreover, paraffin-embedded tumours from two patients were analysed for loss of heterozygosity. Co-occurrence of the variant with a deleterious mutation was further determined in a large data set of 43,029 index cases. Nature and position of the UV and conservation among species were evaluated. Results We identified the unclassified variant S384F in three of the four breast cancer patients (the three were diagnosed at 41, 43 and 57 years of age). One woman with bilateral breast cancer (diagnosed at ages 32 and 50) did not carry the variant. Both tumours were heterozygous for the S384F variant, so loss of the wild-type allele could be excluded. Ser384 is not located in a region of functional importance and cross-species sequence comparison revealed incomplete conservation in the human, dog, rodent and chicken BRCA2 homologues. Overall, the variant was detected in 116 patients, five of which co-occurred with different deleterious mutations. The combined likelihood ratio of co-occurrence, co-segregation and loss of heterozygosity revealed a value of 1.4 × 10-8 in favour of neutrality of the variant. Conclusion Our data provide conclusive evidence that the S384F variant is not a disease causing mutation. PMID:16168123

  14. Gastric Cancer Regional Detection System.

    PubMed

    Ural, Berkan; Hardalaç, Fırat; Serhatlioğlu, Selami; İlhan, Mustafa Necmi

    2016-01-01

    In this study, a novel system was created to localize cancerous regions for stomach images which were taken with computed tomography(CT). The aim was to determine the coordinates of cancerous regions which spread in the stomach area in the color space with using this system. Also, to limit these areas with a high accuracy ratio and to feedback to the user of this system were the other objectives. This integration was performed with using energy mapping, analysis methods and multiple image processing methods and the system which was consisted from these advanced algorithms was appeared. For this work, in the range of 25-40 years and when gender discrimination was insignificant, 30 volunteer patients were chosen. During the formation of the system, to exalt the accuracy to the maximum level, 2 main stages were followed up. First, in the system, advanced image processing methods were processed between each other and obtained data were studied. Second, in the system, FFT and Log transformations were used respectively for the first two cases, then these transformations were used together for the third case. For totally three cases, energy distribution and DC energy intensity analysis were done and the performance of this system was investigated. Finally, with using the system's unique algorithms, a non-invasive method was achieved to detect the gastric cancer and when FFT and Log transformation were used together, the maximum success rate was obtained and this rate was calculated as 83,3119 %.

  15. High frequency of loss of heterozygosity at 11p15 and IGF2 overexpression is not associated with clinical outcome in childhood adrenocortical tumors positive for the R337H TP53 mutation

    PubMed Central

    Rosati, Roberto; Cerrato, Flavia; Doghman, Mabrouka; Pianovski, Mara A.D.; Parise, Guilherme A.; Custódio, Gislaine; Zambetti, Gerard P.; Ribeiro, Raul C.; Riccio, Andrea; Figueiredo, Bonald C.; Lalli, Enzo

    2008-01-01

    A germline TP53 R337H mutation is present in childhood adrenocortical tumors (ACT) from southern Brazil. Other genetic alterations are also frequently found in these tumors. This study was designed to assess whether alterations of the 11p15 region exist in childhood ACT, accounting for IGF2 overexpression in these tumours, and how they are related to clinical outcome. Tumor DNA of 12 children with ACT (4 adenomas and 8 carcinomas) and from the blood of their parents was analyzed. All patients showed 11p15 LOH in the tumor. In contrast to the single case of paternal LOH, IGF2 was overexpressed in tumors with maternal allele loss. Our data show that 11p15 LOH is a widespread finding in childhood ACT not related with malignancy, contrarily to adult ACT. Alterations in the expression of other genes in the same region (e.g. CDKN1C) may contribute to ACT tumorigenesis. PMID:18786438

  16. Loss of heterozygosity (LOH) for markers on chromosome 8q in a human chondrosarcoma cell line and in a tumor that developed in a man with Hereditary Multiple Exostoses (HME)

    SciTech Connect

    Raskind, W.H.; Conrad, E.U.; Robbins, J.R.

    1994-09-01

    HME is an autosomal dominant disorder in which multiple benign cartilage-capped lesions develop on otherwise histologically normal bones. The majority of chondrosarcomas are sporadic, but the presence of HME greatly increases the risk to develop this tumor. Sarcoma may also arise in sporadically-occurring exostoses. The study of inherited disorders that predispose to malignant diseases has led to discoveries regarding molecular changes involved in carcinogenesis in general. In an analogous manner, somatic mutations in HME genes may be responsible for sporadic exostoses and/or chondrosarcomas. HME is genetically heterogeneous; EXT genes have been assigned to 8q24, the pericentromeric region of 11 and 19p11-p13. We compared chondrosarcoma cell DNA to DNA from white blood cells for LOH at polymorphic loci in these 3 regions. LOH for 4 of 5 markers in 8q24 was detected in a chondrosarcoma that arose in a man with HME. Heterozygosity was retained for markers and chromosomes 11 and 19. We then evaluated cultured cells from 10 sporadic chondrosarcomas. LOH for multiple markers in 8q24 was detected in a cell line, Ch-1, established from an aggressive tumor, but not in 9 other tumors. Of the 9 tumors studied, only the Ch-1 line exhibited LOH for chromosome 11 markers. LOH for a 19p marker was not detected in any of 6 tumors examined, including Ch-1. The karyotype of Ch-1 contains many structurally rearranged chromosomes. The two chromosome 11s appear normal but both chromosome 8 homologues have been replaced by der(8)t(5;8)(q22;q21.2). LOH at 8q24 was also detected in the uncultured tumor. These results suggest that genes responsible for HME may have tumor suppressor functions whose loss may be related to the development of a subset of chondrosarcomas.

  17. Northeast Regional Cancer Institute's Cancer Surveillance and Risk Factor Program

    SciTech Connect

    Lesko, Samuel M.

    2007-07-31

    OBJECTIVES The Northeast Regional Cancer Institute is conducting a program of ongoing epidemiologic research to address cancer disparities in northeast Pennsylvania. Of particular concern are disparities in the incidence of, stage at diagnosis, and mortality from colorectal cancer. In northeast Pennsylvania, age-adjusted incidence and mortality rates for colorectal cancer are higher, and a significantly smaller proportion of new colorectal cancer cases are diagnosed with local stage disease than is observed in comparable national data. Further, estimates of the prevalence of colorectal cancer screening in northeast Pennsylvania are lower than the US average. The Northeast Regional Cancer Institute’s research program supports surveillance of common cancers, investigations of cancer risk factors and screening behaviors, and the development of resources to further cancer research in this community. This project has the following specific objectives: I. To conduct cancer surveillance in northeast Pennsylvania. a. To monitor incidence and mortality for all common cancers, and colorectal cancer, in particular, and b. To document changes in the stage at diagnosis of colorectal cancer in this high-risk, underserved community. II. To conduct a population-based study of cancer risk factors and screening behavior in a six county region of northeast Pennsylvania. a. To monitor and document changes in colorectal cancer screening rates, and b. To document the prevalence of cancer risk factors (especially factors that increase the risk of colorectal cancer) and to identify those risk factors that are unusually common in this community. APPROACH Cancer surveillance was conducted using data from the Northeast Regional Cancer Institute’s population-based Regional Cancer Registry, the Pennsylvania Cancer Registry, and NCI’s SEER program. For common cancers, incidence and mortality were examined by county within the region and compared to data for similar populations in the US

  18. LARG at chromosome 11q23 has functional characteristics of a tumor suppressor in human breast cancer

    SciTech Connect

    Ong, Danny C.T.; Rudduck, Christina; Chin, Koei; Kuo, Wen-Lin; Lie, Daniel K.H.; Chua, Constance L.M.; Wong, Chow Yin; Hong, Ga Sze; Gray, Joe; Lee, Ann S.G.

    2008-05-06

    Deletion of 11q23-q24 is frequent in a diverse variety of malignancies, including breast and colorectal carcinoma, implicating the presence of a tumor suppressor gene at that chromosomal region. We show here that LARG, from 11q23, has functional characteristics of a tumor suppressor. We examined a 6-Mb region on 11q23 by high-resolution deletion mapping, utilizing both loss of heterozygosity (LOH) analysis and microarray comparative genomic hybridization (CGH). LARG (also called ARHGEF12), identified from the analyzed region, was underexpressed in 34% of primary breast carcinomas and 80% of breast cancer cell lines including the MCF-7 line. Multiplex ligation-dependent probe amplification on 30 primary breast cancers and six breast cancer cell lines showed that LARG had the highest frequency of deletion compared to the BCSC-1 and TSLC1 genes, two known candidate tumor suppressor genes from 11q. In vitro analysis of breast cancer cell lines that underexpress LARG showed that LARG could be reactivated by trichostatin A, a histone deacetylase inhibitor, but not by 5-Aza-2{prime}-deoxycytidine, a demethylating agent. Bisulfite sequencing and quantitative high-throughput analysis of DNA methylation confirmed the lack of CpG island methylation in LARG in breast cancer. Restoration of LARG expression in MCF-7 cells by stable transfection resulted in reduced proliferation and colony formation, suggesting that LARG has functional characteristics of a tumor suppressor gene.

  19. Deletion at chromosome arms 6q16-22 and 10q22.3-23.1 associated with initiation of prostate cancer.

    PubMed

    Lu, T; Hano, H

    2008-01-01

    Loss of heterozygosity (LOH) at 6q16-22 and 10q22.3-23.1 is common chromosomal alteration in advanced prostate cancer and suggests that one or more tumor suppressor genes may lie within these chromosome arms. However, the genetic changes in early stage prostate cancer and premalignant lesions remain to be investigated. We used 11 informative microsatellite markers at 6q16-22 and 10q22.3-23.1 in Japanese patients to compare the frequency of LOH in 53 lesions of high-grade prostatic intraepithelial neoplasia (HGPIN), 38 cases (38 lesions) of incidental prostate cancer (IPC) and 107 cases (168 lesions) of clinical prostate cancer (CPC). The frequency of LOH at 6q16-22 with at least one marker was 38 and 49% in IPC and CPC cases, respectively. Similarly, allelic loss at 10q22.3-23.1 was present in 35 and 39% of IPC and CPC, respectively. High-frequency LOH was detected in both the clinically insignificant and significant prostate cancers at 6q16-22 and 10q22.3-23.1 (P>0.05). However, no allelic loss was detected in any markers at the same regions in HGPIN (0%), which is usually considered a premalignant lesion to prostate cancer. Deletions of both the chromosome regions, 6q16-22 and 10q22.3-23.1, are more likely important events in the initiation and/or promotion of prostate cancer.

  20. Germline large genomic alterations on 7q in patients with multiple primary cancers

    PubMed Central

    Villacis, R. A. R.; Basso, T. R.; Canto, L. M.; Nóbrega, A. F.; Achatz, M. I.; Rogatto, S. R.

    2017-01-01

    Patients with multiple primary cancers (MPCs) are suspected to have a hereditary cancer syndrome. However, only a small proportion may be explained by mutations in high-penetrance genes. We investigate two unrelated MPC patients that met Hereditary Breast and Ovaria Cancer criteria, both presenting triple negative breast tumors and no mutations in BRCA1, BRCA2 and TP53 genes. Germline rearrangements on chromosome 7q, involving over 40 Mb of the same region, were found in both patients: one with mosaic loss (80% of cells) and the other with cnLOH (copy-neutral loss of heterozygosity) secondary to maternal allele duplication. Five children tested had no alterations on 7q. The patients shared 330 genes in common on 7q22.1-q34, including several tumor suppressor genes (TSGs) previously related to breast cancer risk and imprinted genes. The analysis of the triple negative BC from one patient revealed a mosaic gain of 7q translated for over-expressed cancer-related genes. The involvement of TSGs and imprinted genes, mapped on 7q, has the potential of being associated to MPC risk, as well as cancer progression. To our knowledge, this is the first description of patients with MPCs that harbor constitutive large alterations on 7q. PMID:28139749

  1. Cancer mortality in agricultural regions of Minnesota.

    PubMed Central

    Schreinemachers, D M; Creason, J P; Garry, V F

    1999-01-01

    Because of its unique geology, Minnesota can be divided into four agricultural regions: south-central region one (corn, soybeans); west-central region two (wheat, corn, soybeans); northwest region three (wheat, sugar beets, potatoes); and northeast region four (forested and urban in character). Cancer mortality (1980-1989) in agricultural regions one, two, and three was compared to region four. Using data compiled by the National Center for Health Statistics, cancer mortality was summarized by 5-year age groups, sex, race, and county. Age-standardized mortality rate ratios were calculated for white males and females for all ages combined, and for children aged 0-14. Increased mortality rate ratios and 95% confidence intervals (CIs) were observed for the following cancer sites: region one--lip (men), standardized rate ratio (SRR) = 2.70 (CI, 1.08-6.71); nasopharynx (women), SRR = 3.35 (CI, 1.20-9.31); region two--non-Hodgkin's lymphoma (women), SRR = 1.35 (CI, 1.09-1.66); and region three--prostate (men), SRR = 1.12 (CI, 1.00-1.26); thyroid (men), SRR = 2.95 (CI, 1.35-6.44); bone (men), SRR = 2.09 (CI, 1. 00-4.34); eye (women), SRR = 5.77 (CI, 1.90-17.50). Deficits of smoking-related cancers were noted. Excess cancers reported are consistent with earlier reports of agriculturally related cancers in the midwestern United States. However, reports on thyroid and bone cancer in association with agricultural pesticides are few in number. The highest use of fungicides occurs in region three. Ethylenebisdithiocarbamates, whose metabolite is a known cause of thyroid cancer in rats, are frequently applied. This report provides a rationale for evaluation of the carcinogenic potential of this suspect agent in humans. Images Figure 1 PMID:10064550

  2. Exclusion of the retinoblastoma gene and chromosome 13q as the site of a primary lesion for human breast cancer.

    PubMed Central

    Bowcock, A M; Hall, J M; Hebert, J M; King, M C

    1990-01-01

    Chromosome 13q has been suggested as the site of a gene predisposing to human breast cancer, because loss of heterozygosity of alleles on this chromosome has been observed in some ductal breast tumors and because two breast cancer lines are altered at the retinoblastoma gene (RB1) at 13q14. To test this possibility, linkage of breast cancer susceptibility to 14 loci on chromosome 13q loci was assessed in extended families in which breast cancer is apparently inherited as an autosomal dominant trait. RB1 was excluded as the site of a breast cancer gene by a lod score of Z = -7.60 at close linkage for 13 families. Multipoint analysis yielded negative lod scores throughout the region between 13q12 and 13q34; over most of this distance, Z less than -2.0. Therefore, chromosome 13q appears to be excluded as the site of primary lesion for breast cancer in these families. In addition, comparison of tumor versus normal tissues of nonfamilial breast cancer patients revealed an alteration at the 5' end of RB1 in a mucoid carcinoma but no alterations of RB1 in five informative ductal adenocarcinomas. Linkage data and comparisons of tumor and normal tissues suggest that changes in the RBI locus either are secondary alterations associated with progression of some tumors or occur by chance. Images Figure 2 PMID:2294744

  3. Cancer prevention in the Asia Pacific region.

    PubMed

    Yoo, Keun-Young

    2010-01-01

    Cancer incidences as well as the most prevalent cancer types vary greatly across Asian countries since people have differing health behaviors as well as lifestyle factors related to cancer risk. Countries have varying systems of government organization, laws, resources, facilities, and management strategies for addressing the cancer burden. Examples such as Korea and Japan with existing national cancer control programs need to focus on early screening and detection and quality of screening methods. If screening and detection increase to cover more than 50% of the target population, survival rate increases and thus the number of cancer patients detected increases resulting in higher medical cost. Thus, expansion of cancer screening, in addition to smoking prevention, immunization increase, and diet control awareness, are needed for cancer prevention strategies. Countries such as Thailand, China, Malaysia, and Turkey need to begin organized efforts to reduce cancer deaths through state-wide cancer screening programs. Strategies focused on increasing survival among cancer patients are also needed. In addition, government organizations and law regulations need to be in place as the first step towards cancer prevention. For the countries such as Nepal, Pakistan, Mongolia, and Iraq which do not have any cancer-related organizations in place, the first step that is needed is to raise public awareness about cancer; a public awareness campaign is the number one priority and should begin immediately. The easiest and most feasible step at this point is dissemination of cancer education materials during school health education and physical health screening. This must be started immediately because we need to avoid the development of existing cancers where patients will need to seek specialized cancer treatment facilities that are non-existent in these regions. In addition, hospitals need to take a step further and start undergoing registration of cancer prevalence and

  4. Genetic analysis of the BRCA1 region in a large breast/ovarian family: refinement of the minimal region containing BRCA1.

    PubMed

    Kelsell, D P; Black, D M; Bishop, D T; Spurr, N K

    1993-11-01

    We have analyzed a single multi-affected breast/ovarian cancer pedigree (BOV3) and have shown consistent inheritance of markers on chromosome 17q with the disease confirming that this family is due to the BRCA1 gene. Analysis of 17q haplotypes shows a recombination event in a bilateral breast cancer case which suggests that the BRCA1 gene lies distal to D17S857; D17S857 is thus the new proximal boundary for the region containing BRCA1. Combining this information with previously published mapping information suggests that BRCA1 is contained in a region estimated at 1-1.5 Mb in length. All seven breast tumour/blood pairs examined from this family show loss of heterozygosity in the tumours. The allel retained in each tumour was from the disease-bearing chromosome implicating BRCA1 as a tumour suppressor gene. We have sequenced the 17 beta-oestradiol dehydrogenase genes (EDH17B1 and EDH17B2) which have been suggested as candidate genes for BRCA1 in four members of this family. No germline mutations were detected.

  5. Lack of Correlation Between Survival and Allele Loss on Chromosome 7q31-32 in Primary Breast Cancer.

    PubMed

    Sztán, Marianna; Besznyák, István; Kovács, Tibor; Tóth, József; Szémel, Irén; Oláh, Edith

    1996-01-01

    High incidence of loss of heterozygosity (LOH), affecting the 7q31-32 chromosome region in sporadic primary human breast carcinomas suggests the presence of a tumor suppressor gene in this region which seems relevant to the development of breast cancer. To further determine the possible role of this region in the pathogenesis of human primary breast cancer and association with survival, LOH analysis was performed on 52 primary breast cancer patients using a set of highly polymorphic microsatellite markers. Our panel contained twenty biopsy cases of unknown survival, nineteen cases with more than five years survival and fourteen cases with less than two years survival. Corresponding normal and tumor DNAs were analyzed by polymerase chain reaction (PCR). The data presented here demonstrate that all patients were informative at least at one locus and 20 (38%) out of 53 cases showed LOH at one or more loci on chromosome 7q31-32. Relatively high incidence of LOH (34%) was detected at the D7S522 microsatellite marker located near to the cMet proto-oncogene while lower frequencies were observed at D7S523 (19%) and D7S495 (17%) loci, supporting the existence of a putative tumor suppressor gene at the chromosome 7q31.1 region. Our results suggest that allelic imbalance on 7q may occur at an early stage of breast carcinogenesis, as no correlation was observed between allelic loss and clinico-pathological data.

  6. Regional Multiteam Systems in Cancer Care Delivery

    PubMed Central

    Monson, John R.T.; Rizvi, Irfan; Savastano, Ann; Green, James S.A.; Sevdalis, Nick

    2016-01-01

    Teamwork is essential for addressing many of the challenges that arise in the coordination and delivery of cancer care, especially for the problems that are presented by patients who cross geographic boundaries and enter and exit multiple health care systems at various times during their cancer care journeys. The problem of coordinating the care of patients with cancer is further complicated by the growing number of treatment options and modalities, incompatibilities among the vast variety of technology platforms that have recently been adopted by the health care industry, and competing and misaligned incentives for providers and systems. Here we examine the issue of regional care coordination in cancer through the prism of a real patient journey. This article will synthesize and elaborate on existing knowledge about coordination approaches for complex systems, in particular, in general and cancer care multidisciplinary teams; define elements of coordination derived from organizational psychology and human factors research that are applicable to team-based cancer care delivery; and suggest approaches for improving multidisciplinary team coordination in regional cancer care delivery and avenues for future research. The phenomenon of the mobile, multisystem patient represents a growing challenge in cancer care. Paradoxically, development of high-quality, high-volume centers of excellence and the ease of virtual communication and data sharing by using electronic medical records have introduced significant barriers to effective team-based cancer care. These challenges urgently require solutions. PMID:27650833

  7. Regional Multiteam Systems in Cancer Care Delivery.

    PubMed

    Noyes, Katia; Monson, John R T; Rizvi, Irfan; Savastano, Ann; Green, James S A; Sevdalis, Nick

    2016-11-01

    Teamwork is essential for addressing many of the challenges that arise in the coordination and delivery of cancer care, especially for the problems that are presented by patients who cross geographic boundaries and enter and exit multiple health care systems at various times during their cancer care journeys. The problem of coordinating the care of patients with cancer is further complicated by the growing number of treatment options and modalities, incompatibilities among the vast variety of technology platforms that have recently been adopted by the health care industry, and competing and misaligned incentives for providers and systems. Here we examine the issue of regional care coordination in cancer through the prism of a real patient journey. This article will synthesize and elaborate on existing knowledge about coordination approaches for complex systems, in particular, in general and cancer care multidisciplinary teams; define elements of coordination derived from organizational psychology and human factors research that are applicable to team-based cancer care delivery; and suggest approaches for improving multidisciplinary team coordination in regional cancer care delivery and avenues for future research. The phenomenon of the mobile, multisystem patient represents a growing challenge in cancer care. Paradoxically, development of high-quality, high-volume centers of excellence and the ease of virtual communication and data sharing by using electronic medical records have introduced significant barriers to effective team-based cancer care. These challenges urgently require solutions.

  8. Variable maternal methylation overlapping the nc886/vtRNA2-1 locus is locked between hypermethylated repeats and is frequently altered in cancer

    PubMed Central

    Romanelli, Valeria; Nakabayashi, Kazuhiko; Vizoso, Miguel; Moran, Sebastián; Iglesias-Platas, Isabel; Sugahara, Naoko; Sugahara, Naoko; Simón, Carlos; Simón, Carlos; Hata, Kenichiro; Hata, Kenichiro; Esteller, Manel; Esteller, Manel; Court, Franck; Court, Franck; Monk, David; Monk, David

    2014-01-01

    Cancer is as much an epigenetic disease as a genetic one; however, the interplay between these two processes is unclear. Recently, it has been shown that a large proportion of DNA methylation variability can be explained by allele-specific methylation (ASM), either at classical imprinted loci or those regulated by underlying genetic variants. During a recent screen for imprinted differentially methylated regions, we identified the genomic interval overlapping the non-coding nc886 RNA (previously known as vtRNA2-1) as an atypical ASM that shows variable levels of methylation, predominantly on the maternal allele in many tissues. Here we show that the nc886 interval is the first example of a polymorphic imprinted DMR in humans. Further analysis of the region suggests that the interval subjected to ASM is approximately 2 kb in size and somatically acquired. An in depth analysis of this region in primary cancer samples with matching normal adjacent tissue from the Cancer Genome Atlas revealed that aberrant methylation in bladder, breast, colon and lung tumors occurred in approximately 27% of cases. Hypermethylation occurred more frequently than hypomethylation. Using additional normal-tumor paired samples we show that on rare occasions the aberrant methylation profile is due to loss-of-heterozygosity. This work therefore suggests that the nc886 locus is subject to variable allelic methylation that undergoes cancer-associated epigenetic changes in solid tumors. PMID:24589629

  9. Variation in the RAD51 gene and familial breast cancer

    PubMed Central

    Lose, Felicity; Lovelock, Paul; Chenevix-Trench, Georgia; Mann, Graham J; Pupo, Gulietta M; Spurdle, Amanda B

    2006-01-01

    Introduction Human RAD51 is a homologue of the Escherichia coli RecA protein and is known to function in recombinational repair of double-stranded DNA breaks. Mutations in the lower eukaryotic homologues of RAD51 result in a deficiency in the repair of double-stranded DNA breaks. Loss of RAD51 function would therefore be expected to result in an elevated mutation rate, leading to accumulation of DNA damage and, hence, to increased cancer risk. RAD51 interacts directly or indirectly with a number of proteins implicated in breast cancer, such as BRCA1 and BRCA2. Similar to BRCA1 mice, RAD51-/- mice are embryonic lethal. The RAD51 gene region has been shown to exhibit loss of heterozygosity in breast tumours, and deregulated RAD51 expression in breast cancer patients has also been reported. Few studies have investigated the role of coding region variation in the RAD51 gene in familial breast cancer, with only one coding region variant – exon 6 c.449G>A (p.R150Q) – reported to date. Methods All nine coding exons of the RAD51 gene were analysed for variation in 46 well-characterised, BRCA1/2-negative breast cancer families using denaturing high-performance liquid chromatography. Genotyping of the exon 6 p.R150Q variant was performed in an additional 66 families. Additionally, lymphoblastoid cell lines from breast cancer patients were subjected to single nucleotide primer extension analysis to assess RAD51 expression. Results No coding region variation was found, and all intronic variation detected was either found in unaffected controls or was unlikely to have functional consequences. Single nucleotide primer extension analysis did not reveal any allele-specific changes in RAD51 expression in all lymphoblastoid cell lines tested. Conclusion Our study indicates that RAD51 is not a major familial breast cancer predisposition gene. PMID:16762046

  10. Microsatellite instability in colorectal cancer.

    PubMed

    Iacopetta, Barry; Grieu, Fabienne; Amanuel, Benhur

    2010-12-01

    Approximately 20 percent of right-sided colon cancers and 5 percent of left-sided colon and rectal cancers have a deficient DNA mismatch repair system. This results in the widespread accumulation of mutations to nucleotide repeats, some of which occur within the coding regions of cancer-related genes such as TGFβRII and BAX. A standardized definition for microsatellite instability (MSI) based on the presence of deletions to mononucleotide repeats is gaining widespread acceptance in both research and the clinic. Colorectal cancer (CRC) with MSI are characterized histologically by an abundance of tumor-infiltrating lymphocytes, poor differentiation and a signet ring or mucinous phenotype. In younger patients these tumors usually develop along the chromosomal instability pathway, in which case the mismatch repair genes are inactivated by germline mutation, somatic mutation and loss of heterozygosity. In older patients MSI CRC usually develops against a background of widespread hypermethylation that includes methylation-induced silencing of the mismatch repair gene MLH1. The overall biological and clinical phenotype of MSI CRC that arise in these two pathways is likely to be different and may account for some of the discordant results reported in the literature relating to the clinical properties of these tumors. The available evidence indicates that MSI is unlikely to be a clinically useful marker for the prognostic stratification of early-stage CRC. The predictive value of MSI for response to 5-fluorouracil-based chemotherapy remains controversial, while for other agents the predictive value is difficult to assess because they are used in combination regimens. The MSI phenotype is being actively investigated for novel therapeutic approaches based on the principle of synthetic lethality. Finally, the MSI status of CRC is an extremely useful marker for population-based screening programs that aim to identify individuals and families with the hereditary cancer

  11. Mitotic abnormalities leading to cancer predisposition and progression.

    PubMed

    Cavenee, W K

    1989-01-01

    The development of human cancer is generally thought to entail a series of events that cause a progressively more malignant phenotype. Such a hypothesis predicts that tumor cells of the ultimate stage will carry each of the events, cells of the penultimate stage will carry each of the events less the last one, and so on. That is to say a dissection of the pathway from a normal cell to a fully malignant tumor may be viewed as the unraveling of a nested set of aberrations. In experiments designed to elucidate these events, we have compared genotypic combinations at genomic loci defined by restriction endonuclease recognition site variation in normal and tumor tissues from patients with various forms and stages of cancer. The first step, inherited predisposition, is best described for retinoblastoma in which a recessive mutation of a locus residing in the 13q14 region of the genome is unmasked by aberrant, but specific, mitotic chromosomal segregation. A similar mechanism involving the distal short arm of chromosome 17 is apparent in astrocytic tumors and the event is shared by cells in each malignancy stage. This is distinct from a loss of heterozygosity for loci on chromosome 10 which is restricted to the ultimate stage, glioblastoma multiforme. These results suggest a genetic approach to defining degrees of tumor progression and means for determining the genomic locations of genes involved in the pathway as a prelude to their molecular isolation and characterization.

  12. Loss of chromosome 17 regions in early-stage prostate tumors detected by quantitative PCR and single-copy fluorescence in situ hybridization: Involvement of the BRCA-1 locus?

    SciTech Connect

    Brothman, A.R.; Steele, M.; Williams, B.J.

    1994-09-01

    Prostate cancer is the leading male malignancy in the U.S., yet no consistent cellular defect has been associated with the disease. Loss of whole chromosome 17 has been observed in primary prostate tumors by fluorescence in situ hybridization (FISH). A small subset of late-stage tumors showed abnormalities in the p53 gene on 17p, but no loss of heterozygosity (LOH) has been observed on the long arm of 17 in prostate cancer. An increased incidence of prostate cancers in families with linkage to the familial breast-ovarian cancer predisposition gene, BRCA-1, indicates that this locus, which maps to 17q, may also be involved in prostate cancers. We studied 23 early-stage primary prostate tumors, obtained from radical prostatectomies, for LOH at five initial sites on chromosome 17 using highly informative microsatellite markers and quantitative analysis of polymerase chain reaction (PCR) product. Six of the 23 specimens (26%) showed tumor-specific LOH on chromosome 17. Two specimens showed interstitial loss near the BRCA-1 region on 17q. We confirmed these losses by single copy FISH on fixed cell suspensions from the primary tumors using selected P1 probes flanking the markers. Our findings suggest that genes on proximal 17q may play a pivotal role in the development of at least a subset of prostate tumors.

  13. Decreased expression of haemoglobin beta (HBB) gene in anaplastic thyroid cancer and recovory of its expression inhibits cell growth

    PubMed Central

    Onda, M; Akaishi, J; Asaka, S; Okamoto, J; Miyamoto, S; Mizutani, K; Yoshida, A; Ito, K; Emi, M

    2005-01-01

    Anaplastic thyroid cancer (ATC) is one of the most fulminant and foetal diseases in human malignancies. However, the genetic alterations and carcinogenic mechanisms of ATC are still unclear. Recently, we investigated the gene expression profile of 11 anaplastic thyroid cancer cell lines (ACL) and significant decreased expression of haemoglobin beta (HBB) gene in ACL. Haemoglobin beta is located at 11p15.5, where loss of heterozygosity (LOH) was reported in various kinds of cancers, including ATC, and it has been suggested that novel tumour suppressor genes might exist in this region. In order to clarify the meaning of decreased expression of HBB in ATC, the expression status of HBB was investigated with ACL, ATC, papillary thyroid cancer (PTC) and normal human tissues. Haemoglobin beta showed significant decreased expression in ACLs and ATCs; however, in PTC, HBB expressed equal to the normal thyroid gland. In addition, HBB expressed in normal human tissues ubiquitously. To validate the tumour-suppressor function of HBB, cell growth assay was performed. Forced expression of HBB in KTA2 cell, which is a kind of ACL, significantly suppressed KTA2 growth. The mechanism of downregulation of HBB in ATC is still unclear; however, our results suggested the possibility of HBB as a novel tumour-suppressor gene. PMID:15956966

  14. Prevalence of mutations in APC, CTNNB1, and BRAF in Tunisian patients with sporadic colorectal cancer.

    PubMed

    Bougatef, Karim; Ouerhani, Slah; Moussa, Amel; Kourda, Nadia; Coulet, Florence; Colas, Chrystelle; Lahely, Yannick Blondeau; Najjar, Tawfik; Ben Jilani, Sarra; Benammar-Elgaaied, Amel; Soubrier, Florent; Marrakchi, Raja

    2008-11-01

    Sporadic colorectal tumorigenesis is caused by alterations in the Wnt (APC, CTNNB1) and Ras pathways. Our objective was to analyze the occurrence of these genetic alterations in relation to tumor and patient characteristics. The prevalence of somatic alteration in the hot-spot regions of the APC, BRAF, and CTNNB1 genes was investigated in 48 unselected and unrelated Tunisian patients with sporadic colorectal cancer, and the association between the molecular features at these genes in relation to tumor and patient characteristics (age at diagnosis, sex, tumor localization, stage, and differentiation) was analyzed. Loss of heterozygosity was observed at the APC locus in 52% of the analyzed tumors. 6 novel mutations were detected by polymerase chain reaction sequencing in the mutation cluster region of the APC gene. No mutations were observed in the CTNNB1 gene in any tumor, but 8% of tumors harbored mutation in the BRAF gene. Clinicopathological analyses showed an association between APC point mutations and the earliest occurrence of sporadic colorectal cancer. The findings confirm the heterogeneity of APC gene alteration and also reveal a particular profile of this pathology among Tunisian patients that confirms the epidemiological data for this country.

  15. [Frequent allelic losses in tumor-associated stromal cells and tumor epitelium of prostate cancer].

    PubMed

    Kekeeva, T V; Popova, O P; Shegaĭ, P V; Zavalishina, L E; Andreeva, Iu Iu; Zaletaev, D V; Nemtsova, M V

    2008-01-01

    It has become increasingly clear that tumor microenvironment plays a critical role in carcinogenesis. Accumulation of genetic alterations is typical not only for cancer epithelial cells but tumor-associated fibroblasts as well. Tumor epithelia, tumor-associated stroma from prostatectomy specimens of patients with prostate cancer and cells from prostatic intraepithelial neoplasia (PIN) and adjacent stroma from males with PIN were isolated by using laser capture microdissection. Microsatellite allelotyping was evaluated using 4 highly polymorphic markers for chromosomal regions 8p22, 16q23-24 and 13q14. Incidences of alterations (loss of heterozygosity or allelic imbalance) were 48% for region 8p22, 72% for 16q23 and 37% for 13q14. The LOH frequencies in tumor-associated stroma cells were very similar. Alterations at chromosome 13q were significantly associated with advanced tumor stage, whereas AI at 16q was also associated with high Gleason score and lymph node metastasis. We find some incidences of allelic imbalance in premalignant lesions in epithelial (16-27%) and stromal (7-22%) components. Our results show that the frequencies of genetic aberrations are as high in stromal cells as in tumor cells.

  16. Substantial reduction of the gastric carcinoma critical region at 6q16.3-q23.1.

    PubMed

    Carvalho, B; Seruca, R; Carneiro, F; Buys, C H; Kok, K

    1999-09-01

    Deletions of the long arm of chromosome 6 are a common event in gastric carcinomas. In a previous study, deletion mapping of 6q identified two smallest regions of overlap (SROs) of heterozygous deletions: one interstitial, spanning 12-16 cM, bordered by D6S268 (6q16.3-q21) and ARG1 (6q22.3-q23.1), and one distal to IFNGR1 (6q23-q24), spanning more than 30 cM. Loss of heterozygosity (LOH) of the interstitial SRO was detected in 50% of informative tumors. We analyzed 60 primary gastric tumors with 19 highly polymorphic markers from 6q16.3-q23.3 to delimit the interstitial SRO further. Of the 50 tumors that were informative for at least one locus, 18 (36%) showed allelic imbalance (AI). The overlap of these cases allowed us to define an SRO of approximately 3 Mb flanked by D6S278 and D6S404. AI or LOH of this region occurs in all histologic types of gastric carcinoma and in early stages of development, indicating that loss of a gene from this region of 6q is a crucial step in a main route of gastric carcinogenesis. For cases with retention of 6q, alternative routes of gastric carcinogenesis may exist. Genes Chromosomes Cancer 26:29-34, 1999.

  17. Both gene amplification and allelic loss occur at 14q13.3 in lung cancer

    PubMed Central

    Harris, Thomas; Pan, Qiulu; Sironi, Juan; Lutz, Dionne; Tian, Jianmin; Sapkar, Jana; Perez-Soler, Roman; Keller, Steven; Locker, Joseph

    2010-01-01

    Purpose Because loss of Nkx2-8 increases lung cancer in the mouse, we studied suppressive mechanisms in human lung cancer. Experimental Design NKX2-8 is located within 14q13.3, adjacent to its close relative TTF1/NKX2-1. We first analyzed loss of heterozygosity (LOH) of 14q13.3 in 45 matched human lung cancer and control specimens. DNA from tumors with LOH was then analyzed with high-density SNP arrays. For correlation with this genetic analysis, we quantified expression of Nkx2-8 and TTF1 mRNA in tumors. Finally, suppressive function of Nkx2-8 was assessed via colony formation assays in 5 lung cancer cell lines. Results 13/45 (29%) tumors had LOH. In 6 tumors, most adenocarcinomas, LOH was caused by gene amplification. The 0.8 Mb common region of amplification included MBIP, SFTA, TTF1, NKX2-8, and PAX9. In 4 squamous or adenosquamous cancers, LOH was caused by deletion. In 3 other tumors, LOH resulted from whole chromosome mechanisms (14−, 14+, or aneuploidy). The 1.2 Mb common region of deletion included MBIP, SFTA, TTF1, NKX2-8, PAX9, SLC25A21, and MIPOL1. Most tumors had low expression of Nkx2-8. Nevertheless, sequencing did not show NKX2-8 mutations that could explain the low expression. TTF1 overexpression, in contrast, was common and usually independent of Nkx2-8 expression. Finally, stable transfection of Nkx2-8 selectively inhibited growth of H522 lung cancer cells. Conclusions 14q13.3, which contains NKX2-8, is subject to both amplification and deletion in lung cancer. Most tumors have low expression of NKX2-8, and its expression can inhibit growth of some lung cancer cells. PMID:21148747

  18. Identifying Human Genome-Wide CNV, LOH and UPD by Targeted Sequencing of Selected Regions

    PubMed Central

    Guo, Wenying; Li, Jinliang; Zhao, Xia; Sun, Yepeng; Hu, Juan; Zhen, Hefu; Zhang, Xiandong; Chen, Chao; Shi, Yujian; Li, Lin; Cao, Hongzhi; Du, Hongli; Li, Jian

    2015-01-01

    Copy-number variations (CNV), loss of heterozygosity (LOH), and uniparental disomy (UPD) are large genomic aberrations leading to many common inherited diseases, cancers, and other complex diseases. An integrated tool to identify these aberrations is essential in understanding diseases and in designing clinical interventions. Previous discovery methods based on whole-genome sequencing (WGS) require very high depth of coverage on the whole genome scale, and are cost-wise inefficient. Another approach, whole exome genome sequencing (WEGS), is limited to discovering variations within exons. Thus, we are lacking efficient methods to detect genomic aberrations on the whole genome scale using next-generation sequencing technology. Here we present a method to identify genome-wide CNV, LOH and UPD for the human genome via selectively sequencing a small portion of genome termed Selected Target Regions (SeTRs). In our experiments, the SeTRs are covered by 99.73%~99.95% with sufficient depth. Our developed bioinformatics pipeline calls genome-wide CNVs with high confidence, revealing 8 credible events of LOH and 3 UPD events larger than 5M from 15 individual samples. We demonstrate that genome-wide CNV, LOH and UPD can be detected using a cost-effective SeTRs sequencing approach, and that LOH and UPD can be identified using just a sample grouping technique, without using a matched sample or familial information. PMID:25919136

  19. Identifying Human Genome-Wide CNV, LOH and UPD by Targeted Sequencing of Selected Regions.

    PubMed

    Wang, Yu; Li, Wei; Xia, Yingying; Wang, Chongzhi; Tang, Y Tom; Guo, Wenying; Li, Jinliang; Zhao, Xia; Sun, Yepeng; Hu, Juan; Zhen, Hefu; Zhang, Xiandong; Chen, Chao; Shi, Yujian; Li, Lin; Cao, Hongzhi; Du, Hongli; Li, Jian

    2014-01-01

    Copy-number variations (CNV), loss of heterozygosity (LOH), and uniparental disomy (UPD) are large genomic aberrations leading to many common inherited diseases, cancers, and other complex diseases. An integrated tool to identify these aberrations is essential in understanding diseases and in designing clinical interventions. Previous discovery methods based on whole-genome sequencing (WGS) require very high depth of coverage on the whole genome scale, and are cost-wise inefficient. Another approach, whole exome genome sequencing (WEGS), is limited to discovering variations within exons. Thus, we are lacking efficient methods to detect genomic aberrations on the whole genome scale using next-generation sequencing technology. Here we present a method to identify genome-wide CNV, LOH and UPD for the human genome via selectively sequencing a small portion of genome termed Selected Target Regions (SeTRs). In our experiments, the SeTRs are covered by 99.73%~99.95% with sufficient depth. Our developed bioinformatics pipeline calls genome-wide CNVs with high confidence, revealing 8 credible events of LOH and 3 UPD events larger than 5M from 15 individual samples. We demonstrate that genome-wide CNV, LOH and UPD can be detected using a cost-effective SeTRs sequencing approach, and that LOH and UPD can be identified using just a sample grouping technique, without using a matched sample or familial information.

  20. New genetic variants of LATS1 detected in urinary bladder and colon cancer

    PubMed Central

    Saadeldin, Mona K.; Shawer, Heba; Mostafa, Ahmed; Kassem, Neemat M.; Amleh, Asma; Siam, Rania

    2015-01-01

    LATS1, the large tumor suppressor 1 gene, encodes for a serine/threonine kinase protein and is implicated in cell cycle progression. LATS1 is down-regulated in various human cancers, such as breast cancer, and astrocytoma. Point mutations in LATS1 were reported in human sarcomas. Additionally, loss of heterozygosity of LATS1 chromosomal region predisposes to breast, ovarian, and cervical tumors. In the current study, we investigated LATS1 genetic variations including single nucleotide polymorphisms (SNPs), in 28 Egyptian patients with either urinary bladder or colon cancers. The LATS1 gene was amplified and sequenced and the expression of LATS1 at the RNA level was assessed in 12 urinary bladder cancer samples. We report, the identification of a total of 29 variants including previously identified SNPs within LATS1 coding and non-coding sequences. A total of 18 variants were novel. Majority of the novel variants, 13, were mapped to intronic sequences and un-translated regions of the gene. Four of the five novel variants located in the coding region of the gene, represented missense mutations within the serine/threonine kinase catalytic domain. Interestingly, LATS1 RNA steady state levels was lost in urinary bladder cancerous tissue harboring four specific SNPs (16045 + 41736 + 34614 + 56177) positioned in the 5′UTR, intron 6, and two silent mutations within exon 4 and exon 8, respectively. This study identifies novel single-base-sequence alterations in the LATS1 gene. These newly identified variants could potentially be used as novel diagnostic or prognostic tools in cancer. PMID:25628642

  1. Identifying novel homozygous deletions by microsatellite analysis and characterization of tumor suppressor candidate 1 gene, TUSC1, on chromosome 9p in human lung cancer

    PubMed Central

    Shan, Zhihong; Parker, Tracy; Wiest, Jonathan S

    2012-01-01

    Loss of heterozygosity (LOH) studies indicate that genetic alterations of chromosome 9p occur in numerous tumor types, suggesting the presence of tumor suppressor genes (TSGs) on chromosome 9p critical in carcinogenesis. Our previous LOH analyses in primary lung tumors led us to propose that chromosome 9p harbors other TSGs important in lung tumorigenesis. In this study, 30 non-small-cell lung cancer and 12 small-cell lung cancer cell lines were screened with 55 markers to identify new regions of homozygous deletion (HD) on chromosome 9p. Three novel noncontiguous homozygously deleted regions were detected and ranged in size from 840 kb to 7.4 Mb. One gene identified in the deletion at D9S126, TUSC1 (tumor suppressor candidate 1), is an intronless gene. Multiplex polymerase chain reaction and Southern blot confirmed the HD of TUSC1. Northern blot analysis of TUSC1 demonstrated two transcripts of approximately 2 and 1.5 kb that are likely generated by alternative polyadenylation signals. Both transcripts are expressed in several human tissues and share an open-reading frame encoding a peptide of 209 amino acids. Analysing cell line cDNAs by reverse transcriptase (RT)–PCR demonstrated downregulation of TUSC1 in cell lines with or without HDs, suggesting that TUSC1 may play a role in lung tumorigenesis. PMID:15208665

  2. Alteration of WWOX in human cancer, a clinical view

    PubMed Central

    Baryła, Izabela; Styczeń-Binkowska, Ewa

    2015-01-01

    WWOX gene is located in FRA16D, the highly affected chromosomal fragile site. Its tumor suppressor activity has been proposed on a basis of numerous genomic alterations reported in chromosome 16q23.3–24.1 locus. WWOX is affected in many cancers, showing as high as 80% loss of heterozygosity in breast tumors. Unlike most tumor suppressors impairing of both alleles of WWOX is very rare. Despite cellular and animal models information on a WWOX role in cancer tissue is limited and sometimes confusing. This review summarizes information on WWOX in human tumors. PMID:25681467

  3. Frequent loss of sequences from the long arm of chromosome 10 in endometrial cancers

    SciTech Connect

    Peiffer, S.; Tribune, D.; Goodfellow, P.J.

    1994-09-01

    Endometrial cancer is the most common gynecological malignancy in the United States, with an estimated 33,000 new cases diagnosed annually. Cancers develop as the result of the accumulation of mutations in proto-oncogenes and tumor suppressor genes. Mutations in KRAS and TP53 in endometrial cancer have been reported, but for the most part the genetic events underlying endometrial tumorigenesis have not been defined. Previous loss of heterozygosity studies (LOH) in endometrial cancers revealed frequent loss of sequences from 3p, 10q, 17p and 18q, suggesting a role for tumor suppressor genes that lie within these regions of loss. We have undertaken a series of experiments to identify tumor suppressor genes involved in endometrial tumorigenesis, focusing on a region of chromosome 10 that is likely to include a novel tumor suppressor gene. We have allelotyped 40 normal/tumor DNA pairs with 5 microsatellite repeat markers from 10q and one from 10p. LOH for at least one 10q marker was seen in 45% of informative samples. Chromosome 10 LOH was seen most frequently in Grade 1 adenocarcinoma (5/8; 60%). Grade 3 adenocarcinomas were also characterized by LOH of 10q sequences. Grade 2 tumors, on the other hand, did not reveal chromosome 10 LOH but were instead characterized by frequent microsatellite instability (RER). Other tumor types did not show the same patterns of genetic alteration seen in adenocarcinoma. We are currently defining the smallest region(s) of loss on 10q by typing 75 tumor/normal pairs using a set of ordered microsatellite repeat markers from distal 10q. A candidate tumorigenesis gene within what is the common region of deletion is being characterized in detail in a series of tumors.

  4. Low Gene Dosage of Cdc42 Is Not Associated with Protein Dysfunction in Patients with Colorectal Cancer.

    PubMed

    González-Quiroz, Matías; Calderón, Ximena; Oyarzún, Ingrid; Hoepfner, Claudia; Azócar, Andrés; Aguirre, Adam; Álvarez, Karin; Quera, Rodrigo; López-Köstner, Francisco; Meléndez, Jaime

    2016-12-01

    High incidence of Rho Cdc42-GTPase overexpression has been found in Colorectal Cancer (CRC) samples, suggesting its potential role in tumor development. However, no conclusive studies have shown the lack of mutations and/or copy number of Cdc42 gene in this type of samples. To understand mutation/deletion and copy number status of Cdc42 gene, CRC patients were evaluated for both parameters. More than Cdc42 mutants, single-nucleotide variants were found. Analysis of regions flanking the Cdc42 gene showed allelic imbalance; 58.7% were loss of heterozygosity (LOH) positive and 14.8% presented microsatellite instability. The highest LOH percentage was located between microsatellite markers D1S199 and D1S2674, where the Cdc42 gene is located. No association between gender, age, and tumor stage was found. LOH validation through gene dosage analysis showed most CRC patients with allelic imbalance also presented a low gene dosage of Cdc42, although equal amounts of Cdc42 mRNA were detected in all samples. Although changes in Cdc42 expression were not found in any condition, Cdc42 activation was different between high and normal gene dosage samples, but not between samples with normal and low copy number. Low dosage of Cdc42 was also not related to changes in methylation status at the Cdc42 promoter region. Results suggest that low copy of Cdc42 gene is not associated with Cdc42 protein dysfunction in CRC patients.

  5. Evidence of the presence of both oncogene and tumor suppressor gene on chromosome 1q in primary breast cancer, together with a genic dosage effect

    SciTech Connect

    Bieche, I.; Champeme, M.H.; Lidereau, R.

    1994-09-01

    Alterations of the long arm of chromosome 1 are the most consistent cytogenetic abnormalities found in human breast carcinoma. We examined genetic alterations on chromosome 1q in 124 human breast tumors, using restriction fragment length polymorphism (RFLP) markers mapping to the long (thirteen markers) and the short arm (four markers). Imbalance of heterozygosity at one or more loci on the long arm was observed in 80 (65%) of the 124 tumors. Among these 80 tumor DNAs, 38 showed a gain of heterozygosity (GOH), 16 a loss of heterozygosity (LOH) and one both GOH and LOH, at each locus on the long arm, indicating that 55 tumor DNAs had a gain and/or loss of the entire long arm of chromosome 1. Detailed alteration mapping of the other 25 tumors showing partial alterations of chromosome 1q identified two distinct altered regions: a smallest common deleted region at 1q21-31 and a smallest common overrepresented region at 1q41-q44. The results suggest that both oncogene(s) and tumor suppressor gene(s) are present on chromosome 1q and are associated with breast carcinomas. Moreover, the frequent loss or gain of a whole copy of chromosome 1q suggests that involvement a genic dosage effect in the pathogenesis of breast cancer.

  6. Novel high-grade serous epithelial ovarian cancer cell lines that reflect the molecular diversity of both the sporadic and hereditary disease

    PubMed Central

    Carmona, Euridice; Portelance, Lise; Arcand, Suzanna L.; Rahimi, Kurosh; Tonin, Patricia N.; Provencher, Diane; Mes-Masson, Anne-Marie

    2015-01-01

    Few cell line models of epithelial ovarian cancer (EOC) have been developed for the high-grade serous (HGS) subtype, which is the most common and lethal form of gynaecological cancer. Here we describe the establishment of six new EOC cell lines spontaneously derived from HGS tumors (TOV2978G, TOV3041G and TOV3291G) or ascites (OV866(2), OV4453 and OV4485). Exome sequencing revealed somatic TP53 mutations in five of the cell lines. One cell line has a novel BRCA1 splice-site mutation, and another, a recurrent BRCA2 nonsense mutation, both of germline origin. The novel BRCA1 mutation induced abnormal splicing, mRNA instability, resulting in the absence of BRCA1 protein. None of the cell lines harbor mutations in KRAS or BRAF, which are characteristic of other EOC subtypes. SNP arrays showed that all of the cell lines exhibited structural chromosomal abnormalities, copy number alterations and regions of loss of heterozygosity, consistent with those described for HGS. Four cell lines were able to produce 3D-spheroids, two exhibited anchorage-independent growth, and three (including the BRCA1 and BRCA2 mutated cell lines) formed tumors in SCID mice. These novel HGS EOC cell lines and their detailed characterization provide new research tools for investigating the most common and lethal form of EOC. PMID:26622941

  7. The genes of interferons and interferon-related factors: localization and relationships with chromosome aberrations in cancer.

    PubMed

    Haus, O

    2000-01-01

    The paper presents a review of data on the localization of interferons (IFNs) and IFN system genes and their relationship with human diseases, mainly cancer. Genes of interferon system proteins are located at the sites of breakpoints of the structural chromosome aberrations in cancer. Thus, any of them are rearranged or translocated in various tumor types. As the activity of these genes plays a role in cancer development, their rearrangements may be one of the crucial points in the pathogenesis of some cancer types. Besides, they also take part in organism immunity against viral infections. Transfection experiments with IFN system genes have proved the influence of these genes on cancer behavior and may serve as a basis for clinical gene therapy. IFN-alpha and IFN-beta genes are located at 9p21-22, the site of frequent homozygotic deletions in cancer. Their loss sensitizes cells to the growth inhibitory actions of exogenous IFNs. The IFN-gamma gene, a representative of class II genes, is located at 12q24.1. Transfection of class II IFNs genes to cancer cell lines causes cell proliferation arrest and augments the expression of HLA antigens, which may be clinically useful in stimulating the immune destruction of tumor cells. The interferon regulatory factor 1 (IRF-1) gene is located at 5q31, the site of common deletions in myelodysplastic syndromes (MDS) and secondary leukemias. The loss of heterozygosity of this gene was found in MDS, which proves that IRF-1 may be a tumor suppressor. A transfection of its gene causes neoplastic transformation arrest. The double-stranded RNA-activated protein kinase (PKR) gene is located at 2p21-22, a region which is frequently rearranged in leukemia. Transfection of a wild type PKR gene reverses neoplastic transformation caused by transfection of a mutated PKR gene, proving that PKR acts as a dominant negative cancer suppressor.

  8. Trends in UK regional cancer mortality 1991–2007

    PubMed Central

    Marshall, Dominic C; Webb, Thomas E; Hall, Richard A; Salciccioli, Justin D; Ali, Raghib; Maruthappu, Mahiben

    2016-01-01

    Background: Until 1990, there was an upward trend in mortality from breast, lung, prostate, and colon cancers in the United Kingdom. With improvements in cancer treatment there has, in general, been a fall in mortality over the last 20 years. We evaluate regional cancer mortality trends in the United Kingdom between 1991 and 2007. Methods: We analysed mortality trends for breast, lung, prostate, and colon cancers using data obtained from the EUREG cancer database. We have described changes in age-standardised rates (using European standard population) per 100 000 for cancer mortality and generated trends in mortality for the 11 regions using Joinpoint regression. Results: Across all regions in the United Kingdom there was a downward trend in mortality for the four most common cancers in males and females. Overall, deaths from colon cancer decreased most rapidly and deaths from prostate cancer decreased at the slowest rate. Similar downward trends in mortality were observed across all regions of the United Kingdom with the data for lung cancer exhibiting the greatest variation. Conclusions: Mortality from the four most common cancers decreased across all regions of the United Kingdom; however, the rate of decline varied between cancer type and in some instances by region. PMID:26766741

  9. Molecular clonality analysis of esophageal adenocarcinoma by multiregion sequencing of tumor samples.

    PubMed

    van Nistelrooij, Anna M J; van Marion, Ronald; Koppert, Linetta B; Biermann, Katharina; Spaander, Manon C W; Tilanus, Hugo W; van Lanschot, J Jan B; Wijnhoven, Bas P L; Dinjens, Winand N M

    2017-04-04

    Intratumor heterogeneity has been demonstrated in several cancer types, following a model of branched evolution. It is unknown to which extent intratumor heterogeneity is applicable to esophageal adenocarcinoma. Therefore the aim of this study was to characterise intratumor heterogeneity in esophageal adenocarcinoma. Multiregional targeted sequencing of four commonly altered genes was performed on 19 tumor regions collected from five esophageal adenocarcinomas. Alterations were classified as homogeneous or heterogeneous based on mutational and loss of heterozygosity analysis. Identical TP53 mutations and homogeneously loss of heterozygosity of the TP53 locus were identified in all separated tumor regions in each of five adenocarcinomas, and in the corresponding Barrett's esophagus and tumor positive lymph node of one primary tumor. Loss of heterozygosity of the P16 locus was homogeneous among all tumor regions in four adenocarcinomas, and an identical pattern of loss of heterozygosity was present in the Barrett's esophagus. Loss of heterozygosity of the SMAD4 and APC loci was observed in a heterogeneous pattern. Known driver alterations, such as TP53 and P16 are homogeneously present within each adenocarcinoma, and therefore occur early during carcinogenesis and subsequently clonally expand throughout the entire tumor. However, loss of heterozygosity of the SMAD4 and APC loci shows a heterogeneous pattern, indicating intratumor heterogeneity of esophageal adenocarcinoma.

  10. Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/β-catenin signalling thresholds for tumourigenesis.

    PubMed

    Christie, M; Jorissen, R N; Mouradov, D; Sakthianandeswaren, A; Li, S; Day, F; Tsui, C; Lipton, L; Desai, J; Jones, I T; McLaughlin, S; Ward, R L; Hawkins, N J; Ruszkiewicz, A R; Moore, J; Burgess, A W; Busam, D; Zhao, Q; Strausberg, R L; Simpson, A J; Tomlinson, I P M; Gibbs, P; Sieber, O M

    2013-09-26

    Biallelic protein-truncating mutations in the adenomatous polyposis coli (APC) gene are prevalent in sporadic colorectal cancer (CRC). Mutations may not be fully inactivating, instead producing WNT/β-catenin signalling levels 'just-right' for tumourigenesis. However, the spectrum of optimal APC genotypes accounting for both hits, and the influence of clinicopathological features on genotype selection remain undefined. We analysed 630 sporadic CRCs for APC mutations and loss of heterozygosity (LOH) using sequencing and single-nucleotide polymorphism microarrays, respectively. Truncating APC mutations and/or LOH were detected in 75% of CRCs. Most truncating mutations occurred within a mutation cluster region (MCR; codons 1282-1581) leaving 1-3 intact 20 amino-acid repeats (20AARs) and abolishing all Ser-Ala-Met-Pro (SAMP) repeats. Cancers commonly had one MCR mutation plus either LOH or another mutation 5' to the MCR. LOH was associated with mutations leaving 1 intact 20AAR. MCR mutations leaving 1 vs 2-3 intact 20AARs were associated with 5' mutations disrupting or leaving intact the armadillo-repeat domain, respectively. Cancers with three hits had an over-representation of mutations upstream of codon 184, in the alternatively spliced region of exon 9, and 3' to the MCR. Microsatellite unstable cancers showed hyper-mutation at MCR mono- and di-nucleotide repeats, leaving 2-3 intact 20AARs. Proximal and distal cancers exhibited different preferred APC genotypes, leaving a total of 2 or 3 and 0 to 2 intact 20AARs, respectively. In conclusion, APC genotypes in sporadic CRCs demonstrate 'fine-tuned' interdependence of hits by type and location, consistent with selection for particular residual levels of WNT/β-catenin signalling, with different 'optimal' thresholds for proximal and distal cancers.

  11. Chromosome 8p alterations in sporadic and BRCA2 999del5 linked breast cancer

    PubMed Central

    Sigbjornsdottir, B. I.; Ragnarsson, G.; Agnarsson, B. A.; Huiping, C.; Barkardottir, R. B.; Egilsson, V.; Ingvarsson, S.

    2000-01-01

    Chromosomal losses involving the short arm of chromosome 8 are frequent in a variety of tumour types, including breast cancer, suggesting the presence of one or more tumour suppressor genes in this region. In this study, we have used 11 microsatellite markers to analyse loss of heterozygosity (LOH) at chromosome 8p in 151 sporadic breast tumours and 50 tumours from subjects carrying the BRCA2 999del5 mutation. Fifty percent of sporadic tumours compared to 78% of BRCA2 linked tumours exhibit LOH at one or more markers at 8p showing that chromosome 8p alterations in breast tumours from BRCA2 999del5 carriers are more pronounced than in sporadic breast tumours. The pattern of LOH is different in the two groups and a higher proportion of BRCA2 tumours have LOH in a large region of chromosome 8p. In the total patient material, LOH of 8p is associated with LOH at other chromosome regions, for example, 1p, 3p, 6q, 7q, 9p, 11p, 13q, 17p, and 20q, but no association is found between LOH at 8p and chromosome regions 11q, 16q, 17q, and 18q. Furthermore, an association is detected between LOH at 8p and positive node status, large tumour size, aneuploidy, and high S phase fraction. Breast cancer patients with LOH at chromosome 8p have a worse prognosis than patients without this defect. Multivariate analysis suggests that LOH at 8p is an independent prognostic factor. We conclude that chromosome 8p carries a tumour suppressor gene or genes, the loss of which results in growth advantage of breast tumour cells, especially in carriers of the BRCA2 999del5 mutation.


Keywords: chromosome 8; BRCA2; LOH; breast cancer PMID:10807692

  12. Germ-line mutation of NKX3.1 cosegregates with hereditary prostate cancer and alters the homeodomain structure and function.

    PubMed

    Zheng, S Lilly; Ju, Jeong-ho; Chang, Bao-li; Ortner, Elizabeth; Sun, Jielin; Isaacs, Sarah D; Sun, Jishang; Wiley, Kathy E; Liu, Wennuan; Zemedkun, Micheas; Walsh, Patrick C; Ferretti, James; Gruschus, James; Isaacs, William B; Gelmann, Edward P; Xu, Jianfeng

    2006-01-01

    NKX3.1, a gene mapped to 8p21, is a member of the NK class of homeodomain proteins and is expressed primarily in the prostate. NKX3.1 exerts a growth-suppressive and differentiating effect on prostate epithelial cells. Because of its known functions and its location within a chromosomal region where evidence for prostate cancer linkage and somatic loss of heterozygosity is found, we hypothesize that sequence variants in the NKX3.1 gene increase prostate cancer risk. To address this, we first resequenced the NKX3.1 gene in 159 probands of hereditary prostate cancer families recruited at Johns Hopkins Hospital; each family has at least three first-degree relatives affected with prostate cancer. Twenty-one germ-line variants were identified in this analysis, including one previously described common nonsynonymous change (R52C), two novel rare nonsynonymous changes (A17T and T164A), and a novel common 18-bp deletion in the promoter. Overall, the germ-line variants were significantly linked to prostate cancer, with a peak heterogeneity logarithm of odds of 2.04 (P = 0.002) at the NKX3.1 gene. The rare nonsynonymous change, T164A, located in the homeobox domain of the gene, segregated with prostate cancer in a family with three affected brothers and one unaffected brother. Importantly, nuclear magnetic resonance solution structure analysis and circular dichroism studies showed this specific mutation to affect the stability of the homeodomain of the NKX3.1 protein and decreased binding to its cognate DNA recognition sequence. These results suggest that germ-line sequence variants in NKX3.1 may play a role in susceptibility to hereditary prostate cancer and underscore a role for NKX3.1 as a prostate cancer gatekeeper.

  13. Leading Causes of Cancer Mortality - Caribbean Region, 2003-2013.

    PubMed

    Razzaghi, Hilda; Quesnel-Crooks, Sarah; Sherman, Recinda; Joseph, Rachael; Kohler, Betsy; Andall-Brereton, Glennis; Ivey, Marsha A; Edwards, Brenda K; Mery, Les; Gawryszewski, Vilma; Saraiya, Mona

    2016-12-16

    Cancer is one of the leading causes of deaths worldwide (1); in 2012, an estimated 65% of all cancer deaths occurred in the less developed regions of the world (2). In the Caribbean region, cancer is the second leading cause of mortality, with an estimated 87,430 cancer-related deaths reported in 2012 (3). The Pan American Health Organization defines the Caribbean region as a group of 27 countries that vary in size, geography, resources, and surveillance systems.* CDC calculated site- and sex-specific proportions of cancer deaths and age-standardized mortality rates (ASMR) for 21 English- and Dutch-speaking Caribbean countries, the United States, and two U.S. territories (Puerto Rico and the U.S. Virgin Islands [USVI]), using the most recent 5 years of mortality data available from each jurisdiction during 2003-2013. The selection of years varied by availability of the data from the countries and territories in 2015. ASMR for all cancers combined ranged from 46.1 to 139.3 per 100,000. Among males, prostate cancers were the leading cause of cancer deaths, followed by lung cancers; the percentage of cancer deaths attributable to prostate cancer ranged from 18.4% in Suriname to 47.4% in Dominica, and the percentage of cancer deaths attributable to lung cancer ranged from 5.6% in Barbados to 24.4% in Bermuda. Among females, breast cancer was the most common cause of cancer deaths, ranging from 14.0% of cancer deaths in Belize to 29.7% in the Cayman Islands, followed by cervical cancer. Several of the leading causes of cancer deaths in the Caribbean can be reduced through primary and secondary preventions, including prevention of exposure to risk factors, screening, early detection, and timely and effective treatment.

  14. Patterns of somatic uniparental disomy identify novel tumor suppressor genes in colorectal cancer.

    PubMed

    Torabi, Keyvan; Miró, Rosa; Fernández-Jiménez, Nora; Quintanilla, Isabel; Ramos, Laia; Prat, Esther; del Rey, Javier; Pujol, Núria; Killian, J Keith; Meltzer, Paul S; Fernández, Pedro Luis; Ried, Thomas; Lozano, Juan José; Camps, Jordi; Ponsa, Immaculada

    2015-10-01

    Colorectal cancer (CRC) is characterized by specific patterns of copy number alterations (CNAs), which helped with the identification of driver oncogenes and tumor suppressor genes (TSGs). More recently, the usage of single nucleotide polymorphism arrays provided information of copy number neutral loss of heterozygosity, thus suggesting the occurrence of somatic uniparental disomy (UPD) and uniparental polysomy (UPP) events. The aim of this study is to establish an integrative profiling of recurrent UPDs/UPPs and CNAs in sporadic CRC. Our results indicate that regions showing high frequencies of UPD/UPP mostly coincide with regions typically involved in genomic losses. Among them, chromosome arms 3p, 5q, 9q, 10q, 14q, 17p, 17q, 20p, 21q and 22q preferentially showed UPDs/UPPs over genomic losses suggesting that tumor cells must maintain the disomic state of certain genes to favor cellular fitness. A meta-analysis using over 300 samples from The Cancer Genome Atlas confirmed our findings. Several regions affected by recurrent UPDs/UPPs contain well-known TSGs, as well as novel candidates such as ARID1A, DLC1, TCF7L2 and DMBT1. In addition, VCAN, FLT4, SFRP1 and GAS7 were also frequently involved in regions of UPD/UPP and displayed high levels of methylation. Finally, sequencing and fluorescence in situ hybridization analysis of the gene APC underlined that a somatic UPD event might represent the second hit to achieve biallelic inactivation of this TSG in colorectal tumors. In summary, our data define a profile of somatic UPDs/UPPs in sporadic CRC and highlights the importance of these events as a mechanism to achieve the inactivation of TSGs.

  15. Chromosome 8p alterations in sporadic and BRCA2 999del5 linked breast cancer.

    PubMed

    Sigbjörnsdottir, B I; Ragnarsson, G; Agnarsson, B A; Huiping, C; Barkardottir, R B; Egilsson, V; Ingvarsson, S

    2000-05-01

    Chromosomal losses involving the short arm of chromosome 8 are frequent in a variety of tumour types, including breast cancer, suggesting the presence of one or more tumour suppressor genes in this region. In this study, we have used 11 microsatellite markers to analyse loss of heterozygosity (LOH) at chromosome 8p in 151 sporadic breast tumours and 50 tumours from subjects carrying the BRCA2 999del5 mutation. Fifty percent of sporadic tumours compared to 78% of BRCA2 linked tumours exhibit LOH at one or more markers at 8p showing that chromosome 8p alterations in breast tumours from BRCA2 999del5 carriers are more pronounced than in sporadic breast tumours. The pattern of LOH is different in the two groups and a higher proportion of BRCA2 tumours have LOH in a large region of chromosome 8p. In the total patient material, LOH of 8p is associated with LOH at other chromosome regions, for example, 1p, 3p, 6q, 7q, 9p, 11p, 13q, 17p, and 20q, but no association is found between LOH at 8p and chromosome regions 11q, 16q, 17q, and 18q. Furthermore, an association is detected between LOH at 8p and positive node status, large tumour size, aneuploidy, and high S phase fraction. Breast cancer patients with LOH at chromosome 8p have a worse prognosis than patients without this defect. Multivariate analysis suggests that LOH at 8p is an independent prognostic factor. We conclude that chromosome 8p carries a tumour suppressor gene or genes, the loss of which results in growth advantage of breast tumour cells, especially in carriers of the BRCA2 999del5 mutation.

  16. Patterns of somatic uniparental disomy identify novel tumor suppressor genes in colorectal cancer

    PubMed Central

    Torabi, Keyvan; Miró, Rosa; Fernández-Jiménez, Nora; Quintanilla, Isabel; Ramos, Laia; Prat, Esther; del Rey, Javier; Pujol, Núria; Killian, J. Keith; Meltzer, Paul S.; Fernández, Pedro Luis; Ried, Thomas; Lozano, Juan José; Camps, Jordi; Ponsa, Immaculada

    2015-01-01

    Colorectal cancer (CRC) is characterized by specific patterns of copy number alterations (CNAs), which helped with the identification of driver oncogenes and tumor suppressor genes (TSGs). More recently, the usage of single nucleotide polymorphism arrays provided information of copy number neutral loss of heterozygosity, thus suggesting the occurrence of somatic uniparental disomy (UPD) and uniparental polysomy (UPP) events. The aim of this study is to establish an integrative profiling of recurrent UPDs/UPPs and CNAs in sporadic CRC. Our results indicate that regions showing high frequencies of UPD/UPP mostly coincide with regions typically involved in genomic losses. Among them, chromosome arms 3p, 5q, 9q, 10q, 14q, 17p, 17q, 20p, 21q and 22q preferentially showed UPDs/UPPs over genomic losses suggesting that tumor cells must maintain the disomic state of certain genes to favor cellular fitness. A meta-analysis using over 300 samples from The Cancer Genome Atlas confirmed our findings. Several regions affected by recurrent UPDs/UPPs contain well-known TSGs, as well as novel candidates such as ARID1A, DLC1, TCF7L2 and DMBT1. In addition, VCAN, FLT4, SFRP1 and GAS7 were also frequently involved in regions of UPD/UPP and displayed high levels of methylation. Finally, sequencing and fluorescence in situ hybridization analysis of the gene APC underlined that a somatic UPD event might represent the second hit to achieve biallelic inactivation of this TSG in colorectal tumors. In summary, our data define a profile of somatic UPDs/UPPs in sporadic CRC and highlights the importance of these events as a mechanism to achieve the inactivation of TSGs. PMID:26243311

  17. Digestive cancers in Morocco: Fez-Boulemane region

    PubMed Central

    Chbani, Laila; Hafid, Imane; Berraho, Mohamed; Nejjari, Chakib; Amarti, Afaf

    2012-01-01

    Introduction To describe the epidemiological and pathological aspects of gastrointestinal cancers in Fez-Boulemane. Methods This was a retrospective descriptive study of 1120 gastrointestinal cancers diagnosed between 2004 and 2010 in the department of Pathology of Hassan II University Hospital in Fez Morocco. Results The average age of our patients was 53 years with a male predominance in 52% of cases. Digestive cancers in this study are distinguished by the predominance of colorectal and stomach location. Conclusion Gastrointestinal cancers are the most frequent cancer in our region. An epidemiological monitoring program is needed. PMID:23330037

  18. DNA repair genes implicated in triple negative familial non-BRCA1/2 breast cancer predisposition.

    PubMed

    Ollier, Marie; Radosevic-Robin, Nina; Kwiatkowski, Fabrice; Ponelle, Flora; Viala, Sandrine; Privat, Maud; Uhrhammer, Nancy; Bernard-Gallon, Dominique; Penault-Llorca, Frédérique; Bignon, Yves-Jean; Bidet, Yannick

    2015-01-01

    Among breast cancers, 10 to 15% of cases would be due to hereditary risk. In these familial cases, mutations in BRCA1 and BRCA2 are found in only 15% to 20%, meaning that new susceptibility genes remain to be found. Triple-negative breast cancers represent 15% of all breast cancers, and are generally aggressive tumours without targeted therapies available. Our hypothesis is that some patients with triple negative breast cancer could share a genetic susceptibility different from other types of breast cancers. We screened 36 candidate genes, using pyrosequencing, in all the 50 triple negative breast cancer patients with familial history of cancer but no BRCA1 or BRCA2 mutation of a population of 3000 families who had consulted for a familial breast cancer between 2005 and 2013. Any mutations were also sequenced in available relatives of cases. Protein expression and loss of heterozygosity were explored in tumours. Seven deleterious mutations in 6 different genes (RAD51D, MRE11A, CHEK2, MLH1, MSH6, PALB2) were observed in one patient each, except the RAD51D mutation found in two cases. Loss of heterozygosity in the tumour was found for 2 of the 7 mutations. Protein expression was absent in tumour tissue for 5 mutations. Taking into consideration a specific subtype of tumour has revealed susceptibility genes, most of them in the homologous recombination DNA repair pathway. This may provide new possibilities for targeted therapies, along with better screening and care of patients.

  19. DNA repair genes implicated in triple negative familial non-BRCA1/2 breast cancer predisposition

    PubMed Central

    Ollier, Marie; Radosevic-Robin, Nina; Kwiatkowski, Fabrice; Ponelle, Flora; Viala, Sandrine; Privat, Maud; Uhrhammer, Nancy; Bernard-Gallon, Dominique; Penault-Llorca, Frédérique; Bignon, Yves-Jean; Bidet, Yannick

    2015-01-01

    Among breast cancers, 10 to 15% of cases would be due to hereditary risk. In these familial cases, mutations in BRCA1 and BRCA2 are found in only 15% to 20%, meaning that new susceptibility genes remain to be found. Triple-negative breast cancers represent 15% of all breast cancers, and are generally aggressive tumours without targeted therapies available. Our hypothesis is that some patients with triple negative breast cancer could share a genetic susceptibility different from other types of breast cancers. We screened 36 candidate genes, using pyrosequencing, in all the 50 triple negative breast cancer patients with familial history of cancer but no BRCA1 or BRCA2 mutation of a population of 3000 families who had consulted for a familial breast cancer between 2005 and 2013. Any mutations were also sequenced in available relatives of cases. Protein expression and loss of heterozygosity were explored in tumours. Seven deleterious mutations in 6 different genes (RAD51D, MRE11A, CHEK2, MLH1, MSH6, PALB2) were observed in one patient each, except the RAD51D mutation found in two cases. Loss of heterozygosity in the tumour was found for 2 of the 7 mutations. Protein expression was absent in tumour tissue for 5 mutations. Taking into consideration a specific subtype of tumour has revealed susceptibility genes, most of them in the homologous recombination DNA repair pathway. This may provide new possibilities for targeted therapies, along with better screening and care of patients. PMID:26328243

  20. BRG1 and LKB1: tales of two tumor suppressor genes on chromosome 19p and lung cancer.

    PubMed

    Rodriguez-Nieto, Salvador; Sanchez-Cespedes, Montse

    2009-04-01

    Losses of heterozygosity (LOH) of the short arm of chromosome 19 are frequent in lung cancer, suggesting that one or more tumor suppressor genes are present in this region. The LKB1 gene, also called STK11, is somatically inactivated through point mutations and large deletions in lung tumors, demonstrating that LKB1 is a target of the LOH of this chromosomal arm. Data from several independent groups have provided information about the profiles of lung tumors with LKB1 inactivation and it is generally agreed that this alteration strongly predominates in non-small cell lung cancer, in particular adenocarcinomas, in smokers. The LKB1 protein has serine-threonine kinase activity and is involved in the regulation of the cell energetic checkpoint through the phosphorylation and activation of adenosine monophosphate-dependent kinase (AMPK). LKB1 is also involved in other processes such as cell polarization, probably through substrates other than AMPK. Interestingly, another gene on chromosome 19p, BRG1, encoding a component of the SWI/SNF chromatin-remodeling complex, has emerged as a tumor suppressor gene that is altered in lung tumors. Similar to LKB1, BRG1 is somatically inactivated by point mutations or large deletions in lung tumors featuring LOH of chromosome 19p. These observations suggest an important role for BRG1 in lung cancer and highlight the need to further our understanding of the function of Brahma/SWI2-related gene 1 (BRG1) in cancer. Finally, simultaneous mutations at LKB1 and BRG1 are common in lung cancer cells, which exemplifies how a single event, LOH of chromosome 19p in this instance, targets two different tumor suppressors.

  1. Molecular genetics of human cancer predisposition and progression.

    PubMed

    Cavenee, W K; Scrable, H J; James, C D

    1991-04-01

    The development of human cancer is generally thought to entail a series of events that cause a progressively more malignant phenotype. Such a hypothesis predicts that tumor cells of the ultimate stage will carry each of the events, cells of the penultimate stage will carry each of the events less the last one and so on. A dissection of the pathway from a normal cell to a fully malignant tumor may thus be viewed as the unraveling of a nested set of aberrations. In experiments designed to elucidate these events we have compared genotypic combinations at genomic loci defined by restriction endonuclease recognition site variation in normal and tumor tissues from patients with various forms and stages of cancer. The first step, inherited predisposition, is best described for retinoblastoma in which a recessive mutation of a locus residing in the 13q14 region of the genome is unmasked by aberrant, but specific, mitotic chromosomal segregation. Similar mechanisms involving the distal short arm of chromosome 17 are apparent in astrocytic tumors and the events are shared by cells in each malignancy state. DNA sequencing indicates that these events accomplish the homozygosis of mutant alleles of the p53 gene. Copy number amplification of the epidermal growth factor receptor gene occurs in intermediate and late-stage tumors whereas loss of heterozygosity for loci on chromosome 10 is restricted to the ultimate stage, glioblastoma multiforme. These results suggest a genetic approach to defining degrees of tumor progression and the locations of genes involved in the pathway as a prelude to their molecular isolation and characterization.

  2. Clues to the pathogenesis of familial colorectal cancer

    SciTech Connect

    Aaltonen, L.A.; Peltomaeki, P.; Pylkkaenen, L.; Chappelle, A. de la ); Leach, F.S.; Powell, S.M.; Jen, J.; Hamilton, S.R.; Petersen, G.M.; Kinzler, K.W.; Vogelstein, B. Johns Hopkins Hospital, Baltimore, MD ); Sistonen, P. Finnish Red Cross Blood Transfusion Service, Helsinki ); Mecklin, J.P. ); Jaervinen, H. )

    1993-05-07

    A predisposition to colorectal cancer is shown to be linked to markers on chromosome 2 in some families. Molecular features of familial cancers were compared with those of sporadic colon cancers. Neither the familial nor sporadic cancers showed loss of heterozygosity for chromosome 2 markers, and the incidence of mutations in KRAS, P53, and APC was similar in the two groups of tumors. Most of the familial cancers, however, had widespread alterations in short repeated DNA sequences, suggesting that numerous replication errors had occurred during tumor development. Thirteen percent of sporadic cancers had identical abnormalities and these cancers shared biologic properties with the familial cases. These data suggest a mechanism for familial tumorigenesis different from that mediated by classic tumor suppressor genes. 22 refs., 2 figs., 2 tabs.

  3. Sorafenib in Treating Patients With Regional or Metastatic Cancer of the Urothelium

    ClinicalTrials.gov

    2014-05-20

    Adenocarcinoma of the Bladder; Distal Urethral Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Proximal Urethral Cancer; Recurrent Bladder Cancer; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Urethral Cancer; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Squamous Cell Carcinoma of the Bladder; Stage III Bladder Cancer; Stage IV Bladder Cancer; Transitional Cell Carcinoma of the Bladder; Urethral Cancer Associated With Invasive Bladder Cancer

  4. Asian Cancer Registry Forum 2014 - regional cooperation for cancer registration: priorities and challenges.

    PubMed

    Moore, Malcolm A; Sangrajrang, Suleeporn; Bray, Freddie

    2014-01-01

    On February 6-7th, the Thai National Cancer Institute, the International Agency for Research on Cancer and its Mumbai Hub for Cancer Registration, together with the International Association of Cancer Registries and the APOCP/APJCP, jointly organized an Asian cancer registry forum to discuss regional cooperation for cancer registration. Held in the Grande Mercure Fortune Hotel, Bangkok, the meeting brought together leading scientists in cancer registration from South-East and North-East Asia as well as Australia, India and Iran and IARC itself, with coverage of various priorities and challenges of cancer registries regarding cancer control policy, operational parameters, assessment of survival and contributions to screening, for example. The current situation was highlighted and future directions and possible expansion of activities were discussed, with especial attention to the necessity for networks to help improve cancer registration across Asia and Africa.

  5. Identity by Descent Mapping of Founder Mutations in Cancer Using High-Resolution Tumor SNP Data

    PubMed Central

    Letouzé, Eric; Sow, Aliou; Petel, Fabien; Rosati, Roberto; Figueiredo, Bonald C.; Burnichon, Nelly; Gimenez-Roqueplo, Anne-Paule

    2012-01-01

    Dense genotype data can be used to detect chromosome fragments inherited from a common ancestor in apparently unrelated individuals. A disease-causing mutation inherited from a common founder may thus be detected by searching for a common haplotype signature in a sample population of patients. We present here FounderTracker, a computational method for the genome-wide detection of founder mutations in cancer using dense tumor SNP profiles. Our method is based on two assumptions. First, the wild-type allele frequently undergoes loss of heterozygosity (LOH) in the tumors of germline mutation carriers. Second, the overlap between the ancestral chromosome fragments inherited from a common founder will define a minimal haplotype conserved in each patient carrying the founder mutation. Our approach thus relies on the detection of haplotypes with significant identity by descent (IBD) sharing within recurrent regions of LOH to highlight genomic loci likely to harbor a founder mutation. We validated this approach by analyzing two real cancer data sets in which we successfully identified founder mutations of well-characterized tumor suppressor genes. We then used simulated data to evaluate the ability of our method to detect IBD tracts as a function of their size and frequency. We show that FounderTracker can detect haplotypes of low prevalence with high power and specificity, significantly outperforming existing methods. FounderTracker is thus a powerful tool for discovering unknown founder mutations that may explain part of the “missing” heritability in cancer. This method is freely available and can be used online at the FounderTracker website. PMID:22567117

  6. Allelic loss on distal chromosome 17p is associated with poor prognosis in a group of Brazilian breast cancer patients.

    PubMed Central

    Nagai, M. A.; Pacheco, M. M.; Brentani, M. M.; Marques, L. A.; Brentani, R. R.; Ponder, B. A.; Mulligan, L. M.

    1994-01-01

    We examined loss of heterozygosity (LOH) for two loci on chromosome 17p (D17S5 and TP53), and erbB-2 gene amplification, in primary breast cancers from 67 Brazilian patients. We identified two distinct regions of LOH on chromosome 17p, one spanning TP53 and the other a more telomeric region (D17S5). Based on a short-term follow-up, Kaplan-Meier analyses of patients' disease-free survival showed that patients with LOH for D17S5, but retaining heterozygosity for TP53, were at higher risk of recurrence (P = 0.007) than those who retained heterozygosity for D17S5. Bivariate analyses indicated that patients with LOH for D17S5 alone had an increased risk of recurrence (hazard ratio = 7.2) over patients with erbB-2 amplification (hazard ratio = 3.7), when compared with patients with neither alteration (hazard ratio = 1.0). Further, lymph node-positive patients whose tumours had both LOH for D17S5 and erbB-2 gene amplification had a higher risk of recurrence than patients whose tumours had neither of these genetic alterations. Our data confirm previous reports of a putative tumour-suppressor gene, distinct from TP53, on distal chromosome 17p which is associated with breast cancer. They further suggest that LOH for loci in this region may provide an independent indicator to identify patients with poor prognosis. Images Figure 1 Figure 3 PMID:7908218

  7. DNA Methylation in Promoter Region as Biomarkers in Prostate Cancer

    PubMed Central

    Yang, Mihi; Park, Jong Y.

    2013-01-01

    The prostate gland is the most common site of cancer and the second leading cause of cancer death in American men. Recent emerging molecular biological technologies help us to know that epigenetic alterations such as DNA methylation within the regulatory (promoter) regions of genes are associated with transcriptional silencing in cancer. Promoter hypermethylation of critical pathway genes could be potential biomarkers and therapeutic targets for prostate cancer. In this chapter, we updated current information on methylated genes associated with the development and progression of prostate cancer. Over 40 genes have been investigated for methylation in promoter region in prostate cancer. These methylated genes are involved in critical pathways, such as DNA repair, metabolism, and invasion/metastasis. The role of hypermethylated genes in regulation of critical pathways in prostate cancer is discussed. These findings may provide new information of the pathogenesis, the exciting potential to be predictive and to provide personalized treatment of prostate cancer. Indeed, some epigenetic alterations in prostate tumors are being translated into clinical practice for therapeutic use. PMID:22359288

  8. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis

    PubMed Central

    Edwards, S M; Evans, D G R; Hope, Q; Norman, A R; Barbachano, Y; Bullock, S; Kote-Jarai, Z; Meitz, J; Falconer, A; Osin, P; Fisher, C; Guy, M; Jhavar, S G; Hall, A L; O'Brien, L T; Gehr-Swain, B N; Wilkinson, R A; Forrest, M S; Dearnaley, D P; Ardern-Jones, A T; Page, E C; Easton, D F; Eeles, R A

    2010-01-01

    Background: The germline BRCA2 mutation is associated with increased prostate cancer (PrCa) risk. We have assessed survival in young PrCa cases with a germline mutation in BRCA2 and investigated loss of heterozygosity at BRCA2 in their tumours. Methods: Two cohorts were compared: one was a group with young-onset PrCa, tested for germline BRCA2 mutations (6 of 263 cases had a germline BRAC2 mutation), and the second was a validation set consisting of a clinical set from Manchester of known BRCA2 mutuation carriers (15 cases) with PrCa. Survival data were compared with a control series of patients in a single clinic as determined by Kaplan–Meier estimates. Loss of heterozygosity was tested for in the DNA of tumour tissue of the young-onset group by typing four microsatellite markers that flanked the BRCA2 gene, followed by sequencing. Results: Median survival of all PrCa cases with a germline BRCA2 mutation was shorter at 4.8 years than was survival in controls at 8.5 years (P=0.002). Loss of heterozygosity was found in the majority of tumours of BRCA2 mutation carriers. Multivariate analysis confirmed that the poorer survival of PrCa in BRCA2 mutation carriers is associated with the germline BRCA2 mutation per se. Conclusion: BRCA2 germline mutation is an independent prognostic factor for survival in PrCa. Such patients should not be managed with active surveillance as they have more aggressive disease. PMID:20736950

  9. Mapping HPV Vaccination and Cervical Cancer Screening Practice in the Pacific Region-Strengthening National and Regional Cervical Cancer Prevention.

    PubMed

    Obel, J; McKenzie, J; Buenconsejo-Lum, L E; Durand, A M; Ekeroma, A; Souares, Y; Hoy, D; Baravilala, W; Garland, S M; Kjaer, S K; Roth, A

    2015-01-01

    To provide background information for strengthening cervical cancer prevention in the Pacific by mapping current human papillomavirus (HPV) vaccination and cervical cancer screening practices, as well as intent and barriers to the introduction and maintenance of national HPV vaccination programmes in the region. A cross-sectional questionnaire-based survey among ministry of health officials from 21 Pacific Island countries and territories (n=21). Cervical cancer prevention was rated as highly important, but implementation of prevention programs were insufficient, with only two of 21 countries and territories having achieved coverage of cervical cancer screening above 40%. Ten of 21 countries and territories had included HPV vaccination in their immunization schedule, but only two countries reported coverage of HPV vaccination above 60% among the targeted population. Key barriers to the introduction and continuation of HPV vaccination were reported to be: (i) Lack of sustainable financing for HPV vaccine programs; (ii) Lack of visible government endorsement; (iii) Critical public perception of the value and safety of the HPV vaccine; and (iv) Lack of clear guidelines and policies for HPV vaccination. Current practices to prevent cervical cancer in the Pacific Region do not match the high burden of disease from cervical cancer. A regional approach, including reducing vaccine prices by bulk purchase of vaccine, technical support for implementation of prevention programs, operational research and advocacy could strengthen political momentum for cervical cancer prevention and avoid risking the lives of many women in the Pacific.

  10. Regional anaesthesia and analgesia: relationship to cancer recurrence and survival.

    PubMed

    Tedore, T

    2015-12-01

    Cancer treatment is associated with significant morbidity and mortality. Surgery is a mainstay of treatment for many tumours, and anaesthetists care for cancer patients on a daily basis. Surgery itself induces a stress response and inhibits the immune system, and cancer surgery is associated with the release of tumour cells systemically. Preclinical and clinical studies suggest that the anaesthetics and adjuvants given in the perioperative period can affect cancer recurrence and survival, perhaps tipping the balance in some instances to determine whether cancer progresses or regresses. Retrospective studies have hinted that regional anaesthesia can play a protective role in cancer surgery, but many of these studies are small and subject to bias. We eagerly await the results of several large, randomized controlled trials examining the impact of regional anaesthesia and analgesia on cancer recurrence and survival. © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. A Transcript Map for the 2.8-Mb Region Containing the Multiple Endocrine Neoplasia Type 1 Locus

    PubMed Central

    Guru, Siradanahalli C.; Agarwal, Sunita K.; Manickam, Pachiappan; Olufemi, Shodimu-Emmanuel; Crabtree, Judy S.; Weisemann, Jane M.; Kester, Mary Beth; Kim, Young S.; Wang, Yingping; Emmert-Buck, Michael R.; Liotta, Lance A.; Spiegel, Allen M.; Boguski, Mark S.; Roe, Bruce A.; Collins, Francis S.; Marx, Stephen J.; Burns, Lee; Chandrasekharappa, Settara C.

    1997-01-01

    Multiple endocrine neoplasia type 1 (MEN 1) is an inherited cancer syndrome in which affected individuals develop multiple parathyroid, enteropancreatic, and pituitary tumors. The locus for MEN1 is tightly linked to the marker PYGM on chromosome 11q13, and linkage analysis places the MEN1 gene within a 2-Mb interval flanked by the markers D11S1883 and D11S449. Loss of heterozygosity studies in MEN 1 and sporadic tumors suggest that the MEN1 gene encodes a tumor suppressor and have helped to narrow the location of the gene to a 600-kb interval between PYGM and D11S449. Focusing on this smaller MEN1 interval, we have identified and mapped 12 transcripts to this 600-kb region. A precise ordered map of 33 transcripts, including 12 genes known to map to this region, was generated for the 2.8-Mb D11S480–D11S913 interval. Fifteen candidate genes (of which 10 were examined exhaustively) were evaluated by Southern blot and/or dideoxy fingerprinting analysis to identify the gene harboring disease-causing mutations. [The sequence data described in this paper have been submitted to GenBank under accession nos. EST06996, U93236, AF001540–AF001547, AF001433–AF001436, AF001891–AF001893, N55476, R19205, and W37647 (see Table 1 for listing of transcripts). The BAC clone sequences have been submitted to GenBank under accession nos. AC000134, AC000159, and AC000353.] PMID:9253601

  12. Cure of cancer for seven cancer sites in the Flemish Region.

    PubMed

    Silversmit, Geert; Jegou, David; Vaes, Evelien; Van Hoof, Elke; Goetghebeur, Els; Van Eycken, Liesbet

    2017-03-01

    Cumulative relative survival curves for many cancers reach a plateau several years after diagnosis, indicating that the cancer survivor group has reached "statistical" cure. Parametric mixture cure model analysis on grouped relative survival curves provide an interesting way to determine the proportion of statistically cured cases and the mean survival time of the fatal cases in particular for population-based cancer registries. Based on the relative survival data from the Belgian Cancer Registry, parametric cure models were applied to seven cancer sites (cervix, colon, corpus uteri, skin melanoma, pancreas, stomach and oesophagus), at the Flemish Regional level for the incidence period 1999-2011. Statistical cure was observed for the examined cancer sites except for oesophageal cancer. The estimated cured proportion ranged from 5.9% [5.7, 6.1] for pancreatic cancer to 80.8% [80.5, 81.2] for skin melanoma. Cure results were further stratified by gender or age group. Stratified cured proportions were higher for females compared to males in colon cancer, stomach cancer, pancreas cancer and skin melanoma, which can mainly be attributed to differences in stage and age distribution between both sexes. This study demonstrates the applicability of cure rate models for the selected cancer sites after 14 years of follow-up and presents the first population-based results on the cure of cancer in Belgium.

  13. A genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies.

    PubMed

    Shames, David S; Girard, Luc; Gao, Boning; Sato, Mitsuo; Lewis, Cheryl M; Shivapurkar, Narayan; Jiang, Aixiang; Perou, Charles M; Kim, Young H; Pollack, Jonathan R; Fong, Kwun M; Lam, Chi-Leung; Wong, Maria; Shyr, Yu; Nanda, Rita; Olopade, Olufunmilayo I; Gerald, William; Euhus, David M; Shay, Jerry W; Gazdar, Adi F; Minna, John D

    2006-12-01

    Promoter hypermethylation coupled with loss of heterozygosity at the same locus results in loss of gene function in many tumor cells. The "rules" governing which genes are methylated during the pathogenesis of individual cancers, how specific methylation profiles are initially established, or what determines tumor type-specific methylation are unknown. However, DNA methylation markers that are highly specific and sensitive for common tumors would be useful for the early detection of cancer, and those required for the malignant phenotype would identify pathways important as therapeutic targets. In an effort to identify new cancer-specific methylation markers, we employed a high-throughput global expression profiling approach in lung cancer cells. We identified 132 genes that have 5' CpG islands, are induced from undetectable levels by 5-aza-2'-deoxycytidine in multiple non-small cell lung cancer cell lines, and are expressed in immortalized human bronchial epithelial cells. As expected, these genes were also expressed in normal lung, but often not in companion primary lung cancers. Methylation analysis of a subset (45/132) of these promoter regions in primary lung cancer (n = 20) and adjacent nonmalignant tissue (n = 20) showed that 31 genes had acquired methylation in the tumors, but did not show methylation in normal lung or peripheral blood cells. We studied the eight most frequently and specifically methylated genes from our lung cancer dataset in breast cancer (n = 37), colon cancer (n = 24), and prostate cancer (n = 24) along with counterpart nonmalignant tissues. We found that seven loci were frequently methylated in both breast and lung cancers, with four showing extensive methylation in all four epithelial tumors. By using a systematic biological screen we identified multiple genes that are methylated with high penetrance in primary lung, breast, colon, and prostate cancers. The cross-tumor methylation pattern we observed for these novel markers suggests

  14. A Genome-Wide Screen for Promoter Methylation in Lung Cancer Identifies Novel Methylation Markers for Multiple Malignancies

    PubMed Central

    Shames, David S; Girard, Luc; Gao, Boning; Sato, Mitsuo; Lewis, Cheryl M; Shivapurkar, Narayan; Jiang, Aixiang; Perou, Charles M; Kim, Young H; Pollack, Jonathan R; Fong, Kwun M; Lam, Chi-Leung; Wong, Maria; Shyr, Yu; Nanda, Rita; Olopade, Olufunmilayo I; Gerald, William; Euhus, David M; Shay, Jerry W; Gazdar, Adi F; Minna, John D

    2006-01-01

    Background Promoter hypermethylation coupled with loss of heterozygosity at the same locus results in loss of gene function in many tumor cells. The “rules” governing which genes are methylated during the pathogenesis of individual cancers, how specific methylation profiles are initially established, or what determines tumor type-specific methylation are unknown. However, DNA methylation markers that are highly specific and sensitive for common tumors would be useful for the early detection of cancer, and those required for the malignant phenotype would identify pathways important as therapeutic targets. Methods and Findings In an effort to identify new cancer-specific methylation markers, we employed a high-throughput global expression profiling approach in lung cancer cells. We identified 132 genes that have 5′ CpG islands, are induced from undetectable levels by 5-aza-2′-deoxycytidine in multiple non-small cell lung cancer cell lines, and are expressed in immortalized human bronchial epithelial cells. As expected, these genes were also expressed in normal lung, but often not in companion primary lung cancers. Methylation analysis of a subset (45/132) of these promoter regions in primary lung cancer (n = 20) and adjacent nonmalignant tissue (n = 20) showed that 31 genes had acquired methylation in the tumors, but did not show methylation in normal lung or peripheral blood cells. We studied the eight most frequently and specifically methylated genes from our lung cancer dataset in breast cancer (n = 37), colon cancer (n = 24), and prostate cancer (n = 24) along with counterpart nonmalignant tissues. We found that seven loci were frequently methylated in both breast and lung cancers, with four showing extensive methylation in all four epithelial tumors. Conclusions By using a systematic biological screen we identified multiple genes that are methylated with high penetrance in primary lung, breast, colon, and prostate cancers. The cross-tumor methylation

  15. Oral cancer in Libya and development of regional oral cancer registries: A review

    PubMed Central

    BenNasir, E.; El Mistiri, M.; McGowan, R.; Katz, R.V.

    2015-01-01

    The aims of this paper are three-fold: (1) to summarize the current epidemiological data on oral cancer in Libya as reported in the published literature and as compared to other national oral cancer rates in the region; (2) to present both the history of the early development, and future goals, of population-based oral cancer tumor registries in Libya as they partner with the more established regional and international population-based cancer tumor registries; and, (3) to offer recommendations that will likely be required in the near future if these nascent, population-based Libyan oral cancer registries are to establish themselves as on-going registries for describing the oral cancer disease patterns and risk factors in Libya as well as for prevention and treatment. This comprehensive literature review revealed that the current baseline incidence of oral cancer in Libya is similar to those of other North Africa countries and China, but is relatively low compared to the United Kingdom, the United States, and India. The recently established Libyan National Cancer Registry Program, initiated in 2007, while envisioning five cooperating regional cancer registries, continues to operate at a relatively suboptimal level. Lack of adequate levels of national funding continue to plague its development…and the accompanying quality of service that could be provided to the Libyan people. PMID:26644751

  16. [Incidence and regional distribution of colorectal cancers in Austria].

    PubMed

    Hanusch, J; Friedl, H P; Schemper, M; Schiessel, R

    1985-05-10

    Based on data obtained from the official Austrian cancer registry, we evaluated the incidence of, and death rate from cancer of the colon and rectum. The increase in the incidence of colorectal cancer in Austria is comparable to that of other western industrial countries. There is an estimated rise in the annual figures of newly registered patients from 3174 in 1971 to 3981 cases in 1981. Regional distribution within Austria is not homogeneous: the highest risk of disease was observed in Vienna (60 new cases per year per 100000 inhabitants), the lowest in Tyrol with 40 new cases per 100000. The marked east-west slope in the incidence of colorectal cancer in Austria is a good basis for the investigation of pathogenetic factors.

  17. Survival of women with breast cancer in Kaunas Region, Lithuania.

    PubMed

    Ivanauskienė, Rugilė; Gedminaitė, Jurgita; Juozaitytė, Elona; Vanagas, Giedrius; Simoliūnienė, Renata; Padaiga, Zilvinas

    2012-01-01

    OBJECTIVE. The assessment of breast cancer survival rates and comparison with those of other countries may help to deepen knowledge among decision makers in the health care system and to improve the inequalities in accessibility to early detection and effective treatment. The aim of this study was to evaluate breast cancer survival rates in Kaunas region, Lithuania, and to compare them with those in the selected European countries. MATERIAL AND METHODS. A retrospective study was carried out using medical records and data gathered from the Lithuanian Cancer Registry. A group of 240 patients with primary breast cancer diagnosed in 2008 in Kaunas region was analyzed. All causes of death were included in the analysis. The closing date of follow-up was September 30, 2010. Survival was determined using the life-table method and the Kaplan-Meier method. Cox proportional hazard models were used to estimate the effects of prognostic risk factors on survival. RESULTS. The median age of the patients was 63 years (range, 28-95). The 1-year and 2-year cumulative survival for breast cancer patients in Kaunas region, Lithuania, was 94.2% and 90.1%, respectively. As expected, the survival of patients with diagnosed advanced disease (stage III and IV) was significantly worse than that of patients with stage I (P<0.001) and II (P=0.003) disease. The screening group (aged 50-69 years) showed better survival in comparison with the group older than 69 years. Age, T4 tumor, and distant metastasis were the prognostic factors significantly associated with an increased relative mortality risk of breast cancer. CONCLUSIONS. Compared to the European survival rates, the 1-year and 2-year survival of patients with breast cancer in Lithuania was found to be similar to most European countries.

  18. Colorectal cancer carcinogenesis: a review of mechanisms.

    PubMed

    Tariq, Kanwal; Ghias, Kulsoom

    2016-03-01

    Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men globally. CRC arises from one or a combination of chromosomal instability, CpG island methylator phenotype, and microsatellite instability. Genetic instability is usually caused by aneuploidy and loss of heterozygosity. Mutations in the tumor suppressor or cell cycle genes may also lead to cellular transformation. Similarly, epigenetic and/or genetic alterations resulting in impaired cellular pathways, such as DNA repair mechanism, may lead to microsatellite instability and mutator phenotype. Non-coding RNAs, more importantly microRNAs and long non-coding RNAs have also been implicated at various CRC stages. Understanding the specific mechanisms of tumorigenesis and the underlying genetic and epigenetic traits is critical in comprehending the disease phenotype. This paper reviews these mechanisms along with the roles of various non-coding RNAs in CRCs.

  19. Multiregion sequencing reveals the intratumor heterogeneity of driver mutations in TP53-driven non-small cell lung cancer.

    PubMed

    Zhang, Le-Le; Kan, Mengyuan; Zhang, Man-Man; Yu, Sha-Sha; Xie, Hui-Jun; Gu, Zhao-Hui; Wang, Hai-Ning; Zhao, Shuang-Xia; Zhou, Guang-Biao; Song, Huai-Dong; Zheng, Cui-Xia

    2017-01-01

    Intratumor heterogeneity (ITH) in non-small cell lung cancer (NSCLC) may account for resistance after a period of targeted therapies because drugs destroy only a portion of tumor cells. The recognition of ITH helps identify high-risk patients to make effective treatment decisions. However, ITH studies are confounded by interpatient heterogeneity in NSCLC and a large amount of passenger mutations. To address these issues, we recruited NSCLC patients carrying TP53 mutations and selected driver mutations within recurrently mutated genes in NSCLC. A total of 12-paired normal-tumor tissues were subjected to whole-genome/whole-exome sequencing. From these, 367 non-silent mutations were selected as driver mutations and deeply sequenced in 61 intratumoral microdissections. We identified a universal prevalence of heterogeneity in all 12 tumors, indicating branched evolution. Although TP53 mutations were observed in single biopsy of all 12 tumors, most tumors consist of both TP53 mutated and non-mutated cells in separate regions within the same tumor. This suggests the late molecular timing of the acquisition of TP53 mutations; therefore, the detection of TP53 mutations in a single biopsy may simply not reflect the early malignant potential. In addition, we identified regions of loss of heterozygosity surrounding TP53 and CDKN2A mutations in tumor 711, which also exhibited heterogeneity in different regional samples. Because the ITH of driver mutations likely has clinical consequences, further efforts are needed to limit the impact of ITH and to improve therapeutic efficiency, which will benefit NSCLC patients receiving targeted treatments.

  20. DEAR1 Is a Dominant Regulator of Acinar Morphogenesis and an Independent Predictor of Local Recurrence-Free Survival in Early-Onset Breast Cancer

    PubMed Central

    Lott, Steven T.; Chen, Nanyue; Chandler, Dawn S.; Yang, Qifeng; Wang, Luo; Rodriguez, Marivonne; Xie, Hongyan; Balasenthil, Seetharaman; Buchholz, Thomas A.; Sahin, Aysegul A.; Chaung, Katrina; Zhang, Baili; Olufemi, Shodimu-Emmanu; Chen, Jinyun; Adams, Henry; Band, Vimla; El-Naggar, Adel K.; Frazier, Marsha L.; Keyomarsi, Khandan; Hunt, Kelly K.; Sen, Subrata; Haffty, Bruce; Hewitt, Stephen M.; Krahe, Ralf; Killary, Ann McNeill

    2009-01-01

    Background Breast cancer in young women tends to have a natural history of aggressive disease for which rates of recurrence are higher than in breast cancers detected later in life. Little is known about the genetic pathways that underlie early-onset breast cancer. Here we report the discovery of DEAR1 (ductal epithelium–associated RING Chromosome 1), a novel gene encoding a member of the TRIM (tripartite motif) subfamily of RING finger proteins, and provide evidence for its role as a dominant regulator of acinar morphogenesis in the mammary gland and as an independent predictor of local recurrence-free survival in early-onset breast cancer. Methods and Findings Suppression subtractive hybridization identified DEAR1 as a novel gene mapping to a region of high-frequency loss of heterozygosity (LOH) in a number of histologically diverse human cancers within Chromosome 1p35.1. In the breast epithelium, DEAR1 expression is limited to the ductal and glandular epithelium and is down-regulated in transition to ductal carcinoma in situ (DCIS), an early histologic stage in breast tumorigenesis. DEAR1 missense mutations and homozygous deletion (HD) were discovered in breast cancer cell lines and tumor samples. Introduction of the DEAR1 wild type and not the missense mutant alleles to complement a mutation in a breast cancer cell line, derived from a 36-year-old female with invasive breast cancer, initiated acinar morphogenesis in three-dimensional (3D) basement membrane culture and restored tissue architecture reminiscent of normal acinar structures in the mammary gland in vivo. Stable knockdown of DEAR1 in immortalized human mammary epithelial cells (HMECs) recapitulated the growth in 3D culture of breast cancer cell lines containing mutated DEAR1, in that shDEAR1 clones demonstrated disruption of tissue architecture, loss of apical basal polarity, diffuse apoptosis, and failure of lumen formation. Furthermore, immunohistochemical staining of a tissue microarray from a

  1. Regional copy number-independent deregulation of transcription in cancer.

    PubMed

    Stransky, Nicolas; Vallot, Céline; Reyal, Fabien; Bernard-Pierrot, Isabelle; de Medina, Sixtina Gil Diez; Segraves, Rick; de Rycke, Yann; Elvin, Paul; Cassidy, Andrew; Spraggon, Carolyn; Graham, Alexander; Southgate, Jennifer; Asselain, Bernard; Allory, Yves; Abbou, Claude C; Albertson, Donna G; Thiery, Jean Paul; Chopin, Dominique K; Pinkel, Daniel; Radvanyi, François

    2006-12-01

    Genetic and epigenetic alterations have been identified that lead to transcriptional deregulation in cancers. Genetic mechanisms may affect single genes or regions containing several neighboring genes, as has been shown for DNA copy number changes. It was recently reported that epigenetic suppression of gene expression can also extend to a whole region; this is known as long-range epigenetic silencing. Various techniques are available for identifying regional genetic alterations, but no large-scale analysis has yet been carried out to obtain an overview of regional epigenetic alterations. We carried out an exhaustive search for regions susceptible to such mechanisms using a combination of transcriptome correlation map analysis and array CGH data for a series of bladder carcinomas. We validated one candidate region experimentally, demonstrating histone methylation leading to the loss of expression of neighboring genes without DNA methylation.

  2. Regionalization and Outcomes of Lung Cancer Surgery in Ontario, Canada.

    PubMed

    Bendzsak, Anna M; Baxter, Nancy N; Darling, Gail E; Austin, Peter C; Urbach, David R

    2017-08-20

    Purpose Regionalization of complex surgery to high-volume hospitals has been advocated based on cross-sectional volume-outcome studies. In April 2007, the agency overseeing cancer care in Ontario, Canada, implemented a policy to regionalize lung cancer surgery at 14 designated hospitals, enforced by economic incentives and penalties. We studied the effects of implementation of this policy. Methods Using administrative health data, we used interrupted time series models to analyze the immediate and delayed effects of implementation of the policy on the distribution of lung cancer surgery among hospitals, surgical outcomes, and health services use. Results From 2004 to 2012, 16,641 patients underwent surgery for lung cancer. The proportion of operations performed in designated hospitals increased from 71% to 89% after the policy was implemented. Although operative mortality decreased from 4.1% to 2.9% (adjusted odds ratio, 0.68; 95% CI, 0.58 to 0.81; P < .001), the reduction was due to a preexisting declining trend in mortality. In contrast, in the years after implementation of the policy, length of hospital stay decreased more than expected from the baseline trend by 7% per year (95% CI, 5% to 9%; P < .001), and the distance traveled by all patients to the hospital for surgery increased by 4% per year (95% CI, 0% to 8%; P = .03), neither of which were explained by preexisting trends. Analyses limited to patients ≥ 70 years of age demonstrated a reduction in operative mortality (odds ratio, 0.80 per year after regionalization; 95% CI, 0.67 to 0.95; P = .01). Conclusion A policy to regionalize lung cancer surgery in Ontario led to increased centralization of surgery services but was not independently associated with improvements in operative mortality. Improvements in length of stay and in operative mortality among elderly patients suggest areas where regionalization may be beneficial.

  3. [The parameter "relative survival": Analysis of regional cancer registry data for prostate cancer].

    PubMed

    Leuchter, M; Kalata, P; Hildebrandt, G; Zettl, H; Hakenberg, O W

    2016-02-01

    There is a lack of comparability of relative survival rates due to differences in regional mortality. How should relative survival be calculated to be able to compare regional cancer mortality? Calculation of relative survival rates of prostate cancer patients from a regional cancer registry using diagnosis year and stage, based on differential mortality tables. Calculation of relative survival for all prostate cancer patients shows a very slight excess mortality after 5 years compared to a matched general population. Introduction of new imaging techniques and PSA screening led to a change in the distribution of diagnosed stages. Differentiation by stage is therefore essential. Thus, patients with UICC stage I, II, and III have a very low excess mortality, while patients with a UICC stage IV have a significantly higher excess mortality; however, it is very surprising that the excess mortality of patients without specification of the UICC stage is similarly unfavorable as in the case of patients with UICC stage IV. If data from a regional cancer registry are used, adequate mortality tables from the catchment area of the registry should be used as a reference due to regional mortality differences. Thus, progress in patient survival can be more precisely mapped. With respect to prostate cancer patients, differential consideration by stage is also necessary because improved early detection methods has led to a change in the stage distribution and, thus, survival.

  4. Regional nodal irradiation in the conservative treatment of breast cancer

    SciTech Connect

    Haffty, B.G.; Fischer, D.; Fischer, J.J. )

    1990-10-01

    At this institution conservative treatment of breast cancer was begun in the 1960's. The following analysis represents our experience through 1984 with specific reference to the management of the regional lymph nodes. A total of 432 patients with clinical stage I and II breast cancer were treated between 1962 and 1984 with lumpectomy and radiation therapy. The breast was treated with tangential fields to a median dose of 4800 cGy and electron conedown to a total tumor bed dose of 6400 cGy. Axillary dissection was not routinely performed, particularly in the earlier years. More recently, axillary dissection has been used with increasing frequency if it was felt that the results of the dissection would influence systemic treatment. One hundred eighty-seven patients (43%) underwent axillary dissection and routinely received regional nodal irradiation to the internal mammary and supraclavicular lymph nodes. Two hundred forty-five patients (57%) did not undergo axillary dissection and routinely received regional nodal irradiation to the internal mammary, supraclavicular, and entire axillary regions to a total median dose of 4600 cGy. As of May 1989 with a median follow-up of 7.5 years, there have been a total of 12 nodal failures for an actuarial nodal control rate of 97% at 5 years and 96% at 10 years. The actuarial 5-year regional nodal control rate was the same for both the group of patients receiving regional RT alone without axillary dissection and the group of patients receiving axillary dissection and supraclavicular/internal mammary radiation. There has been minimal morbidity associated with this treatment policy. We conclude that regional nodal irradiation, with or without axillary dissection, results in a high rate of regional nodal control and minimal treatment morbidity in patients undergoing conservative treatment of early stage breast cancer.

  5. Regional but fatal: Intraperitoneal metastasis in gastric cancer

    PubMed Central

    Wei, Jia; Wu, Nan-Die; Liu, Bao-Rui

    2016-01-01

    Peritoneal carcinomatosis appears to be the most common pattern of metastasis or recurrence and is associated with poor prognosis in gastric cancer patients. Many efforts have been made to improve the survival in patients with peritoneal metastasis. Hyperthermic intraperitoneal chemotherapy remains a widely accepted strategy in the treatment of peritoneal dissemination. Several phase II-III studies confirmed that the combined cytoreducitve surgery and hyperthermic intraperitoneal chemotherapy resulted in longer survival in patients with peritoneal carcinomatosis. In addition, proper selection and effective regional treatment in patients with high risk of peritoneal recurrence after resection will further improve prognosis in local advanced gastric cancer patients. PMID:27672270

  6. Molecular mechanisms by which selenoproteins affect cancer risk and progression.

    PubMed

    Zhuo, Pin; Diamond, Alan M

    2009-11-01

    Selenoproteins comprise a unique class of proteins that contain selenium in the form of selenocysteine. Several selenoproteins have been implicated in the risk or development of cancers in humans by genetic data. These include Selenoprotein P, 3 members of the glutathione peroxidase family of anti-oxidant enzymes and Sep15. At-risk alleles in the germline indicate a likely role in determining susceptibility to cancer, while loss of heterozygosity or chromosomal epigenetic silencing indicate that the reduction in the levels of the corresponding proteins contribute to malignant progression. Lower levels of these proteins are likely to be detrimental due to the resulting cellular stress and perturbations in important regulatory signaling pathways. The genetic data indicating the involvement of these selenoproteins in cancer etiology are discussed, as are the possible mechanisms by which these genes might promote carcinogenesis.

  7. A 2-Mb YAC contig linking the plasminogen-apoprotein(a) gene family to the insulin-like growth factor 2 receptor (IGF2R) gene on the telomeric region of chromosome 6 (6q26-q27)

    SciTech Connect

    Acquati, F.; Taramelli, R.; Malgaretti, N.

    1994-08-01

    Chromosome 6 has been reported to be frequently rearranged in several human malignancies. In particular, deletions of the long arm of this chromosome are observed in melanomas, renal cell carcinomas, salivary gland adenocarcinomas, and ovarian carcinomas, as well as in lymphoid tumors such as acute lymphoblastic leukemia and B-cell non-Hodgkin lymphomas. Molecular studies of B-cell non-Hodgkin lymphomas using the loss of heterozygosity analysis allowed the definition of two distinct regions of minimal deletion (RMD), which were mapped to 6q25 to 6q27 and to 6q21 to 6q23, respectively. 24 refs., 2 figs.

  8. Patterns of regional recurrence after definitive radiotherapy for cervical cancer.

    PubMed

    Beadle, Beth M; Jhingran, Anuja; Yom, Sue S; Ramirez, Pedro T; Eifel, Patricia J

    2010-04-01

    To determine the patterns of regional recurrence in patients treated with definitive radiotherapy (RT) for cervical cancer. The records of 198 patients treated with definitive RT for cervical cancer between 1980 and 2000 who experienced a regional recurrence without a central or distal vaginal recurrence were reviewed. All patients received a combination of external-beam RT and intracavitary brachytherapy. In the 180 patients with a documented location of regional recurrence, the relationship between the recurrence and the radiation fields was determined. The median time to regional recurrence was 13 months (range, 2-85 months). Of the 180 patients who had an evaluable regional recurrence, 119 (66%) had a component of marginal failure; 71 patients recurred above-the-field, 2 patients occurred in the inguinal nodes, and 2 patients recurred above-the-field and in the inguinal nodes. In addition, 105 patients (58%) had a component of in-field failure; 59 patients recurred in-field only, 39 patients recurred in-field and above-the-field, 2 patients recurred in-field, above-the-field, and in the inguinal nodes, and 5 patients recurred in-field and in the inguinal nodes. The median survival after regional recurrence was 8 months (range, 0-194 months). Most regional recurrences after definitive RT for cervical cancer include a component of marginal failure, usually immediately superior to the radiation field. These recurrences suggest a deficiency in target volume. Recurrences also occur in-field, suggesting a deficiency in dose. Developments in pretreatment staging, field delineation, dose escalation, and posttreatment surveillance may help to improve outcome in these patients.

  9. Patterns of Regional Recurrence After Definitive Radiotherapy for Cervical Cancer

    SciTech Connect

    Beadle, Beth M.; Jhingran, Anuja; Yom, Sue S.; Ramirez, Pedro T.; Eifel, Patricia J.

    2010-04-15

    Purpose: To determine the patterns of regional recurrence in patients treated with definitive radiotherapy (RT) for cervical cancer. Methods and Materials: The records of 198 patients treated with definitive RT for cervical cancer between 1980 and 2000 who experienced a regional recurrence without a central or distal vaginal recurrence were reviewed. All patients received a combination of external-beam RT and intracavitary brachytherapy. In the 180 patients with a documented location of regional recurrence, the relationship between the recurrence and the radiation fields was determined. Results: The median time to regional recurrence was 13 months (range, 2-85 months). Of the 180 patients who had an evaluable regional recurrence, 119 (66%) had a component of marginal failure; 71 patients recurred above-the-field, 2 patients occurred in the inguinal nodes, and 2 patients recurred above-the-field and in the inguinal nodes. In addition, 105 patients (58%) had a component of in-field failure; 59 patients recurred in-field only, 39 patients recurred in-field and above-the-field, 2 patients recurred in-field, above-the-field, and in the inguinal nodes, and 5 patients recurred in-field and in the inguinal nodes. The median survival after regional recurrence was 8 months (range, 0-194 months). Conclusions: Most regional recurrences after definitive RT for cervical cancer include a component of marginal failure, usually immediately superior to the radiation field. These recurrences suggest a deficiency in target volume. Recurrences also occur in-field, suggesting a deficiency in dose. Developments in pretreatment staging, field delineation, dose escalation, and posttreatment surveillance may help to improve outcome in these patients.

  10. Water contamination and esophageal cancer at Gassim Region, Saudi Arabia

    SciTech Connect

    Amer, M.H.; El-Yazigi, A.; Hannan, M.A.; Mohamed, M.E. )

    1990-05-01

    Between January 1980 and December 1982, 183 patients with histologically confirmed carcinoma of the esophagus who were referred to a tertiary referral hospital were studied. Thirty-two (17%) patients were referred from Gassim Region at the north central part of Saudi Arabia. In contrast, only 5% of total cancer patient referrals were from this area. A case-control study showed a significant regional difference within Saudi Arabia and the most referrals from Gassim area. A prospective case-control study showed persistently high numbers of referrals from that region during 1983-1987. When patients from Gassim Region were compared with those referred from other locations, no statistical differences were noted between the two groups except for the source of drinking water. Water analysis from Gassim area showed a high solid content with elevated levels of calcium, magnesium, and to a lesser extent, chromium iron, cadmium, and cobalt. Traces of petroleum oil were found in five of six water samples from Gassim during 1983, compared with 3 of 49 samples from other areas. Mutagenicity tests on water specimens form Gassim Region indicated the presence of possible carcinogens. It is being suggested that the high prevalence of esophageal cancer in this region may be related to contamination of water by impurities such as petroleum oils. Malnutrition, particularly vitamin A deficiency, as well as other factors may have promoted such malignancies.

  11. Implementing colorectal cancer screening in community health centers: addressing cancer health disparities through a regional cancer collaborative.

    PubMed

    Taplin, Stephen H; Haggstrom, David; Jacobs, Tracy; Determan, Ada; Granger, Jennifer; Montalvo, Wanda; Snyder, William M; Lockhart, Susan; Calvo, Ahmed

    2008-09-01

    The population served by Federally Qualified Health Centers (FQHCs) has lower levels of cancer screening compared with the general population and suffers a disproportionate cancer burden. To address these disparities, 3 federal agencies and a primary care association established and tested the feasibility of a Regional Cancer Collaborative (RCC) in 2005. RCC faculty implemented a learning model to improve cancer screening across 4 FQHCs that met explicit organizational readiness criteria. Regional faculty trained "care process leaders," who worked with primary care teams to plan and implement practice changes. FQHCs monitored progress across the following measures of screening implementation: self-management goal-setting; number and percent screened for breast, cervical, and colorectal cancer; percent timely results notification; and percent abnormal screens evaluated within 90 days. Progress and plans were reviewed in regular teleconferences. FQHCs were encouraged to create local communities of practice (LCOP) involving community resources to support cancer screening and to participate in a monthly teleconference that linked the LCOPs into a regional community of practice. Summary reports and administrative data facilitated a process evaluation of the RCC. chi test and test of trends compared baseline and follow-up screening rates. The RCC taught the collaborative process using process leader training, teleconferences, 2 regional meetings, and local process improvement efforts. All organizations created clinical tracking capabilities and 3 of the 4 established LCOPs, which met monthly in an regional community of practice. Screening documentation increased for all 3 cancers from 2005 to 2007. Colorectal cancer screening increased from 8.6% to 21.2%. A regional plan to enable collaborative learning for cancer screening implementation is feasible, and improvements in screening rates can occur among carefully selected organizations.

  12. Genotype Misclassification in Genetic Association Studies of the rs1042522 TP53 (Arg72Pro) Polymorphism: A Systematic Review of Studies of Breast, Lung, Colorectal, Ovarian, and Endometrial Cancer

    PubMed Central

    Dahabreh, Issa J.; Schmid, Christopher H.; Lau, Joseph; Varvarigou, Vasileia; Murray, Samuel; Trikalinos, Thomas A.

    2013-01-01

    Preferential loss of heterozygosity at the rs1042522 locus of the tumor protein 53 gene (TP53) (Arg72Pro) is observed in several tumors. Genetic association studies in oncology often use tumor tissue rather than unaffected tissue for genotyping; in such cases, loss of heterozygosity at the TP53 locus could lead to differential misclassification and could bias estimates of association. We searched multiple databases (through March 8, 2011) for studies investigating the association of Arg72Pro with breast, lung, colorectal, ovarian, or endometrial cancer. Meta-analysis was performed with multilevel Bayesian models. Informative priors for the bias effect were derived from a meta-analysis of the same polymorphism in cervical cancer. Of 160 studies (68 breast, 42 lung, 26 colorectal, 16 ovarian, and 8 endometrial cancer), 22 used tumor tissue as the source of genotyping material for cases. Use of tumor tissue versus other sources of genotyping material was associated with an apparent protective effect of the proline allele (relative odds ratio = 0.78, 95% credible interval: 0.70, 0.88). The probability that use of tumor tissue induced bias was estimated to be higher than 99%. Use of tumor tissue as the source of genotyping material for cases is associated with significant bias in the estimate of the genetic effect in cancer genetic association studies. PMID:23729685

  13. Candidate predisposing germline copy number variants in early onset colorectal cancer patients.

    PubMed

    Brea-Fernandez, A J; Fernandez-Rozadilla, C; Alvarez-Barona, M; Azuara, D; Ginesta, M M; Clofent, J; de Castro, L; Gonzalez, D; Andreu, M; Bessa, X; Llor, X; Xicola, R; Jover, R; Castells, A; Castellvi-Bel, S; Capella, G; Carracedo, A; Ruiz-Ponte, C

    2017-05-01

    A great proportion of the heritability of colorectal cancer (CRC) still remains unexplained, and rare variants, as well as copy number changes, have been proposed as potential candidates to explain the so-called 'missing heritability'. We aimed to identify rare high-to-moderately penetrant copy number variants (CNVs) in patients suspected of having hereditary CRC due to an early onset. We have selected for genome-wide copy number analysis, 27 MMR-proficient early onset CRC patients (<50 years) without identifiable germline mutations in Mendelian genes related to this phenotype. Rare CNVs were selected by removing all CNVs detected at MAF >1% in the in-house control CNV database (n = 629 healthy controls). Copy number assignment was checked by duplex real-time quantitative PCR or multiplex ligation probe amplification. Somatic mutation analysis in candidate genes included: loss of heterozygosity studies, point mutation screening, and methylation status of the promoter. We have identified two rare germline deletions involving the AK3 and SLIT2 genes in two patients. The search for a second somatic mutational event in the corresponding CRC tumors showed loss of heterozygosity in AK3, and promoter hypermethylation in SLIT2. Both genes have been previously related to colorectal carcinogenesis. These findings suggest that AK3 and SLIT2 may be potential candidates involved in genetic susceptibility to CRC.

  14. Inactivation of X-linked tumor suppressor genes in human cancer

    PubMed Central

    Liu, Runhua; Kain, Mandy; Wang, Lizhong

    2015-01-01

    Cancer cells silence autosomal tumor suppressor genes by Knudson’s two-hit mechanism in which loss-of-function mutations and then loss of heterozygosity occur at the tumor suppressor gene loci. However, the identification of X-linked tumor suppressor genes has challenged the traditional theory of “two-hit inactivation” in tumor suppressor genes, introducing the novel concept that a single genetic hit can cause loss of tumor suppressor function. The mechanism through which these genes are silenced in human cancer is unclear, but elucidating the details will greatly enhance our understanding of the pathogenesis of human cancer. Here, we review the identification of X-linked tumor suppressor genes and discuss the potential mechanisms of their inactivation. In addition, we also discuss how the identification of X-linked tumor suppressor genes can potentially lead to new approaches to cancer therapy. PMID:22515449

  15. Inactivation of X-linked tumor suppressor genes in human cancer.

    PubMed

    Liu, Runhua; Kain, Mandy; Wang, Lizhong

    2012-04-01

    Cancer cells silence autosomal tumor suppressor genes by Knudson's two-hit mechanism in which loss-of-function mutations and then loss of heterozygosity occur at the tumor suppressor gene loci. However, the identification of X-linked tumor suppressor genes has challenged the traditional theory of 'two-hit inactivation' in tumor suppressor genes, introducing the novel concept that a single genetic hit can cause loss of tumor suppressor function. The mechanism through which these genes are silenced in human cancer is unclear, but elucidating the details will greatly enhance our understanding of the pathogenesis of human cancer. Here, we review the identification of X-linked tumor suppressor genes and discuss the potential mechanisms of their inactivation. In addition, we also discuss how the identification of X-linked tumor suppressor genes can potentially lead to new approaches in cancer therapy.

  16. Contribution of retinoblastoma LOH and the p53 Arg/Pro polymorphism to cervical cancer.

    PubMed

    Eltahir, Huda A; Elhassan, Ahmed M; Ibrahim, Muntaser E

    2012-09-01

    Epidemiological studies indicate that infections by certain types of human papillomaviruses (HPVs) are causally linked to the development of cervical cancer. It is also known that HPV infections alone do not cause progression to cervical cancer, as additional genetic changes such as loss of distinct chromosomal regions, inactivation of tumor-suppressor genes and activation of oncogenes must also occur in order for malignant transformation to take place. In the present study, 78 patients diagnosed with cervical cancer and 36 cervical cancer-free cases (control) were analyzed for high-risk HPV genotypes (16 and 18) by polymerase chain reaction (PCR). Loss of heterozygosity (LOH) of the retinoblastoma gene (Rb) at two polymorphic intronic sites (intron 1 and 17) and the p53 polymorphism in codon 72 were detected by RFLP and allele-specific PCR, respectively. HPV 16 and 18 were found at frequencies of 93.6 and 8.3% in the cervical cancer and control samples, respectively. LOH was detected in 63% of patients in intron 1 and/or intron 17. p53 allele frequency for Arg/Arg was 43.6% (34/78), for Arg/Pro 37.2% (29/78) and for Pro/Pro 19.2% (15/78). The relative risk (RR) of LOH and Arg/Arg alone was 1.7 and 1.1, respectively, while the combined RR for Rb LOH and p53 Arg/Arg was 2.5. The present study showed a significant association of the chromosomal allelic loss of Rb in Sudanese cervical cancer patients, while no such association was observed with other parameters, such as clinical stage and degree of differentiation; hence, it cannot be a determinant of tumor behavior in cervical carcinoma. Although the p53 arginine allele is itself an important risk factor for cervical cancer, the combined risk with LOH of Rb, which appears to be greater, might indicate a possible epistatic effect of the two genes/polymorphisms.

  17. [Predisposing factors to breast cancer in the Region Langunera (Mexico)].

    PubMed

    Martínez Abundis, Guadalupe; Cano Ríos, Pedro; González Hernández, Sergio; Rosales Hernández, Francisco Javier

    2004-10-01

    To identify the presence and frequency of various predispose factors of breast cancer in the Region Lagunera (Mexico). 38 women with breast cancer (Group A, cases) and 24 women without breast pathology (Group B, controls) were analyzed; throughout a questionnaire the variables that have been described as predisposition factors were researched. Group A included patients from the Instituto Mexicano del Seguro Social, Speciality Hospital # 71, Oncology Department in Torreon, Coahuila, from May 1st to October 31st of 1999. At the same time 24 women (Group B), who attended to have an ultrasound and/or a mammography practice in a private clinic in the same city, were polled having a normal result. The means of the two treatments were compared using the SAS program version 6.3. The following variables showed significant difference: mother and father family background with cancer p=0.032; previous breast pathology p=0.0032; hormone consumption p=0.0289; lactation p=0.038 and time of lactation p=0.036. Overweight, obesity, mother and father family background with cancer, previous breast pathology background, period of consuming hormone, lactation and lactation period had significance in this study.

  18. Smoking and Lung Cancer: A Geo-Regional Perspective.

    PubMed

    Rahal, Zahraa; El Nemr, Shaza; Sinjab, Ansam; Chami, Hassan; Tfayli, Arafat; Kadara, Humam

    2017-01-01

    Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) represents the most frequently diagnosed subtype of this morbid malignancy. NSCLC is causally linked to tobacco consumption with more than 500 million smokers worldwide at high risk for this fatal malignancy. We are currently lagging in our knowledge of the early molecular (e.g., genomic) effects of smoking in NSCLC pathogenesis that would constitute ideal markers for early detection. This limitation is further amplified when considering the variable etiologic factors in NSCLC pathogenesis among different regions around the globe. In this review, we present our current knowledge of genomic alterations arising during early stages of smoking-induced lung cancer initiation and progression, including discussing the premalignant airway field of injury induced by smoking. The review also underscores the wider spectra and higher age-adjusted rates of tobacco (e.g., water-pipe smoke) consumption, along with elevated environmental carcinogenic exposures and relatively poorer socioeconomic status, in low-middle income countries (LMICs), with Lebanon as an exemplar. This "cocktail" of carcinogenic exposures warrants the pressing need to understand the complex etiology of lung malignancies developing in LMICs such as Lebanon.

  19. [Risk management in a regional screening program for breast cancer in the region of Lazio, Italy].

    PubMed

    Federici, A; Consolante, C A; Barca, A; Baiocchi, D; Borgia, P; Marzolini, L; Guasticchi, G

    2006-01-01

    In the Lazio Region, it has been put into effect a plan of clinical Risk Management for the Breast Cancer Screening Regional Program (BCSP), involving all of the 12 Local Health Units and the Public Health Agency of Lazio (ASP). Being the BCSP a health care service, it consists of a perfect integration of health care structures, professionals and skills working for the citizens. This program originates from an unexpressed health need and leads to a evidence-based health benefit. The BCSP provides free breast screening for 700,000 women aged between 50 and 69 in the Lazio region; the Public Health Agency carries out the clinical governance of the BCSP The prevention of errors and incidents represents a fundamental basis of governance: it is a contribution to the achievement of efficacy in breast cancer screening. The BCSP deals with screening incidents from a systemic point of view and actively involves several Local Health Units staff going through each step of the whole patient's clinical path, from the identification of the target population, to the oncological treatment of positive cases. The programme is an integration of different tools: literature research, process analysis using the HFMEA methodology and reporting system. The results reached so far are the following: the regional severity rating scale, the regional Master-List of possible adverse events, occurrence and detection rating scale.

  20. Predictors of loco-regional recurrence and cancer-related death after breast cancer surgery.

    PubMed

    Rausei, Stefano; Rovera, Francesca; Dionigi, Gianlorenzo; Tornese, Deborah; Fachinetti, Anna; Boni, Luigi; Dionigi, Renzo

    2010-01-01

    To determine which tumor-related factors might predispose the patient to loco-regional recurrence or death and the impact of these factors on the different types of events. We retrospectively analyzed the data of 1991 women between January 1998 and March 2010 for a first primary nonmetastatic breast cancer and treated with surgery and neo-adjuvant/adjuvant therapy. The overall survival distribution was estimated using the Kaplan-Meier method. The prognostic impact of several factors on cumulative overall and loco-regional recurrence free survival was evaluated by univariate (log-rank test) and multivariate analysis (Cox regression). At log-rank test, pT, nodal status, histotype, grading, lymphangioinvasive growth, tumor diameter, estrogen receptors (ER) status, progesterone receptors (PR) status, expression of Ki67, and expression of Her2/neu had a prognostic value on loco-regional recurrence or overall survival. In the multivariate analysis grading remained the only independent predictor of loco-regional recurrences. With regard to overall survival, the Cox model selected grading along with nodal status and PR status. Loco-regional recurrences after breast cancer surgery are not frequent events. They are markers of tumor aggressiveness and predictor of an increased likelihood of cancer-related death. However, loco-regional recurrence and systemic tumor progression are partially independent events, since some prognostic factors differ.

  1. Chromosome 19q13 disruption alters expressions of CYP2A7, MIA and MIA-RAB4B lncRNA and contributes to FAP-like phenotype in APC mutation-negative familial colorectal cancer patients

    PubMed Central

    Thean, Lai Fun; Wong, Yu Hui; Lo, Michelle; Loi, Carol; Chew, Min Hoe; Tang, Choong Leong; Cheah, Peh Yean

    2017-01-01

    Familial adenomatous polyposis (FAP) is an autosomal-dominantly inherited form of colorectal cancer (CRC) caused by mutation in the adenomatous polyposis coli (APC) gene. Our ability to exhaustively screen for APC mutations identify microsatellite-stable and APC-mutation negative familial CRC patients, enabling us to search for novel genes. We performed genome-wide scan on two affected siblings of one family and 88 ethnicity- and gender-matched healthy controls to identify deletions shared by the siblings. Combined loss of heterozygosity, copy number and allelic-specific copy number analysis uncovered 5 shared deletions. Long-range polymerase chain reaction (PCR) confirmed chromosome 19q13 deletion, which was subsequently found in one other family. The 32 kb deleted region harbors the CYP2A7 gene and was enriched with enhancer, repressor and insulator sites. The wildtype allele was lost in the polyps of the proband. Further, real-time RT-PCR assays showed that expressions of MIA and MIA-RAB4B located 35 kb upstream of the deletion, were up-regulated in the polyps compared to the matched mucosa of the proband. MIA-RAB4B, the read-through long non-coding RNA (lncRNA), RAB4B, PIM2 and TAOK1 share common binding site of a microRNA, miR-24, in their 3’UTRs. PIM2 and TAOK1, two target oncogenes of miR-24, were co-ordinately up-regulated with MIA-RAB4B in the polyps, suggesting that MIA-RAB4B could function as competitive endogenous RNA to titrate miR-24 away from its other targets. The data suggest that the 19.13 deletion disrupted chromatin boundary, leading to altered expression of several genes and lncRNA, could contribute to colorectal cancer via novel genetic and epigenetic mechanisms. PMID:28306719

  2. Chromosome 19q13 disruption alters expressions of CYP2A7, MIA and MIA-RAB4B lncRNA and contributes to FAP-like phenotype in APC mutation-negative familial colorectal cancer patients.

    PubMed

    Thean, Lai Fun; Wong, Yu Hui; Lo, Michelle; Loi, Carol; Chew, Min Hoe; Tang, Choong Leong; Cheah, Peh Yean

    2017-01-01

    Familial adenomatous polyposis (FAP) is an autosomal-dominantly inherited form of colorectal cancer (CRC) caused by mutation in the adenomatous polyposis coli (APC) gene. Our ability to exhaustively screen for APC mutations identify microsatellite-stable and APC-mutation negative familial CRC patients, enabling us to search for novel genes. We performed genome-wide scan on two affected siblings of one family and 88 ethnicity- and gender-matched healthy controls to identify deletions shared by the siblings. Combined loss of heterozygosity, copy number and allelic-specific copy number analysis uncovered 5 shared deletions. Long-range polymerase chain reaction (PCR) confirmed chromosome 19q13 deletion, which was subsequently found in one other family. The 32 kb deleted region harbors the CYP2A7 gene and was enriched with enhancer, repressor and insulator sites. The wildtype allele was lost in the polyps of the proband. Further, real-time RT-PCR assays showed that expressions of MIA and MIA-RAB4B located 35 kb upstream of the deletion, were up-regulated in the polyps compared to the matched mucosa of the proband. MIA-RAB4B, the read-through long non-coding RNA (lncRNA), RAB4B, PIM2 and TAOK1 share common binding site of a microRNA, miR-24, in their 3'UTRs. PIM2 and TAOK1, two target oncogenes of miR-24, were co-ordinately up-regulated with MIA-RAB4B in the polyps, suggesting that MIA-RAB4B could function as competitive endogenous RNA to titrate miR-24 away from its other targets. The data suggest that the 19.13 deletion disrupted chromatin boundary, leading to altered expression of several genes and lncRNA, could contribute to colorectal cancer via novel genetic and epigenetic mechanisms.

  3. Clinical Implications of Rabphillin-3A-Like Gene Alterations in Breast Cancer

    PubMed Central

    Salih, Chura; Shanmugam, Chandrakumar; Jadhav, Trafina; Bovell, Liselle C.; Behring, Michael P.; Callens, Tom; Messiaen, Ludwine; Bae, Sejong; Grizzle, William E.; Singh, Karan P.; Manne, Upender

    2015-01-01

    For the rabphillin-3A-like (RPH3AL) gene, a putative tumor suppressor, the clinical significance of genetic alterations in breast cancers was evaluated. DNA and RNA were extracted from formalin-fixed, paraffin-embedded (FFPE) cancers and matching normal tissues. DNA samples were assessed for loss of heterozygosity (LOH) at the 17p13.3 locus of RPH3AL and the 17p13.1 locus of the tumor suppressor, TP53. RPH3AL was sequenced, and single nucleotide polymorphisms (SNPs) were genotyped. RNA samples were evaluated for expression of RPH3AL, and FFPE tissues were profiled for its phenotypic expression. Alterations in RPH3AL were correlated with clinicopathological features, LOH of TP53, and patient survival. Of 121 cancers, 80 had LOH at one of the RPH3AL locus. LOH of RHP3AL was associated with nodal metastasis, advanced stage, large tumor size, and poor survival. Although ~50% were positive for LOH at the RPH3AL and TP53 loci, 19 of 105 exhibited LOH only at the RPH3AL locus. Of these, 12 were non-Hispanic Caucasians (Whites), 15 had large tumors, and 12 were older (>50 years). Patients exhibiting LOH at both loci had shorter survival than those without LOH at these loci (log-rank, P = 0.014). LOH at the TP53 locus alone was not associated with survival. Analyses of RPH3AL identified missense point mutations in 19 of 125 cases, a SNP (C>A) in the 5’untranslated region at -25 (5’UTR-25) in 26 of 104, and a SNP (G>T) in the intronic region at 43 bp downstream to exon-6 (intron-6-43) in 79 of 118. Genotype C/A or A/A of the SNP at 5’UTR-25 and genotype T/T of a SNP at intron-6-43 were predominantly in Whites. Low levels of RNA and protein expression of RPH3AL were present in cancers relative to normal tissues. Thus, genetic alterations in RPH3AL are associated with aggressive behavior of breast cancers and with short survival of patients. PMID:26070152

  4. Regional Nodal Irradiation in Early-Stage Breast Cancer.

    PubMed

    Whelan, Timothy J; Olivotto, Ivo A; Parulekar, Wendy R; Ackerman, Ida; Chua, Boon H; Nabid, Abdenour; Vallis, Katherine A; White, Julia R; Rousseau, Pierre; Fortin, Andre; Pierce, Lori J; Manchul, Lee; Chafe, Susan; Nolan, Maureen C; Craighead, Peter; Bowen, Julie; McCready, David R; Pritchard, Kathleen I; Gelmon, Karen; Murray, Yvonne; Chapman, Judy-Anne W; Chen, Bingshu E; Levine, Mark N

    2015-07-23

    Most women with breast cancer who undergo breast-conserving surgery receive whole-breast irradiation. We examined whether the addition of regional nodal irradiation to whole-breast irradiation improved outcomes. We randomly assigned women with node-positive or high-risk node-negative breast cancer who were treated with breast-conserving surgery and adjuvant systemic therapy to undergo either whole-breast irradiation plus regional nodal irradiation (including internal mammary, supraclavicular, and axillary lymph nodes) (nodal-irradiation group) or whole-breast irradiation alone (control group). The primary outcome was overall survival. Secondary outcomes were disease-free survival, isolated locoregional disease-free survival, and distant disease-free survival. Between March 2000 and February 2007, a total of 1832 women were assigned to the nodal-irradiation group or the control group (916 women in each group). The median follow-up was 9.5 years. At the 10-year follow-up, there was no significant between-group difference in survival, with a rate of 82.8% in the nodal-irradiation group and 81.8% in the control group (hazard ratio, 0.91; 95% confidence interval [CI], 0.72 to 1.13; P=0.38). The rates of disease-free survival were 82.0% in the nodal-irradiation group and 77.0% in the control group (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Patients in the nodal-irradiation group had higher rates of grade 2 or greater acute pneumonitis (1.2% vs. 0.2%, P=0.01) and lymphedema (8.4% vs. 4.5%, P=0.001). Among women with node-positive or high-risk node-negative breast cancer, the addition of regional nodal irradiation to whole-breast irradiation did not improve overall survival but reduced the rate of breast-cancer recurrence. (Funded by the Canadian Cancer Society Research Institute and others; MA.20 ClinicalTrials.gov number, NCT00005957.).

  5. Relationships between cancer pattern, country income and geographical region in Asia.

    PubMed

    Ng, Chirk Jenn; Teo, Chin Hai; Abdullah, Nurdiana; Tan, Wei Phin; Tan, Hui Meng

    2015-09-03

    Cancer incidence and mortality varies across region, sex and country's economic status. While most studies focused on global trends, this study aimed to describe and analyse cancer incidence and mortality in Asia, focusing on cancer site, sex, region and income status. Age-standardised incidence and mortality rates of cancer were extracted from the GLOBOCAN 2012 database. Cancer mortality to incidence ratios (MIRs) were calculated to represent cancer survival. The data were analysed based on the four regions in Asia and income. Cancer incidence rate is lower in Asia compared to the West but for MIR, it is the reverse. In Asia, the most common cancers in men are lung, stomach, liver, colorectal and oesophageal cancers while the most common cancers in women are breast, lung, cervical, colorectal and stomach cancers. The MIRs are the highest in lung, liver and stomach cancers and the lowest in colorectal, breast and prostate cancers. Eastern and Western Asia have a higher incidence of cancer compared to South-Eastern and South-Central Asia but this pattern is the reverse for MIR. Cancer incidence rate increases with country income particularly in colorectal and breast cancers but the pattern is the opposite for MIR. This study confirms that there is a wide variation in cancer incidence and mortality across Asia. This study is the first step towards documenting and explaining the changing cancer pattern in Asia in comparison to the rest of the world.

  6. Colorectal Cancer Genetic Heterogeneity Delineated by Multi-Region Sequencing

    PubMed Central

    Liang, Rui; Xie, Zhen-Rong; Luo, Hua-You; Zeng, Yu-Jian; Xu, Yu; Wang, La-Mei; Kong, Xiang-Yang; Wang, Kun-Hua

    2016-01-01

    Intratumor heterogeneity (ITH) leads to an underestimation of the mutational landscape portrayed by a single needle biopsy and consequently affects treatment precision. The extent of colorectal cancer (CRC) genetic ITH is not well understood in Chinese patients. Thus, we conducted deep sequencing by using the OncoGxOne™ Plus panel, targeting 333 cancer-specific genes in multi-region biopsies of primary and liver metastatic tumors from three Chinese CRC patients. We determined that the extent of ITH varied among the three cases. On average, 65% of all the mutations detected were common within individual tumors. KMT2C aberrations and the NCOR1 mutation were the only ubiquitous events. Subsequent phylogenetic analysis showed that the tumors evolved in a branched manner. Comparison of the primary and metastatic tumors revealed that PPP2R1A (E370X), SETD2 (I1608V), SMAD4 (G382T), and AR splicing site mutations may be specific to liver metastatic cancer. These mutations might contribute to the initiation and progression of distant metastasis. Collectively, our analysis identified a substantial level of genetic ITH in CRC, which should be considered for personalized therapeutic strategies. PMID:27023146

  7. WW domain-containing oxidoreductase's role in myriad cancers: clinical significance and future implications.

    PubMed

    Gardenswartz, Aliza; Aqeilan, Rami I

    2014-03-01

    The WW domain-containing oxidoreductase (WWOX) gene, encodes a tumor suppressor located on 16q23.1, spanning FRA16D, one of the most active common fragile sites in the human genome, that is altered in numerous types of cancer. WWOX's alteration in these myriad cancers is due to disparate mechanisms including loss of heterozygosity, homozygous deletion and epigenetic changes. In vitro, WWOX has been found to be reduced or absent in numerous cancer cell lines and WWOX restoration has been found to inhibit tumor cell growth and invasion. Wwox knockout mice developed femoral focal lesions resembling osteosarcomas within one month of their life and aging Wwox heterozygous mice have an increased incidence of spontaneous lung and mammary tumors as well as B-cell lymphomas. We herein review WWOX's role that has been unearthed thus far in different types of malignancies, its clinical significance and future implications.

  8. Regional Nodal Irradiation in Early-Stage Breast Cancer

    PubMed Central

    Whelan, Timothy J.; Olivotto, Ivo A.; Parulekar, Wendy R.; Ackerman, Ida; Chua, Boon H.; Nabid, Abdenour; Vallis, Katherine A.; White, Julia R.; Rousseau, Pierre; Fortin, Andre; Pierce, Lori J.; Manchul, Lee; Chafe, Susan; Nolan, Maureen C.; Craighead, Peter; Bowen, Julie; McCready, David R.; Pritchard, Kathleen I.; Gelmon, Karen; Murray, Yvonne; Chapman, Judy-Anne W.; Chen, Bingshu E.; Levine, Mark N.

    2015-01-01

    BACKGROUND Most women with breast cancer who undergo breast-conserving surgery receive whole-breast irradiation. We examined whether the addition of regional nodal irradiation to whole-breast irradiation improved outcomes. METHODS We randomly assigned women with node-positive or high-risk node-negative breast cancer who were treated with breast-conserving surgery and adjuvant systemic therapy to undergo either whole-breast irradiation plus regional nodal irradiation (including internal mammary, supraclavicular, and axillary lymph nodes) (nodal-irradiation group) or whole-breast irradiation alone (control group). The primary outcome was overall survival. Secondary outcomes were disease-free survival, isolated locoregional disease-free survival, and distant disease-free survival. RESULTS Between March 2000 and February 2007, a total of 1832 women were assigned to the nodal-irradiation group or the control group (916 women in each group). The median follow-up was 9.5 years. At the 10-year follow-up, there was no significant between-group difference in survival, with a rate of 82.8% in the nodal-irradiation group and 81.8% in the control group (hazard ratio, 0.91; 95% confidence interval [CI], 0.72 to 1.13; P = 0.38). The rates of disease-free survival were 82.0% in the nodal-irradiation group and 77.0% in the control group (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P = 0.01). Patients in the nodal-irradiation group had higher rates of grade 2 or greater acute pneumonitis (1.2% vs. 0.2%, P = 0.01) and lymphedema (8.4% vs. 4.5%, P = 0.001). CONCLUSIONS Among women with node-positive or high-risk node-negative breast cancer, the addition of regional nodal irradiation to whole-breast irradiation did not improve overall survival but reduced the rate of breast-cancer recurrence. PMID:26200977

  9. A common region of deletion on chromosome 17q in both sporadic and familial epithelial ovarian tumors distal to BRCA1

    SciTech Connect

    Godwin, A.K.; Vanderveer, L.; Schultz, D.C.; Altomare, D.A.; Buetow, K.H.; Daly, M.; Getts, L.A.; Masny, A.; Rosenblum, N.

    1994-10-01

    Linkage analysis in familial breast and ovarian cancer and studies of allelic deletion in sporadic ovarian tumors have identified a region on chromosome 17q containing a candidate tumor-suppressor gene (referred to as BRCA1) of likely importance in ovarian carcinogenesis. We have examined normal and tumor DNA samples from 32 patients with sporadic and 8 patients with familial forms of the disease, for loss of heterozygosity (LOH) at 21 loci on chromosome 17 (7 on 17p and 14 on 17q). LOH on 17p was 55% (22/40) for informative 17p13.1 and 17p13.3 markers. When six polymorphic markers flanking the familial breast/ovarian cancer susceptibility locus on 17q12-q21 were used, LOH was 58% (23/40), with one tumor showing telomeric retention. Evaluation of a set of markers positioned telomeric to BRCA1 resulted in the highest degree of LOH, 73% (29/40), indicating that a candidate locus involved in ovarian cancer may reside distal to BRCA1. Five of the tumors demonstrating allelic loss for 17q markers were from individuals with a strong family history of breast and ovarian cancer. More important, two of these tumors (unique patient number [UPN] 57 and UPN 79) retained heterozygosity for all informative markers spanning the BRCA1 locus but showed LOH at loci distal to but not including the anonymous markers CMM86 (D17S74) and 42D6 (D17S588), respectively. Deletion mapping of seven cases (two familial and five sporadic) showing limited LOH on 17q revealed a common region of deletion, distal to GH and proximal to D17S4, that spans {approximately} 25 cM. These results suggest that a potential tumor-suppressor gene involved in both sporadic and familial ovarian cancer may reside on the distal portion of chromosome 17q and is distinct from the BRCA1 gene. 58 refs., 3 figs., 4 tabs.

  10. CDH1 promoter hypermethylation and E-cadherin protein expression in infiltrating breast cancer

    PubMed Central

    Caldeira, José Roberto F; Prando, Érika C; Quevedo, Francisco C; Neto, Francisco A Moraes; Rainho, Cláudia A; Rogatto, Silvia R

    2006-01-01

    Background The E-cadherin gene (CDH1) maps, at chromosome 16q22.1, a region often associated with loss of heterozygosity (LOH) in human breast cancer. LOH at this site is thought to lead to loss of function of this tumor suppressor gene and was correlated with decreased disease-free survival, poor prognosis, and metastasis. Differential CpG island methylation in the promoter region of the CDH1 gene might be an alternative way for the loss of expression and function of E-cadherin, leading to loss of tissue integrity, an essential step in tumor progression. Methods The aim of our study was to assess, by Methylation-Specific Polymerase Chain Reaction (MSP), the methylation pattern of the CDH1 gene and its possible correlation with the expression of E-cadherin and other standard immunohistochemical parameters (Her-2, ER, PgR, p53, and K-67) in a series of 79 primary breast cancers (71 infiltrating ductal, 5 infiltrating lobular, 1 metaplastic, 1 apocrine, and 1 papillary carcinoma). Results CDH1 hypermethylation was observed in 72% of the cases including 52/71 ductal, 4/5 lobular carcinomas and 1 apocrine carcinoma. Reduced levels of E-cadherin protein were observed in 85% of our samples. Although not statistically significant, the levels of E-cadherin expression tended to diminish with the CDH1 promoter region methylation. In the group of 71 ductal cancinomas, most of the cases of showing CDH1 hypermethylation also presented reduced levels of expression of ER and PgR proteins, and a possible association was observed between CDH1 methylation and ER expression (p = 0.0301, Fisher's exact test). However, this finding was not considered significant after Bonferroni correction of p-value. Conclusion Our preliminary findings suggested that abnormal CDH1 methylation occurs in high frequencies in infiltrating breast cancers associated with a decrease in E-cadherin expression in a subgroup of cases characterized by loss of expression of other important genes to the mammary

  11. Germline Brca2 heterozygosity promotes Kras(G12D) -driven carcinogenesis in a murine model of familial pancreatic cancer.

    PubMed

    Skoulidis, Ferdinandos; Cassidy, Liam D; Pisupati, Venkat; Jonasson, Jon G; Bjarnason, Hordur; Eyfjord, Jorunn E; Karreth, Florian A; Lim, Michael; Barber, Lorraine M; Clatworthy, Susan A; Davies, Susan E; Olive, Kenneth P; Tuveson, David A; Venkitaraman, Ashok R

    2010-11-16

    Inherited heterozygous BRCA2 mutations predispose carriers to tissue-specific cancers, but somatic deletion of the wild-type allele is considered essential for carcinogenesis. We find in a murine model of familial pancreatic cancer that germline heterozygosity for a pathogenic Brca2 truncation suffices to promote pancreatic ductal adenocarcinomas (PDACs) driven by Kras(G12D), irrespective of Trp53 status. Unexpectedly, tumor cells retain a functional Brca2 allele. Correspondingly, three out of four PDACs from patients inheriting BRCA2(999del5) did not exhibit loss-of-heterozygosity (LOH). Three tumors from these patients displaying LOH were acinar carcinomas, which also developed only in mice with biallelic Brca2 inactivation. We suggest a revised model for tumor suppression by BRCA2 with implications for the therapeutic strategy targeting BRCA2 mutant cancer cells. Copyright © 2010 Elsevier Inc. All rights reserved.

  12. Regional Cancer Registries – 20 Years and Growing

    Cancer.gov

    The NCI, Center for Global Health (CGH), the University of California at Irvine, the Middle East Cancer Consortium, and the International Agency for Research on Cancer partnered in support of the training course, held in Ankara, Turkey this past October, on The Uses of Cancer Registry Data in Cancer Control Research.

  13. Cancer incidence rates in the Kurdistan region/Iraq from 2007-2009.

    PubMed

    Othman, Ramadhan T; Abdulljabar, Rezvan; Saeed, Abdullah; Kittani, Sarwar Sadiq; Sulaiman, Hushyar M; Mohammed, Sami A; Rashid, Rekawt M; Hussein, Nawfal R

    2011-01-01

    Cancer is a disease of gradual increase in incidence overall the world. Kurdistan Region in Iraq has been exposed to several carcinogenic hazards. There are few reports about the increased risk of cancer in different cities in Iraq. These reports did not cover Kurdistan region. The aim of this paper was to study cancer incidence and to identify possible risks of cancer in this region. Cancer registries from 9 hospitals in three cities of Kurdistan were used as a source of data. Information on these cases was subjected to careful verification regarding repetition, place of residence and other possible errors. Overall registered cases in 2007, 2008 and 2009 were 1444, 2081, 2356 respectively. 49% of registered cases were males and 51% were female. The Age Standardized Rate of cancer was 89.83/100 000 among male and 83.93/100 000 among female. The results showed major variation in incidence rates of different types of cancer in the three governorates of Kurdistan. Furthermore, there was evidence of increased risks of cancer in Kurdistan Region in Iraq. Hematological malignancies were the most common cancer among male (21.13% of all cancer in males) and second most common in female (18.8% of all cancer in female), only exceeded by breast cancer. To reach sound conclusions about extent and determinants of cancer in Kurdistan, enormous multi-spectrum efforts are now needed.

  14. The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line.

    PubMed

    Adey, Andrew; Burton, Joshua N; Kitzman, Jacob O; Hiatt, Joseph B; Lewis, Alexandra P; Martin, Beth K; Qiu, Ruolan; Lee, Choli; Shendure, Jay

    2013-08-08

    The HeLa cell line was established in 1951 from cervical cancer cells taken from a patient, Henrietta Lacks. This was the first successful attempt to immortalize human-derived cells in vitro. The robust growth and unrestricted distribution of HeLa cells resulted in its broad adoption--both intentionally and through widespread cross-contamination--and for the past 60 years it has served a role analogous to that of a model organism. The cumulative impact of the HeLa cell line on research is demonstrated by its occurrence in more than 74,000 PubMed abstracts (approximately 0.3%). The genomic architecture of HeLa remains largely unexplored beyond its karyotype, partly because like many cancers, its extensive aneuploidy renders such analyses challenging. We carried out haplotype-resolved whole-genome sequencing of the HeLa CCL-2 strain, examined point- and indel-mutation variations, mapped copy-number variations and loss of heterozygosity regions, and phased variants across full chromosome arms. We also investigated variation and copy-number profiles for HeLa S3 and eight additional strains. We find that HeLa is relatively stable in terms of point variation, with few new mutations accumulating after early passaging. Haplotype resolution facilitated reconstruction of an amplified, highly rearranged region of chromosome 8q24.21 at which integration of the human papilloma virus type 18 (HPV-18) genome occurred and that is likely to be the event that initiated tumorigenesis. We combined these maps with RNA-seq and ENCODE Project data sets to phase the HeLa epigenome. This revealed strong, haplotype-specific activation of the proto-oncogene MYC by the integrated HPV-18 genome approximately 500 kilobases upstream, and enabled global analyses of the relationship between gene dosage and expression. These data provide an extensively phased, high-quality reference genome for past and future experiments relying on HeLa, and demonstrate the value of haplotype resolution for

  15. Cancer Mortality in the Mississippi Delta Region: Descriptive Epidemiology and Needed Future Research and Interventions.

    PubMed

    Zahnd, Whitney E; Jenkins, Wiley D; Mueller-Luckey, Georgia S

    2017-01-01

    The Delta Region is a federally designated, socioeconomically disadvantaged region of the United States covering 252 counties in eight states along the Mississippi River. The objective of this study is to describe the Region's cancer mortality burden. National Center for Health Statistics data were used to calculate age-adjusted mortality rates and rate ratios for the Delta Region for all cancers, lung, colorectal, breast (female), cervical, and prostate cancers. Rates were also calculated for comparison groups, and were stratified by gender, race, rurality, and socioeconomic status. The all-cancer mortality rate in the Delta Region was higher than all comparison groups across all stratifications. Higher rates were seen for cervical and colorectal cancer across comparison groups and stratifications. Delta Blacks had higher rates than Whites, and rural Delta residents had higher rates than their urban peers for most cancers. Further research and interventions should be conducted to elucidate and reduce these disparities.

  16. Feline mammary basal-like adenocarcinomas: a potential model for human triple-negative breast cancer (TNBC) with basal-like subtype

    PubMed Central

    2013-01-01

    Background Breast cancer is one of the leading causes of cancer deaths. Triple-negative breast cancer (TNBC), an immunophenotype defined by the absence of immunolabeling for estrogen receptor (ER), progesterone receptor (PR) and HER2 protein, has a highly aggressive behavior. A subpopulation of TNBCs exhibit a basal-like morphology with immunohistochemical positivity for cytokeratins 5/6 (CK5/6) and/or epidermal growth factor receptor (EGFR), and have a high incidence of BRCA (breast cancer susceptibility) mutations. Feline mammary adenocarcinomas (FMAs) are highly malignant and share a similar basal-like subtype. The purpose of this study was to classify FMAs according to the current human classification of breast cancer that includes evaluation of ER, PR and HER2 status and expression of basal CK 5/6 and EGFR. Furthermore, we selected triple negative, basal-like FMAs to screen for BRCA mutations similar to those described in human TNBC. Methods Twenty four FMAs were classified according to the current human histologic breast cancer classification including immunohistochemistry (IHC) for ER, PR HER2, CK5/6 and EGFR. Genetic alteration and loss of heterozygosity of BRCA1 and BRCA2 genes were analyzed in triple negative, basal-like FMAs. Results IHC for ER, PR and HER2 identified 14 of the 24 (58%) FMAs as a triple negative. Furthermore, 11of these 14 (79%) triple negative FMAs had a basal-like subtype. However, no genetic abnormalities were detected in BRCA1 and BRCA2 by direct sequencing and loss of heterozygosity analysis. Conclusion FMAs are highly aggressive neoplasms that are commonly triple negative and exhibit a basal-like morphology. This is similar to human TNBC that are also commonly classified as a basal-like subtype. While sequencing of a select number of triple negative, basal-like FMAs and testing for loss of heterozygosity of BRCA1 and BRCA2 did not identify mutations similar to those described in human TNBC, further in-depth evaluation is required

  17. p53 mutations in leukemia and myelodysplastic syndrome after ovarian cancer.

    PubMed

    Leonard, Debra G B; Travis, Lois B; Addya, Kathakali; Dores, Graca M; Holowaty, Eric J; Bergfeldt, Kjell; Malkin, David; Kohler, Betsy A; Lynch, Charles F; Wiklund, Tom; Stovall, Marilyn; Hall, Per; Pukkala, Eero; Slater, Diana J; Felix, Carolyn A

    2002-05-01

    Although p53 mutations occur in alkylating agent-related leukemias, their frequency and spectrum in leukemias after ovarian cancer have not been addressed. The purpose of this study was to examine p53 mutations in leukemias after ovarian cancer, for which treatment with platinum analogues was widely used. Adequate leukemic or dysplastic cells were available in 17 of 82 cases of leukemia or myelodysplastic syndrome that occurred in a multicenter, population-based cohort of 23,170 women with ovarian cancer. Eleven of the 17 received platinum compounds and other alkylating agents with or without DNA topoisomerase II inhibitors and/or radiation. Six received other alkylating agents, in one case, with radiation. Genomic DNA was extracted and p53 exons 5, 6, 7, and 8 were amplified by PCR. Mutations and loss of heterozygosity were analyzed on the WAVE instrument (Transgenomic) followed by selected analysis by sequencing. Eleven p53 mutations involving all four exons studied and one polymorphism were identified. Genomic DNA analyses were consistent with loss of heterozygosity for four of the mutations. The 11 mutations occurred in 9 cases, such that 6 of 11 leukemias after platinum-based regimens (55%) and 3 of 6 leukemias after other treatments (50%) contained p53 mutations. Two leukemias that occurred after treatment with platinum analogues contained two mutations. Among eight mutations in leukemias after treatment with platinum analogues, there were four G-to-A transitions and one G-to-C transversion. p53 mutations are common in leukemia and myelodysplastic syndrome after multiagent therapy for ovarian cancer. The propensity for G-to-A transitions may reflect specific DNA damage in leukemias after treatment with platinum analogues.

  18. [Characteristics of lung cancer in a region in northern Spain].

    PubMed

    Alonso-Fernández, M A; García-Clemente, M; Escudero-Bueno, C

    2005-09-01

    To gather information on the disease characteristics and survival rate of patients diagnosed with bronchogenic carcinoma in the respiratory medicine departments of hospitals in Asturias, Spain. This was a retrospective observational study carried out using a standardized data collection protocol. All cases of lung cancer diagnosed during 2001 were included provided there was cytologic or histologic confirmation or they fulfilled a series of clinical, radiological, and/or endoscopic criteria consistent with such a diagnosis. Standard incidence rates adjusted to the world population were 22.4, 42.6, and 4.6 per 100,000 population for the whole population, men, and women respectively. The mean (SD) age was 67 (10.9) years, and 92% of the patients were men. Overall, 98% of the men and 44% of the women were smokers. Diagnosis was confirmed by cytologic or histologic findings in 92% of patients, and the majority were non-small cell tumors (81.4%). At the time of diagnosis, 65% of the patients had advanced disease, with distant metastasis in 26.6% of the non-small cell cancers and 52.8% of the small cell cancers. Patients received surgical treatment in 21.3% of cases, chemotherapy alone or combined with radiation therapy in 43.1%, and radiation therapy alone in 9.3%. In 26.2% of patients only palliative care was given. Overall, median survival in weeks was 36.4 (95% confidence interval [CI], 29.4-43.4). Median survival by treatment type was as follows: 69.3 (95% CI, 49-9.5) for surgery; 39.6 (95% CI, 31.2-48) for chemotherapy alone or with radiation therapy; 30 (95% CI, 15.4-44.6) for radiation therapy alone; and 13.3 (95% CI, 5.9-20.6) for patients who received palliative care alone (P< .05). The findings with respect to age, sex, incidence, histology, extent of tumor, and smoking status of patients with bronchogenic carcinoma in our region does not differ significantly from those reported for other areas of Spain. Current smoking is the primary cause of the high

  19. Integrated map of the chromosome 8p12-p21 region, a region involved in human cancers and Werner syndrome

    SciTech Connect

    Imbert, A.; Chaffanet, M.; Birnbaum, D.; Pebusque, M.J.

    1996-02-15

    This article discusses the genetic mapping of the specific region on human chromosome 8, 8p12-p21, and its implications to human hereditary cancers and diseases. The localization of disease genes such as NEFL and FGFR1 are given, accomplished using contigs which span the region of deletion involved in these hereditary diseases. 59 refs., 4 figs., 3 tabs.

  20. Tumor-specific loss of 11p15. 5 alleles in del11p13 Wilms tumor and in familial adrenocortical carcinoma

    SciTech Connect

    Henry, I.; Grandjouan, S.; Couillin, P.; Barichard, F.; Huerre-Jeanpierre, C.; Glaser, T.; Philip, T.; Lenoir, G.; Chaussain, J.L.; Junien, C. )

    1989-05-01

    The authors have compared constitutional and tumor genotypes in nine cases of hereditary Wilms tumor (WT) and in three unrelated cases of familial adrenocortical carcinoma (ADCC). Since susceptibility to these tumors can be observed in malformation syndromes associated with a constitutional deletion of band 11p13 (WT) and with a constitutional duplication of band 11p15.5 (WT, ADCC), they investigated these two candidate regions by using 11p polymorphic markers. As expected, somatic chromosomal events, resulting in a loss of heterozygosity limited to region 11p15.5, were observed in the tumor of two familial cases of adrenocortical carcinoma. Surprisingly, however, analysis of the WT of two patients with a constitutional deletion of band 11p13, associated with aniridia, genitourinary abnormalities, and mental retardation (WAGR syndrome), revealed a loss of heterozygosity limited to region 11p15.5. These data therefore suggest that observation of a specific loss of heterozygosity may not necessarily point to the site of the initial germinal mutation. Together with previous similar observations of a loss of heterozygosity limited to 11p15.5 in breast cancer and in rhabdomyosarcoma, the data suggest that region 11p15.5 may carry a non-tissue-specific gene that could be involved in genetic predisposition, in tumor progression, or in both.

  1. Intermediate endpoint biomarkers for lung cancer chemoprevention

    NASA Astrophysics Data System (ADS)

    MacAulay, Calum E.; Lam, Stephen; Klein-Parker, Helga; Gazdar, Adi; Guillaud, Martial; Payne, Peter W.; Le Riche, Jean C.; Dawe, Chris; Band, Pierre; Palcic, Branko

    1998-04-01

    Given the demographics of current and ex-smoking populations in North America, lung cancer will be a major problem in the foreseeable future. Early detection and treatment of lung cancer holds great promise for the management of this disease. Unlike cervical cancer, the physical, complete removal/destruction of all dysplastic lesions in the bronchial tree is not possible; however, treatment of the lesions using a chemopreventive agent is. Intermediate biomarkers have been used to screen promising chemopreventive agents for larger population studies. We have examined the natural history of lung cancer development by following a group of subjects at high risk of developing lung cancer using fluorescence endoscopy to identify the areas of abnormality for biopsy. Approximately 900 biopsies have been collected in this fashion and graded by at least two experienced, expert pathologists. Using an interactive version of the Cyto-Savant (Oncometrics Imaging Corp.), cytometric and tissue architectural data were collected from these biopsies. Using only the data from the normal and invasive cancer biopsies, quantitative morphometric and architectural indices were generated and calculated for all the collected biopsies. These indices were compared with Loss of Heterozygosity (LOH) of ten sites commonly associated with cancer. These results and the application of these quantitative measures to two small chemoprevention studies will be reported.

  2. Evaluation of DNA Repair Function as a Predictor of Response in a Clinical Trial of PARP Inhibitor Monotherapy for Recurrent Ovarian Carcinoma

    DTIC Science & Technology

    2016-12-01

    to identify PARPi sensitivity. Large-scale disarray in chromosome structure is common in HRR-deficient cancers and may be quantitated by several...duplication of chromosomal regions, also known as genomic loss of heterozygosity (LOH).4−6 Half of all high-grade serous ovarian carcinomas are estimated...frequent in older ovarian cancer patients. Genes Chromosomes Cancer 2013; 52: 794−801. 6 Marquard AM, Eklund AC, Joshi T, et al. Pan-cancer analysis of

  3. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas.

    PubMed

    Qiu, Wen; Hu, Min; Sridhar, Anita; Opeskin, Ken; Fox, Stephen; Shipitsin, Michail; Trivett, Melanie; Thompson, Ella R; Ramakrishna, Manasa; Gorringe, Kylie L; Polyak, Kornelia; Haviv, Izhak; Campbell, Ian G

    2008-05-01

    There is increasing evidence showing that the stromal cells surrounding cancer epithelial cells, rather than being passive bystanders, might have a role in modifying tumor outgrowth. The molecular basis of this aspect of carcinoma etiology is controversial. Some studies have reported a high frequency of genetic aberrations in carcinoma-associated fibroblasts (CAFs), whereas other studies have reported very low or zero mutation rates. Resolution of this contentious area is of critical importance in terms of understanding both the basic biology of cancer as well as the potential clinical implications of CAF somatic alterations. We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis of CAFs derived from breast and ovarian carcinomas using a 500K SNP array platform. Our data show conclusively that LOH and copy number alterations are extremely rare in CAFs and cannot be the basis of the carcinoma-promoting phenotypes of breast and ovarian CAFs.

  4. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas

    PubMed Central

    Qiu, Wen; Hu, Min; Sridhar, Anita; Opeskin, Ken; Fox, Stephen; Shipitsin, Michail; Trivett, Melanie; Thompson, Ella R; Ramakrishna, Manasa; Gorringe, Kylie L; Polyak, Kornelia; Haviv, Izhak; Campbell, Ian G

    2013-01-01

    There is increasing evidence showing that the stromal cells surrounding cancer epithelial cells, rather than being passive bystanders, might have a role in modifying tumor outgrowth. The molecular basis of this aspect of carcinoma etiology is controversial. Some studies have reported a high frequency of genetic aberrations in carcinoma-associated fibroblasts (CAFs), whereas other studies have reported very low or zero mutation rates. Resolution of this contentious area is of critical importance in terms of understanding both the basic biology of cancer as well as the potential clinical implications of CAF somatic alterations. We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis of CAFs derived from breast and ovarian carcinomas using a 500K SNP array platform. Our data show conclusively that LOH and copy number alterations are extremely rare in CAFs and cannot be the basis of the carcinoma-promoting phenotypes of breast and ovarian CAFs. PMID:18408720

  5. Deletion mapping of gliomas suggests the presence of two small regions for candidate tumor-suppressor genes in a 17-cM interval on chromosome 10q

    SciTech Connect

    Albarosa, R.; Colombo, B.M.; Roz, L.

    1996-06-01

    The loss of genetic material on chromosome 10q is frequent in different tumors and particularly in malignant gliomas. We analyzed 90 of these tumors and found loss of heterozygosity (LOH) in > 90% of the informative loci in glioblastoma multiforme (GBM). Initial studies restricted the common LOH region to 10q24-qter. Subsequently, the study of a pediatric GBM suggested D10S221 and D10S209, respectively, as centromeric and telomeric markers of a 4-cM LOH region. It is interesting to note that, in one subset of cells from this tumor, locus D10S209 seems involved in the allelic imbalance of a larger region, with D10S214 as telomeric marker. This 17-cM region contains the D10S587-D10S216 interval of common deletion recently defined on another set of gliomas. 31 refs., 5 figs., 1 tab.

  6. Sociodemographic Parameters of Esophageal Cancer in Northwest India: A Regional Cancer Center Experience of 10 Years

    PubMed Central

    Kapoor, Akhil; Kumar, Vanita; Singhal, Mukesh Kumar; Nirban, Raj Kumar; Beniwal, Surender Kumar; Kumar, Harvindra Singh

    2015-01-01

    Background: Despite various advances in the treatment of Esophageal Cancer (EC), being one of the least responsive tumors to cancer therapy, the overall prognosis remains poor. Therefore, it is significant to understand various sociodemographic factors associated with EC to find out various schemes for primary prevention of the disease. Materials and Methods: This is a retrospective analysis of medical records of the EC patients registered in the regional cancer center of northwest India from January 2003 to December 2012. The site of the disease and the histology were also recorded in addition to the various sociodemographic parameters. Results: Out of 55,742 patients registered in our hospital; 3,667 were diagnosed to have EC. Male:female ratio was 1.15:1. The mean age was 54.6 ± 11.74 years; 66.15% of the patients were illiterate and 48.6% belonged to the low socioeconomic status. Smoking and alcohol consumption were identified as risk factors in 48 and 25.6% of the patients, respectively. Conclusions: The etiology in majority of the patients is linked to tobacco and alcohol, thus, modification of life style with limiting the use of addictions may be an effective strategy in the prevention of this dreaded and mostly incurable disease. PMID:26435600

  7. Prediction of Potential Cancer-Risk Regions Based on Transcriptome Data: Towards a Comprehensive View

    PubMed Central

    Alisoltani, Arghavan; Fallahi, Hossein; Ebrahimi, Mahdi; Ebrahimi, Mansour; Ebrahimie, Esmaeil

    2014-01-01

    A novel integrative pipeline is presented for discovery of potential cancer-susceptibility regions (PCSRs) by calculating the number of altered genes at each chromosomal region, using expression microarray datasets of different human cancers (HCs). Our novel approach comprises primarily predicting PCSRs followed by identification of key genes in these regions to obtain potential regions harboring new cancer-associated variants. In addition to finding new cancer causal variants, another advantage in prediction of such risk regions is simultaneous study of different types of genomic variants in line with focusing on specific chromosomal regions. Using this pipeline we extracted numbers of regions with highly altered expression levels in cancer condition. Regulatory networks were also constructed for different types of cancers following the identification of altered mRNA and microRNAs. Interestingly, results showed that GAPDH, LIFR, ZEB2, mir-21, mir-30a, mir-141 and mir-200c, all located at PCSRs, are common altered factors in constructed networks. We found a number of clusters of altered mRNAs and miRNAs on predicted PCSRs (e.g.12p13.31) and their common regulators including KLF4 and SOX10. Large scale prediction of risk regions based on transcriptome data can open a window in comprehensive study of cancer risk factors and the other human diseases. PMID:24796549

  8. Macro-environment of breast carcinoma: frequent genetic alterations in the normal appearing skins of patients with breast cancer.

    PubMed

    Moinfar, Farid; Beham, Alfred; Friedrich, Gerhard; Deutsch, Alexander; Hrzenjak, Andelko; Luschin, Gero; Tavassoli, Fattaneh A

    2008-05-01

    Genetic abnormalities in microenvironmental tissues with subsequent alterations of reciprocal interactions between epithelial and mesenchymal cells play a key role in the breast carcinogenesis. Although a few reports have demonstrated abnormal fibroblastic functions in normal-appearing fibroblasts taken from the skins of breast cancer patients, the genetic basis of this phenomenon and its implication for carcinogenesis are unexplored. We analyzed 12 mastectomy specimens showing invasive ductal carcinomas. In each case, morphologically normal epidermis and dermis, carcinoma, normal stroma close to carcinoma, and stroma at a distant from carcinoma were microdissected. Metastatic-free lymphatic tissues from lymph nodes served as a control. Using PCR, DNA extracts were examined with 11 microsatellite markers known for a high frequency of allelic imbalances in breast cancer. Losses of heterozygosity and/or microsatellite instability were detected in 83% of the skin samples occurring either concurrently with or independently from the cancerous tissues. In 80% of these cases at least one microsatellite marker displayed loss of heterozygosity or microsatellite instability in the skin, which was absent in carcinoma. A total of 41% of samples showed alterations of certain loci observed exclusively in the carcinoma but not in the skin compartments. Our study suggests that breast cancer is not just a localized genetic disorder, but rather part of a larger field of genetic alterations/instabilities affecting multiple cell populations in the organ with various cellular elements, ultimately contributing to the manifestation of the more 'localized' carcinoma. These data indicate that more global assessment of tumor micro- and macro-environment is crucial for our understanding of breast carcinogenesis.

  9. Cancer-associated fibroblasts regulate keratinocyte cell-cell adhesion via TGF-β-dependent pathways in genotype-specific oral cancer.

    PubMed

    Cirillo, N; Hassona, Y; Celentano, A; Lim, K P; Manchella, S; Parkinson, E K; Prime, S S

    2017-01-01

    The interrelationship between malignant epithelium and the underlying stroma is of fundamental importance in tumour development and progression. In the present study, we used cancer-associated fibroblasts (CAFs) derived from genetically unstable oral squamous cell carcinomas (GU-OSCC), tumours that are characterized by the loss of genes such as TP53 and p16(INK4A) and with extensive loss of heterozygosity, together with CAFs from their more genetically stable (GS) counterparts that have wild-type TP53 and p16(INK4A) and minimal loss of heterozygosity (GS-OSCC). Using a systems biology approach to interpret the genome-wide transcriptional profile of the CAFs, we show that transforming growth factor-β (TGF-β) family members not only had biological relevance in silico but also distinguished GU-OSCC-derived CAFs from GS-OSCC CAFs and fibroblasts from normal oral mucosa. In view of the close association between TGF-β family members, we examined the expression of TGF-β1 and TGF-β2 in the different fibroblast subtypes and showed increased levels of active TGF-β1 and TGF-β2 in CAFs from GU-OSCC. CAFs from GU-OSCC, but not GS-OSCC or normal fibroblasts, induced epithelial-mesenchymal transition and down-regulated a broad spectrum of cell adhesion molecules resulting in epithelial dis-cohesion and invasion of target keratinocytes in vitro in a TGF-β-dependent manner. The results demonstrate that the TGF-β family of cytokines secreted by CAFs derived from genotype-specific oral cancer (GU-OSCC) promote, at least in part, the malignant phenotype by weakening intercellular epithelial adhesion. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  10. EXCESS CANCER MORTALITY IN AGRICULTURAL REGIONS OF MINNESOTA

    EPA Science Inventory

    Because of its unique geology, Minnesota can be divided into four agricultural regions: south-central region one (corn, soybeans); west-central region two (wheat, corn, soybeans); northwest region three (wheat, sugar beets, potatoes); and northeast region four (forested and urban...

  11. EXCESS CANCER MORTALITY IN AGRICULTURAL REGIONS OF MINNESOTA

    EPA Science Inventory

    Because of its unique geology, Minnesota can be divided into four agricultural regions: south-central region one (corn, soybeans); west-central region two (wheat, corn, soybeans); northwest region three (wheat, sugar beets, potatoes); and northeast region four (forested and urban...

  12. Pattern of Cancer in a Tertiary Care Hospital in Malwa Region of Punjab, in Comparison to Other Regions in India

    PubMed Central

    Manuja; Aditya, Kewal; Singh, G.P.I.

    2015-01-01

    Context: Cancer pattern varies in different regions and depends on race, lifestyle and diet. There is a lack of definitive information regarding hospital-based cancer profile in Southern Punjab, which is a cotton growing area. Excess of toxins in the macro-environment is thought to be the reason for the high incidence of cancer in this area. Aims: To generate data on the magnitude and pattern of cancer cases reporting in the medical college hospital and to plan activities for prevention of cancer in the field practice area. Settings and Design: A five year record-based retrospective study from 1stJanuary 2007 to 31stDecember 2011. Materials and Methods: All cancer cases who reported either for diagnosis or for treatment (radiotherapy/chemotherapy/surgery) were included in the study. These confirmed cases of cancer were classified according to the International classification of Disease (ICD-10) given by WHO. Statistical Analysis: Descriptive statistics, percentages. Results: Out of a total of 1328 cancer cases, females accounted for 809 (60.9%) and males for 519 (39.1%) cases. Male to female ratio was 1:1.55. The maximum number of patients were seen in 35-64 yr age group (63.5%). Top five leading sites of cancer in males were lung (9.6%), myeloid leukemia (8.3%), prostate (6.8%), mouth (6.1%) and gall bladder (6.0%); and in females were breast (35.7%), cervix (19.1%), esophagus (5.1%), myeloid leukemia (4.7%) and gall bladder (3.9%). Our figures have been compared with the national data from NCRP. Conclusion: Population-based epidemiological studies are required to find out the disease burden & its cause in this region. PMID:25954691

  13. Joint disease mapping using six cancers in the Yorkshire region of England

    PubMed Central

    Downing, Amy; Forman, David; Gilthorpe, Mark S; Edwards, Kimberley L; Manda, Samuel OM

    2008-01-01

    Objectives The aims of this study were to model jointly the incidence rates of six smoking related cancers in the Yorkshire region of England, to explore the patterns of spatial correlation amongst them, and to estimate the relative weight of smoking and other shared risk factors for the relevant disease sites, both before and after adjustment for socioeconomic background (SEB). Methods Data on the incidence of oesophagus, stomach, pancreas, lung, kidney, and bladder cancers between 1983 and 2003 were extracted from the Northern & Yorkshire Cancer Registry database for the 532 electoral wards in the Yorkshire region. Using postcode of residence, each case was assigned an area-based measure of SEB using the Townsend index. Standardised incidence ratios (SIRs) were calculated for each cancer site and their correlations investigated. The joint analysis of the spatial variation in incidence used a Bayesian shared-component model. Three components were included to represent differences in smoking (for all six sites), bodyweight/obesity (for oesophagus, pancreas and kidney cancers) and diet/alcohol consumption (for oesophagus and stomach cancers). Results The incidence of cancers of the oesophagus, pancreas, kidney, and bladder was relatively evenly distributed across the region. The incidence of stomach and lung cancers was more clustered around the urban areas in the south of the region, and these two cancers were significantly associated with higher levels of area deprivation. The incidence of lung cancer was most impacted by adjustment for SEB, with the rural/urban split becoming less apparent. The component representing smoking had a larger effect on cancer incidence in the eastern part of the region. The effects of the other two components were small and disappeared after adjustment for SEB. Conclusion This study demonstrates the feasibility of joint disease modelling using data from six cancer sites. Incidence estimates are more precise than those obtained without

  14. Temporal trends and regional variations in gastrointestinal cancer mortality in Peru, 2005-2014.

    PubMed

    Hernández-Vásquez, Akram; Bendezú-Quispe, Guido; Azañedo, Diego; Huarez, Bertha; Rodríguez-Lema, Belén

    2016-01-01

    To estimate and analyze the evolution of mortality rates of gastrointestinal (GI) cancer in Peru and its regions between 2005-2014. We performed a nationwide secondary analysis of Peru's Health Ministry registry of deaths during the period 2005-2014, with a focus on regional differences. Deaths registered with codes C15 to C25 (malignant neoplasms of digestive organs) from the ICD-10 were included. Calculation of age-standarized mortality rates and years of life lost (YLL) due to GI cancer per 100,000 habitants were also performed. Data of 67,527 deaths from GI cancers was analyzed, 35,055 (51.91%) were women. In 2005, the number of GI cancer deaths was 6,484, for 2014, 7,532 cases were recorded. The GI cancer age-standarized mortality rates at the country level showed a decrease of 12.70% between 2005-2014. Stomach cancer presented the highest age-standarized mortality rate despite showing a downward trend in the last years, equal for gallbladder, liver and biliary tract, and esophagus cancer. Colorectal, small intestine and anus cancer show a progressive increase. In 2014, Callao (48.8), Huancavelica (48.5), La Libertad (39.6), Lambayeque (40.5) and Huanuco (38.9) had the highest rates. The three types of GI cancers with the highest rates of YLL in 2014 were stomach cancer (118.51), followed by liver and biliary tract cancer (58.68) and colorectal (44.86). GI cancer mortality in Peru is high and a priority issue in regions like Huancavelica, Huanuco, Callao, La Libertad and Lambayeque. Stomach cancer remains the most frequent GI cancer, but with a downward trend in the study period.

  15. A regional programme to improve skin cancer management.

    PubMed

    McGeoch, Graham R; Sycamore, Mark J; Shand, Brett I; Simcock, Jeremy W

    2015-12-01

    In 2008, public specialist and general practice services in Canterbury were unable to manage demand for skin cancer treatment. Local clinicians decided the solution was to develop a see-and-treat skin excision clinic staffed by plastic surgeons and general practitioners (GPs), and the introduction of subsidised excisions in general practice. This paper describes the collaboration between clinicians, managers and funders and the results and quality management measures of these initiatives. There is an increasing incidence of skin cancer. GPs in Canterbury were unable to meet increasing demand for skin cancer treatment because some lacked confidence and competence in skin cancer management. There was no public funding for primary care management of skin cancer, driving patients to fully funded secondary care services. Secondary care services were at capacity, with no coordinated programme across primary and secondary care. The programme has resulted in a greater number of skin cancers being treated by the public health system, a reduction in waiting times for treatment, and fewer minor skin lesions being referred to secondary care. Quality measures have been achieved and are improving steadily. Development of the programme has improved working relationships between primary and secondary care clinicians. The strategy was to facilitate the working relationship between primary and secondary care and increase the capacity for skin lesion excisions in both sectors. Skin cancer management can be improved by a coordinated approach between primary and secondary care.

  16. Functional annotation of HOT regions in the human genome: implications for human disease and cancer.

    PubMed

    Li, Hao; Chen, Hebing; Liu, Feng; Ren, Chao; Wang, Shengqi; Bo, Xiaochen; Shu, Wenjie

    2015-06-26

    Advances in genome-wide association studies (GWAS) and large-scale sequencing studies have resulted in an impressive and growing list of disease- and trait-associated genetic variants. Most studies have emphasised the discovery of genetic variation in coding sequences, however, the noncoding regulatory effects responsible for human disease and cancer biology have been substantially understudied. To better characterise the cis-regulatory effects of noncoding variation, we performed a comprehensive analysis of the genetic variants in HOT (high-occupancy target) regions, which are considered to be one of the most intriguing findings of recent large-scale sequencing studies. We observed that GWAS variants that map to HOT regions undergo a substantial net decrease and illustrate development-specific localisation during haematopoiesis. Additionally, genetic risk variants are disproportionally enriched in HOT regions compared with LOT (low-occupancy target) regions in both disease-relevant and cancer cells. Importantly, this enrichment is biased toward disease- or cancer-specific cell types. Furthermore, we observed that cancer cells generally acquire cancer-specific HOT regions at oncogenes through diverse mechanisms of cancer pathogenesis. Collectively, our findings demonstrate the key roles of HOT regions in human disease and cancer and represent a critical step toward further understanding disease biology, diagnosis, and therapy.

  17. An Investigation of Cancer Rates in the Argentia Region, Newfoundland and Labrador: An Ecological Study

    PubMed Central

    Duke, Pauline; Godwin, Marshall; Peach, Mandy; Fortier, Jacqueline; Bornstein, Stephen; Buehler, Sharon; McCrate, Farah; Pike, Andrea; Wang, Peizhong Peter; Cullen, Richard M.

    2015-01-01

    Background. The Argentia region of Newfoundland and Labrador, Canada, was home to a US naval base during a 40-year period between the 1940s and the 1990s. Activities on the base resulted in contamination of the soil and groundwater in the region with chemicals such as heavy metals and dioxins, and residents have expressed concern about higher rates of cancer in their community. This study investigated the rate of cancer diagnosis that is disproportionately high in the Argentia region. Methods. Cases of cancer diagnosed between 1985 and 2011 were obtained for the Argentia region, two comparison communities, and the province of Newfoundland and Labrador. Crude and age-standardized incidence rates of cancer diagnosis were calculated and compared. The crude incidence rate was adjusted for differences in age demographics using census data, and age-standardized incidence rates were compared. Results. Although the Argentia region had a higher crude rate of cancer diagnosis, the age-standardized incidence rate did not differ significantly from the comparison communities or the provincial average. Argentia has an aging population, which may have influenced the perception of increased cancer diagnosis in the community. Conclusions. We did not detect an increased burden of cancer in the Argentia region. PMID:26633979

  18. An Assessment of the Pacific Regional Cancer Coalition: Outcomes and Implications of a Regional Coalition Internal and External Assessment

    PubMed Central

    Heckert, Karen A; Buenconsejo-Lum, Lee; Hedson, Johnny; Tamang, Suresh; Palafox, Neal

    2011-01-01

    Significance The Pacific Regional Cancer Coalition Signifi(PRCC) provides regional leadership in the US Affiliated Pacific Islands (USAPI) to implement the Regional Comprehensive Control Plan: 2007–2012, and to evaluate its coalition and partnerships. The Pacific Center of Excellence in the Elimination of Disparities (CEED), aims to reduce cancer disparities and conducts evaluation activities relevant to cancer prevention and control in the USAPI. Purpose The PRCC Self (internal) and Partner (external) Assessments were conducted to assess coalition functioning, regional and national partnerships, sustainability, and the role of regionalism for integrating all chronic disease prevention and control in the Pacific. Methods Self-administered questionnaires and key informant telephone interviews with PRCC members (N=20), and representatives from regional and national partner organizations were administered (N=26). Validated multi item measures using 5-point scales on coalition and partnership characteristics were used. Chronbach's alphas and averages for the measures were computed. Results Internal coalition measures: satisfaction (4.2, SD=0.48) communication (4.0, SD=0.56), respect (4.0, SD=0.60) were rated more highly than external partnership measures: resource sharing (3.5, SD=0.74), regionalism (3.9, SD=0.47), use of findings (3.9, SD=0.50). The PRCC specifically identified its level of “collaboration” with external partners including Pacific CEED. External partners identified its partnership with the PRCC in the “coalition” stage. Principal Conclusions PRCC members and external partners are satisfied with their partnerships. All groups should continue to focus on building collaboration with partners to reflect a truly regional approach to sustain the commitment, the coalitions and the programming to reduce cancer in the USAPI. PRCC and partners should also work together to integrate all chronic disease prevention and control efforts in the Pacific. PMID

  19. An assessment of the Pacific Regional Cancer Coalition: outcomes and implications of a regional coalition internal and external assessment.

    PubMed

    Sy, Angela U; Heckert, Karen A; Buenconsejo-Lum, Lee; Hedson, Johnny; Tamang, Suresh; Palafox, Neal

    2011-11-01

    The Pacific Regional Cancer Coalition (PRCC) provides regional leadership in the U.S. Affiliated Pacific Islands (USAPI) to implement the Regional Comprehensive Control Plan: 2007-2012, and to evaluate its coalition and partnerships. The Pacific Center of Excellence in the Elimination of Disparities (CEED), aims to reduce cancer disparities and conducts evaluation activities relevant to cancer prevention and control in the USAPI. The PRCC Self (internal) and Partner (external) Assessments were conducted to assess coalition functioning, regional and national partnerships, sustainability, and the role of regionalism for integrating all chronic disease prevention and control in the Pacific. Self-administered questionnaires and key informant telephone interviews with PRCC members (N=20), and representatives from regional and national partner organizations were administered (N=26). Validated multi item measures using 5-point scales on coalition and partnership characteristics were used. Chronbach's alphas and averages for the measures were computed. Internal coalition measures: satisfaction (4.2, SD=0.48) communication (4.0, SD=0.56), respect (4.0, SD=0.60) were rated more highly than external partnership measures: resource sharing (3.5, SD=0.74), regionalism (3.9, SD=0.47), use of findings (3.9, SD=0.50). The PRCC specifically identified its level of "collaboration" with external partners including Pacific CEED. External partners identified its partnership with the PRCC in the "coalition" stage. PRCC members and external partners are satisfied with their partnerships. All groups should continue to focus on building collaboration with partners to reflect a truly regional approach to sustain the commitment, the coalitions and the programming to reduce cancer in the USAPI. PRCC and partners should also work together to integrate all chronic disease prevention and control efforts in the Pacific.

  20. The potential benefits of the use of regional anesthesia in cancer patients.

    PubMed

    Xuan, Wei; Hankin, James; Zhao, Hailin; Yao, Shanglong; Ma, Daqing

    2015-12-15

    Cancer is a leading cause of morbidity and mortality worldwide. In light of demographic changes among other factors, it is anticipated this trend will continue. Surgical resection is the primary method of treating solid tumours. Unfortunately, even with the use of adjunct therapies, metastatic disease is a leading cause of death in people with cancer. Recent evidence suggests choice of anesthetic technique may influence cancer outcome. This review considers the latest evidence regarding local and regional anesthesia in the context of cancer biology. There is a focus on the indirect and direct mechanisms involved. An integrated approach is used such that diverse areas of research are explored; ranging from epigenetics to cell death pathways. With a better understanding of how regional anesthesia and/or local anesthetics interact with cancer cells, these techniques can be trialed and evaluated to ascertain potential clinical benefits in cancer patients. Thus far, there is insufficient evidence to warrant a change in clinical practice. © 2014 UICC.

  1. Black raspberries in cancer clinical trials: Past, present and future

    PubMed Central

    Kresty, Laura A.; Mallery, Susan R.; Stoner, Gary D.

    2016-01-01

    BACKGROUND Black raspberries (BRB) inhibit a broad range of cancers in preclinical models, including in vivo models of oral, esophageal, colon, breast and skin cancer. Promising preclinical results have led to clinical evaluations in cancer patients or patients at increased risk for cancer development. OBJECTIVE To summarize clinical investigations targeting cancer or precancerous lesions with BRB and discuss future directions. METHODS A thorough literature search was conducted through December 1, 2015 to identify all published studies evaluating BRB in cancer focused clinical trials. RESULTS Research investigating BRB in clinical settings report positive effects on preneoplastic lesions or cancers of the oral cavity, esophagus and colon. BRB treatment resulted in: histologic regression of oral intraepithelial neoplasia associated with improved histologic grade and significantly reduced loss of heterozygosity at tumor suppressor gene loci, modulated genes linked to RNA processing and growth factor recycling; in the colon, BRB inhibited FAP-associated polyp progression, demethylated tumor suppressor genes and improved plasma cytokine profiles; in Barrett’s patients, BRB consumption increased tissue levels of GST-pi and decreased 8-isoprostane, a marker of lipid peroxidation/oxidative stress. CONCLUSIONS The precise dose, duration and optimum mode of BRB delivery for cancer inhibition remains to be fully elucidated. Common themes across studies support that BRB are anti-proliferative, anti- inflammatory, reduce oxidative stress and restore tumor suppressive activity. Future directions are included in the conclusions section. PMID:27594930

  2. Women's knowledge, attitudes and practice about breast cancer screening in the region of Monastir (Tunisia).

    PubMed

    El Mhamdi, Sana; Bouanene, Ines; Mhirsi, Amel; Sriha, Asma; Ben Salem, Kamel; Soltani, Mohamed Soussi

    2013-01-01

    Breast cancer remains a worldwide public health problem. In Tunisia, it is considered to be the primary women's cancer and causes high morbidity and mortality. This study aimed to investigate female knowledge, attitudes and practice of breast cancer screening in the region of Monastir (Tunisia). We conducted a descriptive cross-sectional design exploring knowledge, attitudes and practices of women in the region of Monastir on breast cancer screening. The study was conducted in health centres of this region from 1 March 2009 to 30 June 2009. Data were collected via a structured questionnaire containing 15 items on demographic status, knowledge of risk factors and screening methods and attitudes towards the relevance and effectiveness of breast cancer screening. A scoring scheme was used to score women's responses. A total of 900 women agreed to take part in the study. Their mean age was 41.6±12.4 years and 64% did not exceed the primary level of education. According to the constructed scores, 92% of participants had poor knowledge of the specific risk factors for breast cancer and 63.2% had poor knowledge of the screening methods. Proper practice of breast cancer screening was observed in 14.3% of cases. Multiple logistic regression analysis showed that good knowledge of risk factors and screening methods, higher level of education and positive family history of breast cancer were independently correlated with breast cancer screening practice. This study revealed poor knowledge of breast cancer and the screening methods as well as low levels of practice of breast cancer screening among women in the region of Monastir. Results justify educational programs to raise women's adherence to breast cancer screening programs in Tunisia.

  3. Analysis of factors related to the use of opioid analgesics in regional cancer centers in Japan.

    PubMed

    Sugiura, Munetoshi; Miyashita, Mitsunori; Sato, Kazuki; Tsuneto, Satoru; Matoba, Motohiro; Sano, Motohiko; Shima, Yasuo

    2010-07-01

    The use of opioid analgesics and nonopioid medicines for the treatment of various symptoms in regional cancer centers is considered to be an index of the effectiveness of the structural plan for palliative care in such institutions. The present study aimed to establish an accurate representation of the actual use of opioid analgesics for palliative care in regional cancer centers. In November 2007, a questionnaire regarding the use of medications for palliative care was conducted in 288 regional cancer centers in Japan. Valid responses were received from 264 institutions (response rate, 91.4%). All regional cancer centers reported using both opioid analgesics and nonopioid medicines. However, regarding opioid analgesics, the use of each standard strength ranged from 7% to 100%. The total amount of opioid analgesics used was 1739.6 +/- 1216.5 g (mean +/- SD). Factors found to be significantly related to the total amount of opioid analgesics used in an institution were the number of opioid analgesic medicines in use (p = 0.008), the number of inpatients with cancer (p < 0.001), the number of deaths among patients with cancer (p < 0.001), and the number of beds (p < 0.001). Increase in the amount of opioid analgesics might improve the quality of palliative care at regional cancer centers.

  4. Intracystic invasive papillary carcinoma of the male breast with analyses of loss of heterozygosity on chromosome 16q.

    PubMed

    Yoshida, Miwa; Mouri, Yukako; Yamamoto, Sohei; Yorozuya, Kyoko; Fujii, Kimihito; Nakano, Shogo; Fukutomi, Takashi; Hara, Kazuo; Tsuda, Hitoshi

    2010-04-01

    A 64-year-old man noticed a right subareolar mass in May 2005. On physical examination, an oval-shaped, well-circumscribedthe tumor (6.0 x 5.5 cm in size) was located just beneath the right nipple. The tumor was elastic, firm and freely movable. Neither axillary nor supraclavicular lymph nodes were palpable. Mammography demonstrated a 5 x 5-cm, relatively distinct and dense mass without microcalcifications or spiculations. There were no findings of concurrent gynecomastia. Ultrasonography revealed a large multilocular cyst with a mural hypoechoic protruding lesion exhibiting wide-based morphology with an irregular margin. On contrast-enhanced computed tomography, the inner lesion enhanced, but direct invasion of the tumor to the major pectoral muscle was not found. An intracystic papillary lesion, possibly papillary carcinoma, was suspected. In December 2007, wide excision of the tumor was performed. On histopathological examination, the tumor had a papillary pattern with a small cribriform component in the cystic wall with microinvasion of the stroma. Marginal status was negative. The final diagnosis of the disease was a microinvasive intracystic papillary carcinoma of low grade without axillary lymph node metastases. Immunohistochemically, estrogen receptor and progesterone receptor were both positive, but negative for HER-2 protein. No LOH on 16q could be detected. The prognosis of the disease was unclear; however, the malignant potential of this condition may be more clearly determined by studying the LOH on chromosome 16q.

  5. p57KIP2 expression and loss of heterozygosity during immortal conversion of cultured human mammary epithelial cells

    SciTech Connect

    Nijjar, Tarlochan; Wigington, Don; Garbe, James C.; Waha, Andreas; Stampfer, Martha R.; Yaswen, Paul

    1999-08-01

    The authors have uncovered a novel role for the cyclin-dependent kinase inhibitor, p57KIP2, during the immortalization of cultured human mammary epithelial cells (HMEC). HMEC immortalized following chemical carcinogen exposure initially expressed little or no telomerase activity, and their telomeres continued to shorten with passage. Cell populations whose mean terminal restriction fragment (TRF) length declined and exhibited slow heterogeneous growth, and contained many non-proliferative cells. These conditionally immortal HMEC cultures accumulated large quantities of p57 protein. With continued passage, the conditionally immortal cell populations very graduall2048nverted to a fully immortal phenotype of good uniform growth, expression of high levels of telomerase activity, and stabilization of telomere length. The fully immortal good growing HMEC did not accumulate p57 in G0 or during the cell cycle. DNA and RNA analysis of mass populations and individual subclones of conditionally immortal HMEC line 184A1 showed that continued growth of conditionally immortal cells with critically short telomeres was repeatedly accompanied by loss of the expressed p57 allele, and transient expression of the previously imprinted allele. Conditionally immortal 184A1 with mean TRF > 3 kb infected with retroviruses containing the p57 gene exhibited premature slow heterogeneous growth. Conversely, exogenous expression of hTERT, the catalytic subunit of telomerase, in 184A1 with mean TRF > 3 kb prevented both the slow heterogeneous growth phase and accumulation of p57 in cycling populations. These data indicate that in HMEC which have overcome replicative senescence, p57 may provide an additional barrier against indefinite proliferation. Overcoming p57 mediated growth inhibition in these cells may be crucial for acquisition of the unlimited growth potential thought to be critical for malignant progression.

  6. Cyclin D3 expression in primary Ta/T1 bladder cancer.

    PubMed

    Lopez-Beltran, A; Requena, M J; Luque, R J; Alvarez-Kindelan, J; Quintero, A; Blanca, A M; Rodriguez, M E; Siendones, E; Montironi, R

    2006-05-01

    Cyclin D3 deregulation has recently been reported in bladder cancer but its prognostic significance remains uncertain. A cohort of 159 patients with stage Ta or T1 primary bladder tumours was investigated to determine the significance of cyclin D3 expression in association with other G1-S phase regulators of the cell cycle (p53, p21Waf1, p27kip1, cyclin D1), including tumour proliferation (ki67-MIB1); its association with conventional clinicopathological parameters; and the relationship between cyclin D3 and loss of heterozygosity (LOH) at the 9p21 (p16INK4a locus) chromosome region. The end point of the study was progression-free survival. Cyclin D3, other G1-S phase regulators, and tumour proliferation were investigated by immunohistochemistry and measured by the grid-counting method. To validate the immunohistochemical expression, cyclin D3 was additionally assessed by western blotting in selected cases. LOH at the 9p21 chromosome region (marker D9S171) was assessed in 125 cases using an AB Prism 310 genetic analyser and a set of microsatellite fluorescence-labelled primers. Cyclin D3 overexpression was related to larger tumour size (>5 cm; p < 0.0001) and high tumour proliferation (>10%; p = 0.025). Mean cyclin D3 expression increased with 2004 WHO grading categories in stage Ta (p = 0.035, ANOVA) and stage T1 (p = 0.047, t test) tumours. Cyclin D3 was not related to other clinicopathological parameters, G1-S phase modulators, or 9p21 LOH. Cox's multivariate analysis selected cyclin D3 as an independent predictor of progression-free survival (p = 0.0012, relative risk (RR) = 5.2366) together with tumour size (p = 0.0115, RR = 4.4442) and cyclin D1 (p = 0.0065, RR = 3.3023). Cyclin D3 expression had the highest risk ratio. Our results suggest that expression of cyclin D3 is relevant to the progression-free survival of patients with Ta/T1 bladder carcinomas. Copyright 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  7. Childhood cancer survival in Ireland: temporal, regional and deprivation-related patterns.

    PubMed

    Walsh, Paul M; Byrne, Julianne; Capra, Michael; Comber, Harry

    2011-08-01

    Survival after childhood cancer varies across Europe, but national or regional studies have so far shown no survival differences related to socio-economic disparity. The relationship of childhood cancer survival to disparity has not been studied in Ireland. We assessed observed survival for Irish children (ages 0-14 years) diagnosed with cancer during the period 1994-2005, overall (for all cancers included in the 3rd edition of the International Classification of Childhood Cancer) and for three main diagnostic groups - leukaemias, lymphomas, and central nervous system tumours. Comparisons were made between two diagnosis periods (1994-1999 and 2000-2005), between four regions of residence, and between five area-based deprivation categories. Regional patterns of treatment were examined to help assess the impact of centralisation of services. There was only limited evidence of improvements in survival over time. No clear evidence was found of deprivation-related influences on childhood cancer survival in Ireland, overall or for the three main diagnostic groups examined, although a weak trend was apparent for lymphoid leukaemias. Regional variation in survival was likewise not clear-cut, with the possible exception of CNS tumours (significantly higher survival amongst patients resident in the Western region). The absence of clear trends or patterns for regional or deprivation-related variation in survival may reflect a high degree of coordination and uniformity of treatment (and perhaps diagnostic) services, and application of standard treatment protocols nationally. Copyright © 2011 Elsevier Ltd. All rights reserved.

  8. Patterns and functional implications of rare germline variants across 12 cancer types

    PubMed Central

    Lu, Charles; Xie, Mingchao; Wendl, Michael C.; Wang, Jiayin; McLellan, Michael D.; Leiserson, Mark D. M.; Huang, Kuan-lin; Wyczalkowski, Matthew A.; Jayasinghe, Reyka; Banerjee, Tapahsama; Ning, Jie; Tripathi, Piyush; Zhang, Qunyuan; Niu, Beifang; Ye, Kai; Schmidt, Heather K.; Fulton, Robert S.; McMichael, Joshua F.; Batra, Prag; Kandoth, Cyriac; Bharadwaj, Maheetha; Koboldt, Daniel C.; Miller, Christopher A.; Kanchi, Krishna L.; Eldred, James M.; Larson, David E.; Welch, John S.; You, Ming; Ozenberger, Bradley A.; Govindan, Ramaswamy; Walter, Matthew J.; Ellis, Matthew J.; Mardis, Elaine R.; Graubert, Timothy A.; Dipersio, John F.; Ley, Timothy J.; Wilson, Richard K.; Goodfellow, Paul J.; Raphael, Benjamin J.; Chen, Feng; Johnson, Kimberly J.; Parvin, Jeffrey D.; Ding, Li

    2015-01-01

    Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C, PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively). Significant, tumour-specific loss of heterozygosity occurs in nine genes (ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2 and RAD51C/D). Moreover, our homology-directed repair assay of 68 BRCA1 rare missense variants supports the utility of allelic enrichment analysis for characterizing variants of unknown significance. The scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumour development, a critical step toward precision medicine. PMID:26689913

  9. Cancer mortality and oil production in the Amazon Region of Ecuador, 1990-2005.

    PubMed

    Kelsh, Michael A; Morimoto, Libby; Lau, Edmund

    2009-02-01

    To compare cancer mortality rates in Amazon cantons (counties) with and without long-term oil exploration and extraction activities. Mortality (1990 through 2005) and population census (1990 and 2001) data for cantons in the provinces of the northern Amazon Region (Napo, Orellana, Sucumbios, and Pastaza), as well as the province with the capital city of Quito (Pichincha province) were obtained from the National Statistical Office of Ecuador, Instituto Nacional del Estadistica y Censos (INEC). Age- and sex-adjusted mortality rate ratios (RR) and 95% confidence intervals (CI) were estimated to evaluate total and cause-specific mortality in the study regions. Among Amazon cantons with long-term oil extraction, activities there was no evidence of increased rates of death from all causes (RR = 0.98; 95% CI = 0.95-1.01) or from overall cancer (RR = 0.82; 95% CI = 0.73-0.92), and relative risk estimates were also lower for most individual site-specific cancer deaths. Mortality rates in the Amazon provinces overall were significantly lower than those observed in Pichincha for all causes (RR = 0.82; 95% CI = 0.81-0.83), overall cancer (RR = 0.46; 95% CI = 0.43-0.49), and for all site-specific cancers. In regions with incomplete cancer registration, mortality data are one of the few sources of information for epidemiologic assessments. However, epidemiologic assessments in this region of Ecuador are limited by underreporting, exposure and disease misclassification, and study design limitations. Recognizing these limitations, our analyses of national mortality data of the Amazon Region in Ecuador does not provide evidence for an excess cancer risk in regions of the Amazon with long-term oil production. These findings were not consistent or supportive of earlier studies in this region that suggested increased cancer risks.

  10. Regional variation in incidence for smoking and alcohol related cancers in Belgium.

    PubMed

    Henau, Kris; Van Eycken, Elizabeth; Silversmit, Geert; Pukkala, Eero

    2015-02-01

    The prevalence of life habits may vary substantially within a country. Incidence maps of strongly related diseases can illustrate the distribution of these life style habits. In this study we explored the spatial variation in Belgium for different cancers related to alcohol and/or tobacco. From the Belgian Cancer Registry, municipality specific World Standardised incidence rates for the years 2004-2011 are used to create detailed smoothed cancer maps by subsite or histology for cancers of oral cavity, pharynx, larynx, oesophagus, liver and lung. Cancer incidence is compared both visually (from incidence maps) and with Poisson regression analysis using mortality from chronic liver disease and chronic obstructive pulmonary disease as a proxy for alcohol and tobacco prevalence, respectively. The incidence rates for oral cavity, pharyngeal and laryngeal cancer were comparable with the alcohol gradient. However, glottic cancer revealed a pattern that was more comparable with lung cancer. These two tumour types resembled more closely to the smoking pattern. Oesophageal cancer showed two patterns: squamous cell carcinoma was highly comparable with the background alcohol consumption, while adenocarcinoma was unrelated to one of our two proxies. Our approach and results are an encouraging example how data from a young cancer registry can be used in studies describing the regional cancer burden. The results can be useful for primary prevention to increase awareness for the public, authorities and health care professionals in specific subpopulations. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  11. Esophageal squamous cell cancer in a highly endemic region

    PubMed Central

    Asombang, Akwi W; Kayamba, Violet; Lisulo, Mpala M; Trinkaus, Kathryn; Mudenda, Victor; Sinkala, Edford; Mwanamakondo, Stayner; Banda, Themba; Soko, Rose; Kelly, Paul

    2016-01-01

    AIM: To identify risk factors associated with esophageal cancer in Zambia and association between dietary intake and urinary 8-iso prostaglandin F2α (8-isoPGF2α). METHODS: We conducted a prospective, case control study at the University Teaching Hospital. Subjects included both individuals admitted to the hospital and those presenting for an outpatient upper endoscopy. Esophageal cancer cases were compared to age and sex-matched controls. Cases were defined as patients with biopsy proven esophageal cancer; controls were defined as subjects without endoscopic evidence of esophageal cancer. Clinical and dietary data were collected using a standard questionnaire, developed a priori. Blood was collected for human immunodeficiency virus (HIV) serology. Urine was collected, and 8-isoPGF2α was measured primarily by enzyme-linked immunosorbent assay and expressed as a ratio to creatinine. RESULTS: Forty five controls (mean age 54.2 ± 15.3, 31 male) and 27 cases (mean age 54.6 ± 16.4, 17 males) were studied. Body mass index was lower in cases (median 16.8) than controls (median 23.2), P = 0.01. Histopathologically, 25/27 (93%) were squamous cell carcinoma and 2/27 (7%) adenocarcinoma. More cases smoked cigarettes (OR = 11.24, 95%CI: 1.37-92.4, P = 0.02) but alcohol consumption and HIV seropositivity did not differ significantly (P = 0.14 for both). Fruit, vegetables and fish consumption did not differ significantly between groups (P = 0.11, 0.12, and 0.10, respectively). Mean isoprostane level was significantly higher in cases (0.03 ng/mg creatinine) than controls (0.01 ng/mg creatinine) (OR = 2.35, 95%CI: 1.19-4.65, P = 0.014). CONCLUSION: Smoking and isoprostane levels were significantly associated with esophageal cancer in Zambians, but diet, HIV status, and alcohol consumption were not. PMID:26973419

  12. Characteristics and comparison of colorectal cancer incidence in Beijing with other regions in the world

    PubMed Central

    Li, Zhongmin; Yang, Lei; Du, Changzheng; Fang, Xuedong; Wang, Ning; Gu, Jin

    2017-01-01

    Background Population-based epidemiologic studies about colorectal cancer are lacking in China. This study aims to provide a basis for colorectal cancer screening and prevention, through analysis and comparisons the characteristics of the trends in colorectal cancer incidence in Beijing and selected representative regions. RESULTS The annual incidence rate in Beijing region increased significantly, from 9.40/100,000 in 1998 to 18.61/100,000 in 2012. The stratified rate showed that the incidence of distal colon adenocarcinoma increased substantially in men, especially in those aged > 75 years and residing in urban areas. Although the incidence rate in Beijing is still lower than in Shanghai, Jiashan, and Hong Kong in China, it is increasing rapidly. Further, the incidence rate in Beijing is lower than in New York, Oxford and Osaka, but higher than in Mumbai and Kyadondo. The incidence trend in Beijing is increasing especially in older groups, while in other regions such as New York, it is decreasing in these age groups. Materials and Methods Colorectal cancer incidence data were obtained from Beijing Cancer Registry and Cancer Incidence in Five Continents Plus database. All incidence rates were age-standardized according to Segi's world population. Incidence trends were characterized by calculating the annual percent changes using the Joinpoint Regression Program. Conclusions Compared with other regions, Beijing has a medium level of colorectal cancer incidence, however, it is increasing significantly. There are obvious differences in the cancer subsite, sex and age distributions between Beijing and other regions. Prevention and screening of colorectal cancer in Beijing should be strengthened. PMID:28445947

  13. Overview of childhood cancers at a regional cancer centre in North-East India.

    PubMed

    Hazarika, Munlima; Krishnatreya, Manigreeva; Bhuyan, Cidananda; Saikia, Bhargab Jyoti; Kataki, Amal Chandra; Nandy, Pintu; Hazarika, Monalisha; Roy, Partha Sarathi

    2014-01-01

    Childhood cancers are relatively uncommon in comparison to adult cancers. There is no literature available to shed light on clinic-pathological types and patterns of care for childhood cancers in our population in North-East India. In this analysis we therefore tried to determine the common childhood cancers diagnosed in our institute, clinical profile of the patients, types of treatment and compliance, and median survival estimates. Leukemia was most common, followed by retinoblastoma, central nervous system tumours and lymphomas. Ascertaining the clinic-pathological profile of childhood cancers in our population is essential for allocation and management of resources for this small but important group of patients.

  14. Cervical cancer screening coverage in a high-incidence region

    PubMed Central

    Navarro, Cibelli; da Fonseca, Allex Jardim; Sibajev, Alexander; Souza, Camila Iasmim de Andrade; Araújo, Daniela Souza; Teles, Daniele Aparecida de Freitas; de Carvalho, Stéphanie Gomes Lins; Cavalcante, Kyldery Wendell Moura; Rabelo, Wendell Lima

    2015-01-01

    OBJECTIVE To analyze the coverage of a cervical cancer screening program in a city with a high incidence of the disease in addition to the factors associated with non-adherence to the current preventive program. METHODS A cross-sectional study based on household surveys was conducted. The sample was composed of women between 25 and 59 years of age of the city of Boa Vista, RR, Northern Brazil who were covered by the cervical cancer screening program. The cluster sampling method was used. The dependent variable was participation in a women’s health program, defined as undergoing at least one Pap smear in the 36 months prior to the interview; the explanatory variables were extracted from individual data. A generalized linear model was used. RESULTS 603 women were analyzed, with an mean age of 38.2 years (SD = 10.2). Five hundred and seventeen women underwent the screening test, and the prevalence of adherence in the last three years was up to 85.7% (95%CI 82.5;88.5). A high per capita household income and recent medical consultation were associated with the lower rate of not being tested in multivariate analysis. Disease ignorance, causes, and prevention methods were correlated with chances of non-adherence to the screening system; 20.0% of the women were reported to have undergone opportunistic and non-routine screening. CONCLUSIONS The informed level of coverage is high, exceeding the level recommended for the control of cervical cancer. The preventive program appears to be opportunistic in nature, particularly for the most vulnerable women (with low income and little information on the disease). Studies on the diagnostic quality of cervicovaginal cytology and therapeutic schedules for positive cases are necessary for understanding the barriers to the control of cervical cancer. PMID:25741655

  15. Regional geographic variations in kidney cancer incidence rates in European countries.

    PubMed

    Li, Peng; Znaor, Ariana; Holcatova, Ivana; Fabianova, Eleonora; Mates, Dana; Wozniak, Magdalena B; Ferlay, Jacques; Scelo, Ghislaine

    2015-06-01

    Marked unexplained national variations in incidence rates of kidney cancer have been observed for decades in Europe. To investigate geographic variations at the regional level and identify European regions with high incidence rates of kidney cancer. Regional- and national-level incidence data were extracted from the Cancer Incidence in Five Continents databases, local cancer registry databases, and local published reports. World population age-standardised rates (ASRs) were calculated for the periods 2003-2007 and 1988-1992. Rates by period and sex were compared using map visualisation. During 2003-2007, the highest ASR was found in the Plzen region, Czech Republic (31.4/100,000 person-years in men). Other regions of the Czech Republic had ASRs of 18.6-27.5/100,000 in men, with a tendency for higher rates in regions south of Prague. Surrounding regions, including eastern Germany and regions of Slovakia and Austria, had medium-to-high incidence rates (13.0-16.8/100,000 in men). Three other areas in Europe showed higher incidence rates in men compared with the rest of the continent: Lithuania, Estonia, Latvia, and Belarus (15.0-17.6/100,000); Iceland (13.5/100,000), and northern Italy (up to 16.0/100,000). Similar regional differences were observed among women, with rates approximately half of those observed in men in the same region. In general, these regional geographic variations remained stable over the periods 1988-1992 and 2003-2007, although higher incidence rates were detected in the Baltic countries in 2003-2007. Several European regions show particularly high rates of kidney cancer incidence. Large variations were observed within countries covered by national health-care systems, implying that overdetection is not the major factor. We present regional geographic variations in kidney cancer incidence rates in Europe. We highlight several regions with high incidence rates where further studies should be conducted for cancer control and prevention. Copyright

  16. Detectable clonal mosaicism and its relationship to aging and cancer

    PubMed Central

    Jacobs, Kevin B; Yeager, Meredith; Zhou, Weiyin; Wacholder, Sholom; Wang, Zhaoming; Rodriguez-Santiago, Benjamin; Hutchinson, Amy; Deng, Xiang; Liu, Chenwei; Horner, Marie-Josephe; Cullen, Michael; Epstein, Caroline G; Burdett, Laurie; Dean, Michael C; Chatterjee, Nilanjan; Sampson, Joshua; Chung, Charles C; Kovaks, Joseph; Gapstur, Susan M; Stevens, Victoria L; Teras, Lauren T; Gaudet, Mia M; Albanes, Demetrius; Weinstein, Stephanie J; Virtamo, Jarmo; Taylor, Philip R; Freedman, Neal D; Abnet, Christian C; Goldstein, Alisa M; Hu, Nan; Yu, Kai; Yuan, Jian-Min; Liao, Linda; Ding, Ti; Qiao, You-Lin; Gao, Yu-Tang; Koh, Woon-Puay; Xiang, Yong-Bing; Tang, Ze-Zhong; Fan, Jin-Hu; Aldrich, Melinda C; Amos, Christopher; Blot, William J; Bock, Cathryn H; Gillanders, Elizabeth M; Harris, Curtis C; Haiman, Christopher A; Henderson, Brian E; Kolonel, Laurence N; Le Marchand, Loic; McNeill, Lorna H; Rybicki, Benjamin A; Schwartz, Ann G; Signorello, Lisa B; Spitz, Margaret R; Wiencke, John K; Wrensch, Margaret; Wu, Xifeng; Zanetti, Krista A; Ziegler, Regina G; Figueroa, Jonine D; Garcia-Closas, Montserrat; Malats, Nuria; Marenne, Gaelle; Prokunina-Olsson, Ludmila; Baris, Dalsu; Schwenn, Molly; Johnson, Alison; Landi, Maria Teresa; Goldin, Lynn; Consonni, Dario; Bertazzi, Pier Alberto; Rotunno, Melissa; Rajaraman, Preetha; Andersson, Ulrika; Freeman, Laura E Beane; Berg, Christine D; Buring, Julie E; Butler, Mary A; Carreon, Tania; Feychting, Maria; Ahlbom, Anders; Gaziano, J Michael; Giles, Graham G; Hallmans, Goran; Hankinson, Susan E; Hartge, Patricia; Henriksson, Roger; Inskip, Peter D; Johansen, Christoffer; Landgren, Annelie; McKean-Cowdin, Roberta; Michaud, Dominique S; Melin, Beatrice S; Peters, Ulrike; Ruder, Avima M; Sesso, Howard D; Severi, Gianluca; Shu, Xiao-Ou; Visvanathan, Kala; White, Emily; Wolk, Alicja; Zeleniuch-Jacquotte, Anne; Zheng, Wei; Silverman, Debra T; Kogevinas, Manolis; Gonzalez, Juan R; Villa, Olaya; Li, Donghui; Duell, Eric J; Risch, Harvey A; Olson, Sara H; Kooperberg, Charles; Wolpin, Brian M; Jiao, Li; Hassan, Manal; Wheeler, William; Arslan, Alan A; Bas Bueno-de-Mesquita, H; Fuchs, Charles S; Gallinger, Steven; Gross, Myron D; Holly, Elizabeth A; Klein, Alison P; LaCroix, Andrea; Mandelson, Margaret T; Petersen, Gloria; Boutron-Ruault, Marie-Christine; Bracci, Paige M; Canzian, Federico; Chang, Kenneth; Cotterchio, Michelle; Giovannucci, Edward L; Goggins, Michael; Bolton, Judith A Hoffman; Jenab, Mazda; Khaw, Kay-Tee; Krogh, Vittorio; Kurtz, Robert C; McWilliams, Robert R; Mendelsohn, Julie B; Rabe, Kari G; Riboli, Elio; Tjønneland, Anne; Tobias, Geoffrey S; Trichopoulos, Dimitrios; Elena, Joanne W; Yu, Herbert; Amundadottir, Laufey; Stolzenberg-Solomon, Rachael Z; Kraft, Peter; Schumacher, Fredrick; Stram, Daniel; Savage, Sharon A; Mirabello, Lisa; Andrulis, Irene L; Wunder, Jay S; García, Ana Patiño; Sierrasesúmaga, Luis; Barkauskas, Donald A; Gorlick, Richard G; Purdue, Mark; Chow, Wong-Ho; Moore, Lee E; Schwartz, Kendra L; Davis, Faith G; Hsing, Ann W; Berndt, Sonja I; Black, Amanda; Wentzensen, Nicolas; Brinton, Louise A; Lissowska, Jolanta; Peplonska, Beata; McGlynn, Katherine A; Cook, Michael B; Graubard, Barry I; Kratz, Christian P; Greene, Mark H; Erickson, Ralph L; Hunter, David J; Thomas, Gilles; Hoover, Robert N; Real, Francisco X; Fraumeni, Joseph F; Caporaso, Neil E; Tucker, Margaret; Rothman, Nathaniel; Pérez-Jurado, Luis A; Chanock, Stephen J

    2012-01-01

    In an analysis of 31,717 cancer cases and 26,136 cancer-free controls drawn from 13 genome-wide association studies (GWAS), we observed large chromosomal abnormalities in a subset of clones from DNA obtained from blood or buccal samples. Mosaic chromosomal abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of size >2 Mb were observed in autosomes of 517 individuals (0.89%) with abnormal cell proportions between 7% and 95%. In cancer-free individuals, the frequency increased with age; 0.23% under 50 and 1.91% between 75 and 79 (p=4.8×10−8). Mosaic abnormalities were more frequent in individuals with solid-tumors (0.97% versus 0.74% in cancer-free individuals, OR=1.25, p=0.016), with a stronger association for cases who had DNA collected prior to diagnosis or treatment (OR=1.45, p=0.0005). Detectable clonal mosaicism was common in individuals for whom DNA was collected at least one year prior to diagnosis of leukemia compared to cancer-free individuals (OR=35.4, p=3.8×10−11). These findings underscore the importance of the role and time-dependent nature of somatic events in the etiology of cancer and other late-onset diseases. PMID:22561519

  17. Regional-Level Correlations in Inappropriate Imaging Rates for Prostate and Breast Cancers

    PubMed Central

    Makarov, Danil V.; Soulos, Pamela R.; Gold, Heather T.; Yu, James B.; Sen, Sounok; Ross, Joseph S.; Gross, Cary P.

    2015-01-01

    IMPORTANCE The association between regional norms of clinical practice and appropriateness of care is incompletely understood. Understanding regional patterns of care across diseases might optimize implementation of programs like Choosing Wisely, an ongoing campaign to decrease wasteful medical expenditures. OBJECTIVE To determine whether regional rates of inappropriate prostate and breast cancer imaging were associated. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study using the the Surveillance, Epidemiology, and End Results–Medicare linked database. We identified patients diagnosed from 2004 to 2007 with low-risk prostate (clinical stage T1c/T2a; Gleason score, ≤6; and prostate-specific antigen level, <10 ng/mL) or breast cancer (in situ, stage I, or stage II disease), based on Choosing Wisely definitions. MAIN OUTCOMES AND MEASURES In a hospital referral region (HRR)-level analysis, our dependent variable was HRR-level imaging rate among patients with low-risk prostate cancer. Our independent variable was HRR-level imaging rate among patients with low-risk breast cancer. In a subsequent patient-level analysis we used multivariable logistic regression to model prostate cancer imaging as a function of regional breast cancer imaging and vice versa. RESULTS We identified 9219 men with prostate cancer and 30 398 women with breast cancer residing in 84 HRRs. We found high rates of inappropriate imaging for both prostate cancer (44.4%) and breast cancer (41.8%). In the first, second, third, and fourth quartiles of breast cancer imaging, inappropriate prostate cancer imaging was 34.2%, 44.6%, 41.1%, and 56.4%, respectively. In the first, second, third, and fourth quartiles of prostate cancer imaging, inappropriate breast cancer imaging was 38.1%, 38.4%, 43.8%, and 45.7%, respectively. At the HRR level, inappropriate prostate cancer imaging rates were associated with inappropriate breast cancer imaging rates (ρ = 0.35; P < .01). At the patient level, a

  18. The Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC): past medical history in children with cancer.

    PubMed Central

    Hartley, A L; Birch, J M; McKinney, P A; Blair, V; Teare, M D; Carrette, J; Mann, J R; Stiller, C A; Draper, G J; Johnston, H E

    1988-01-01

    The Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC) collected interview and medical information relating to the child's past medical experiences from parents of 555 children diagnosed with cancer and parents of 1110 unaffected matched controls. No significant associations emerged overall for ante-natal care, place and mode of delivery, length of gestation, birth weight, condition at birth, special care, neonatal procedures or breast-feeding. Few risk factors relating to previous illnesses and medication were found, although increasing numbers of illnesses appeared to be associated with an increased risk of childhood cancer, particularly acute lymphoblastic leukaemia. A highly significant excess of case children had not been immunised (p = 0.005). In general, these results indicate that past medical experiences have little influence on the development of cancer in children. PMID:3251004

  19. Comparison of Florida skin cancer screening rates with those in different US regions.

    PubMed

    Fernandez, Cristina A; McClure, Laura A; Leblanc, William G; Clarke, Tainya C; Kirsner, Robert S; Fleming, Lora E; Arheart, Kristopher L; Lee, David J

    2012-10-01

    Florida has the second highest incidence of melanoma in the United States, and more than 600 Floridians die from melanoma annually. Given the lack of population-based data on skin cancer screening among the different US geographic regions, we compared skin cancer screening rates among Floridians to those in the rest of the South, the Northeast, the Midwest, and the West. We used data from the 2000 and 2005 National Health Interview Survey. Data were grouped according to whether participants reported ever receiving a skin cancer examination in their lifetime. Data were pooled, and analyses accounted for sample weights and design effects. Multivariable logistic regression analyses were performed with self-reported skin screening as the outcome of interest. Results showed that compared to the rest of the US, Floridians who were women 70 years old and older, reported being of "other" race, of non-Hispanic ethnicity, having a high school education, having health insurance, and employed in the service industry or unemployed, had significantly higher lifetime skin cancer screening rates than their subgroup counterparts residing in the other regions. Multivariable logistic regression showed that Floridians remained significantly more likely to have ever been screened for skin cancer compared to the other US regions after controlling for a variety of sociodemographic variables. Increasing melanoma detection remains a national cancer goal for the US, and future identification of underlying causal factors for higher screening rates in Florida could inform intervention strategies in the other US regions.

  20. Personalization of loco-regional care for primary breast cancer patients (part 2).

    PubMed

    Toi, Masakazu; Winer, Eric P; Benson, John R; Inamoto, Takashi; Forbes, John F; von Minckwitz, Gunter; Robertson, John F R; Grobmyer, Stephen R; Jatoi, Ismail; Sasano, Hironobu; Kunkler, Ian; Ho, Alice Y; Yamauchi, Chikako; Chow, Louis W C; Huang, Chiun-Sheng; Han, Wonshik; Noguchi, Shinzaburo; Pegram, Mark D; Yamauchi, Hideko; Lee, Eun-Sook; Larionov, Alexey A; Bevilacqua, Jose L B; Yoshimura, Michio; Sugie, Tomoharu; Yamauchi, Akira; Krop, Ian E; Noh, Dong Young; Klimberg, V Suzanne

    2015-01-01

    Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the second of a two part conference scene, consensus recommendations for radiation treatment, primary systemic therapies and management of genetic predisposition are reported and focus on the following topics: influence of both clinical response to PST and stage at presentation on recommendations for postmastectomy radiotherapy; use of regional nodal irradiation in selected node-positive patients and those with adverse pathological factors; extent of surgical resection following downstaging of tumors with PST; use of preoperative hormonal therapy in premenopausal women with larger, node-negative luminal A-like tumors and managing increasing demands for contralateral prophylactic mastectomy in patients with a unilateral sporadic breast cancer.

  1. Microsatellite alteration in multiple primary lung cancer

    PubMed Central

    Shen, Cheng; Wang, Xin; Tian, Long

    2014-01-01

    Patients with pulmonary neoplasms have an increased risk for developing a second tumor of the lung, either at the same time or different times. It is important to determine if the second tumor represents an independent primary tumor or recurrence/metastasis, because it will significantly change the management and prognosis. Microsatellite instability (MSI) and loss of heterozygosity (LOH) represents molecular disorders acquired by the cell during neoplastic transformation. Both are associated with genetic instability. Functional silencing of tumour suppressor genes may be the consequence of genomic instability, particularly of the globally occurring LOH phenomenon. Numerous studies have confirmed the role of MSI/LOH at both the early and the late stages of multiple primary lung cancer. This paper reviews the published literatures focused on the role of MSI/LOH significance in multiple primary lung cancer. Additionally, a new method based on the allelic variations at polymorphic microsatellite markers was offered that it does not rely on collection of normal tissue, performed with minimal tumor sample, and will complement clinical criteria for diagnostic discrimination between multiple primary cancers versus solitary metastatic diseases. PMID:25364529

  2. The use of complementary/alternative medicine by cancer patients in a New Zealand regional cancer treatment centre.

    PubMed

    Chrystal, Kathryn; Allan, Simon; Forgeson, Garry; Isaacs, Richard

    2003-01-24

    To study the prevalence and patterns of complementary/alternative medicine (CAM) use in cancer patients managed by a New Zealand regional cancer treatment centre. A self-administered anonymous questionnaire was used to survey patients attending outpatient clinics of the MidCentral Regional Cancer Treatment Service. Questions addressed patient demographics, cancer diagnosis and conventional treatments received. CAM users were asked to identify types of therapies used, reasons for use, perceived effectiveness, safety and financial cost. Questionnaires were distributed to 350 patients, with 200 assessable replies received. Overall, 49% of patients in this group used CAM, with vitamins, antioxidants, alternative diets, and herbal therapies the most commonly used agents and usage was more common in younger patients. CAM was used by 47% to improve quality of life and by 30% in the hope of a cure of their cancer. Of CAM users, 71% believed these therapies had been helpful in the management of their cancer, and 89% felt they were safe. Only 41% of users had discussed CAM with their oncologist and almost one third had started such therapies before being seen at the Cancer Treatment Centre. The median cost of CAM was NZ$55/month. CAM is commonly used by New Zealand cancer patients, who often use multiple therapies, not only during conventional treatment, but also without consultation with their oncologist. This lack of open communication about CAM between patients and medical staff may prevent identification not only of potential harmful effects, but also of positive and negative drug interactions between CAM and conventional therapies.

  3. Building a Latin American cancer patient advocacy movement: Latin American cancer NGO regional overview.

    PubMed

    Durstine, Alessandra; Leitman, Elizabeth

    2009-01-01

    The objective of the this paper is to assess and identify the key strengths and weaknesses for cancer control NGOs in Latin America, with the goal to make recommendations about how to improve thev impact of the patient advocacy movement as it pertains to cancer. The methods included literature review, expert interviews and site visits to Latin American cancer hospitals and NGOs. The overall findings conclude that NGOs currently do not take a leadership role in cancer control in Latin America. The lack of a survivorship movement, faulty patient information services and failure of the governments to include NGOs in policy creation are identified as areas for further project work and collaboration. The stigma of cancer still remains and a burgeoning patient movement can be created to help destigmatize and debunk the myths that surround cancer.

  4. [Results of palliative treatment of advanced regional oropharyngeal cancer].

    PubMed

    Laskus, Z; Szutkowski, Z

    1998-01-01

    We present results of palliative radiotherapy in 76 oropharyngeal advanced cancer patients. We recommend, according to appreciated results of palliative treatment, the two high fractionation dose courses (so called split course) if the first application of high fractionation dose had resulted in partial remission. Conventional fractionation dose in the second part of split course of radiotherapy did not result in better effect in regression, better subjective feeling after radiotherapy and longer survival time in our material. Patients with poor presentation status (Zubrod 3) should be excluded from palliative radiotherapy.

  5. Country and regional variations in purchase prices for essential cancer medications.

    PubMed

    Cuomo, Raphael E; Seidman, Robert L; Mackey, Tim K

    2017-08-24

    Accessibility to essential cancer medications in low- and middle-income countries is threatened by insufficient availability and affordability. The objective of this study is to characterize variation in transactional prices for essential cancer medications across geographies, medication type, and time. Drug purchase prices for 19 national and international buyers (representing 29 total countries) between 2010 and 2014 were obtained from Management Sciences for Health. Median values for drug pricing were computed, to address outliers in the data. For comparing purchase prices across geographic units, medications, and over time; Mann-Whitney U tests were used to compare two groups, Kruskal Wallis H tests were used to compare more than two groups, and linear regression was used to compare across continuous independent variables. During the five-year data period examined, the median price paid for a package of essential cancer medication was $12.63. No significant differences in prices were found based on country-level wealth, country-level disease burden, drug formulation, or year when medication was purchased. Statistical tests found significant differences in prices paid across countries, regions, individual medications, and medication categories. Specifically, countries in the Africa region appeared to pay more for a package of essential cancer medication than countries in the Latin America region, and cancer medications tended to be more expensive than anti-infective medications and cardiovascular medications. Though preliminary, our study found evidence of variation in prices paid by health systems to acquire essential cancer medications. Primarily, variations in pricing based on geographic location and cancer medication type (including when comparing to essential medicines that treat cardiovascular and infectious diseases) indicate that these factors may impact availability, affordability and access to essential cancer drugs. These factors should be taken into

  6. Risk of regional recurrence in triple-negative breast cancer patients: a Dutch cohort study.

    PubMed

    van Roozendaal, Lori M; Smit, Leonie H M; Duijsens, Gaston H N M; de Vries, Bart; Siesling, Sabine; Lobbes, Marc B I; de Boer, Maaike; de Wilt, Johannes H W; Smidt, Marjolein L

    2016-04-01

    Triple-negative breast cancer is associated with early recurrence and low survival rates. Several trials investigate the safety of a more conservative approach of axillary treatment in clinically T1-2N0 breast cancer. Triple-negative breast cancer comprises only 15 % of newly diagnosed breast cancers, which might result in insufficient power for representative results for this subgroup. We aimed to provide a nationwide overview on the occurrence of (regional) recurrences in triple-negative breast cancer patients with a clinically T1-2N0 status. For this cohort study, 2548 women diagnosed between 2005 and 2008 with clinically T1-2N0 triple-negative breast cancer were selected from the Netherlands Cancer Registry. Follow-up data until 2014 were analyzed using Kaplan-Meier. Sentinel lymph node biopsy was performed in 2486 patients, and (completion) axillary lymph node dissection in 562 patients. Final pathologic nodal status was pN0 in 78.5 %, pN1mi in 4.5 %, pN1 in 12.3 %, pN2-3 in 3.6 %, and pNx in 1.1 %. During a follow-up of 5 years, regional recurrence occurred in 2.9 %, local recurrence in 4.2 % and distant recurrence in 12.2 %. Five-year disease-free survival was 78.7 %, distant disease-free survival 80.5 %, and 5-year overall survival 82.3 %. Triple-negative clinically T1-2N0 breast cancer patients rarely develop a regional recurrence. Their disease-free survival is more threatened by distant recurrence, affecting their overall survival. Consequently, it seems justified to include triple-negative breast cancer patients in randomized controlled trials investigating the safety of minimizing axillary staging and treatment.

  7. The Relationship between Eating and Lifestyle Habits and Cancer in Van Lake Region: Another Endemic Region for Esophageal and Gastric Cancers.

    PubMed

    Celik, Sebahattin; Yılmaz, E Murat; Özden, Ferhat; Kotan, Cetin; Okut, Hayrettin

    2015-01-01

    Purpose. To examine the relationship between esophageal and gastric cancers commonly seen in Van Lake region and the traditional eating habits of the geography. Materials and Methods. Esophageal and gastric cancer cases, who underwent surgery between January 1, 2012, and December 31, 2013, were examined. Pathology reports of the patients and presence of Helicobacter pylori (HP) were recorded. Surveys were filled by face to face meeting or telephone call. Control group was created with randomly selected individuals without any cancer diagnosis having age, gender, and socioeconomic characteristics similar to patient group. All data were analyzed using SAS.9.3 statistical programme. Results. Compared with the control group, herby cheese consumption (a component of eating habits) and smoking were significantly higher in the patient group (P < 0.001). Tandoor exposure is compared in terms of female gender, and significant difference was found between the groups (P = 0.0013). As a result of the analysis with logistic regression more than 150 gr of herby cheese consumption per day was found to increase the cancer risk (odds ratio 1.017; 95% CI: 1.012-1.022). Conclusion. A high consumption of herby cheese, cooking bread on tandoor, and heavy smoking were seen to be important risk factors for esophageal and gastric cancers.

  8. Prevention of infection-related cancers in the WHO Western Pacific Region.

    PubMed

    Shin, Hai-Rim; Shin, Aesun; Woo, Hyeongtaek; Fox, Kimberley; Walsh, Nick; Lo, Ying-Ru; Wiesen, Eric; Varghese, Cherian

    2016-01-01

    A considerable number of infectious agents have been classified as human carcinogens Group 1 by the International Agency for Research on Cancer. Major infection-related cancers such as cancers of nasopharynx (53%), stomach (60%) and liver (63%) occur in the World Health Organization Western Pacific Region. Many infection-related cancers are preventable, particularly those associated with human papilloma virus, Helicobacter pylori, human immunodeficiency virus-I, hepatitis B virus and hepatitis C virus and liver flukes. Mongolia shows the highest prevalence of hepatitis B virus and hepatitis C virus, and China shows the highest prevalence of Helicobacter pylori. Chronic infection is attributable for 17-28% of overall cancer incidence or mortality in China, Japan and Korea. Through infant immunization for hepatitis B, 30 of 37 countries and areas in the Western Pacific Region have reached the 2012 milestone of chronic hepatitis B virus infection prevalence of <2% in 5-year-old children and countries and areas of the region are now striving toward reaching the regional goal of <1% by 2017. Human papilloma virus immunization program is implemented either by government funding or, in some low-income countries, by public and private sector organizations. Cervical cancer screening via visual inspection with acetic acid or Pap smear is available in many Western Pacific Region Member States. More efforts are needed to implement new World Health Organization guide to vaccinate 9- to 13-year-old girls with two doses of human papilloma virus vaccine, and use human papilloma virus tests to screen women to prevent and control cervical cancer including guaranteed monitoring and appropriate follow-up for abnormal results. © World Health Organization 2015. All rights reserved. The World Health Organization has granted the Publisher permission for the reproduction of this article.

  9. [Gastric cancer in the Honorio Delgado Regional Hospital in Arequipa].

    PubMed

    Estremadoyro, O; Alvarez de Trillo, Y; Estremadoyro Stagnaro, L; Gamero Tejada, D

    1995-01-01

    We present the study of 120 cases of gastric carcinoma, observed in the Hospital Regional Honorio Delgado from Arequipa Peru, in 2683 gastroscopies, with 4.5% of incidence. We offer date of age, sex, race, occupation, antecedents, social-economic conditions, clinics, diagnosis, pathologies aspects and mortality.

  10. Understanding receptivity to informal supportive cancer care in regional and rural Australia: a Heideggerian analysis.

    PubMed

    Pascal, J; Johnson, N; Dickson-Swift, V; McGrath, P; Dangerfield, F

    2016-05-01

    The concept of receptivity is a new way of understanding the personal and social factors that affect a person living with and beyond cancer, and how these factors influence access to formal supportive care service provision and planning. This article contributes to new knowledge through applying the concept of receptivity to informal supportive cancer care in regional Australia. Literature indicates that a cancer diagnosis is a life-changing experience, particularly in regional communities, where survival rates are lower and there are significant barriers to accessing services. Heideggerian phenomenology informed the design of the study and allowed for a rich and nuanced understanding of participants lived experiences of informal supportive cancer care. These experiences were captured using in-depth interviews, which were subsequently thematically analysed. Nineteen participants were recruited from across regional Victoria, Australia. Participants self-reported a range of stages and types of cancer. Significantly, findings revealed that most participants were not referred to, and did not seek, formal supportive care. Instead, they were receptive to informal supportive care. Understanding receptivity and the role of anxiety and fear of death has implications for partners, family, community members, as well as professionals working with people with living with and beyond cancer.

  11. Prostate cancer incidence and mortality in Portugal: trends, projections and regional differences.

    PubMed

    Pina, Francisco; Castro, Clara; Ferro, Ana; Bento, Maria J; Lunet, Nuno

    2016-08-01

    There is a large geographical variability in prostate cancer incidence and mortality trends, mostly because of heterogeneity in control efforts across regions. We aimed to describe the time trends in prostate cancer incidence and mortality in Portugal, overall and by region, and to estimate the number of incident cases and deaths in 2020. The number of cases and incidence rates in 1998-2009 were collected from the Regional Cancer Registries. The number of deaths and mortality rates were obtained from the WHO mortality database (1988-2003 and 2007-2013) and Statistics Portugal (2004-2006; 1991-2013 by region). JoinPoint analyses were used to identify significant changes in trends in age-standardized incidence and mortality rates. Incidence and mortality predictions for 2020 were performed using Poisson regression models and population projections provided by Statistics Portugal. In Portugal, prostate cancer incidence has been increasing since 1998 (1.8%/year), with the exception of the North Region, with a decrease since 2006 (-3.2%/year). An overall mortality decline has been observed since 1997 (-2.2%/year), although there were two patterns of mortality variation at the regional level: one with an inflection point or significant variation in the rates and the other without significant variation. If these trends are maintained, ∼8600 incident cases and 1700 deaths may be expected to occur in Portugal in 2020. Despite the overall increasing incidence and decreasing mortality, there is a large heterogeneity across regions. Future studies should address regional differences in the trends of prostate specific antigen screening and in the effective management of prostate cancer.

  12. Alternative staging of regional lymph nodes in gastric cancer

    PubMed Central

    Szczepanik, Antoni M.; Paszko, Agata; Szura, Miroslaw; Scully-Horner, Thecla; Kulig, Jan

    2016-01-01

    The TNM pN stage based on the number of metastatic lymph nodes is an independent prognostic factor in gastric cancer. Many studies have highlighted the phenomenon of stage migration and problems in comparing groups of patients with different numbers of total lymph nodes harvested within TNM staging. The current version of UICC/AJCC and JGCA TNM classifications postulates a minimal number of 16 lymph nodes as the base for N stage determination. Alternative systems such as lymph node ratio (LNR), positive to negative lymph node ratio (PNLNR), and LOGODDS (or LODDS), were implemented to increase the quality of LN assessment. These methods have reached the background in the literature, but to date no standard approach according to the cut-offs for the stages has been implemented. LOGODDS is the method that most reflects the number of harvested lymph nodes. The rationale for alternative staging methods, their correlations, and limitations are presented. PMID:27713774

  13. Prognostic value of genomic alterations in minimal residual cancer cells purified from the blood of breast cancer patients

    PubMed Central

    Austrup, F; Uciechowski, P; Eder, C; Böckmann, B; Suchy, B; Driesel, G; Jäckel, S; Kusiak, I; Grill, H-J; Giesing, M

    2000-01-01

    The prognostic value of disseminated tumour cells derived from 353 breast cancer patients was evaluated. Disseminated tumour cells were purified from blood using a newly established method and nucleic acids were subsequently isolated. We investigated genomic imbalances (GI) such as mutation, amplification and loss of heterozygosity of 13 tumour suppressor genes and 2 proto-oncogenes using DNA from isolated minimal residual cancer cells. Significant correlations were found between genomic alterations of the DCC - and c-erbB-2 genes in disseminated breast cancer cells and actuarial relapse-free survival. Furthermore, increasing numbers of genomic imbalances measured in disseminated tumour cells were significantly associated with worse prognosis of recurrent disease. Logistic regression and Cox multivariate analysis led to the identification of genomic imbalances as an independent prognostic factor. Determination of disseminated tumour cells by genotyping of oncogenes and tumour suppressor genes seems not only to be a useful adjunct in follow up of carcinoma patients but provides also valuable additional individualized prognostic and predictive information in breast cancer patients beyond the TNM system. © 2000 Cancer Research Campaign http://www.bjcancer.com PMID:11104564

  14. Morbidity of breast cancer and cervico-uterine cancer in women from the occidental region of Mexico.

    PubMed

    Ortega-Cervantes, Laura; Rojas-García, Aurora Elizabeth; Robledo-Marenco, María de Lourdes; Barrón-Vivanco, Briscia Socorro; Girón-Pérez, Manuel Iván; Vallejo-Ruiz, Verónica; López-Flores, Juan Fernando; Carrillo-Cortez, Agustín; Cantú-De León, David; Rodríguez-Trejo, Amelia; Medina-Díaz, Irma Martha

    2013-01-01

    The incidences of breast cancer (BC) and cervico-uterine cancer (CC) vary widely from country to country. In Mexico, BC mortality has doubled in the last 20 years to become the second leading cause of death for women aged 30 to 54 years. CC is the most common cause of death from neoplasia in women over 25 years old. In 2006, the state of Nayarit had one of the highest mortality rates for these types of cancers in Mexico. To analyze and characterize the current demographics and morbidities associated with BC and CC in the state of Nayarit. In this retrospective study, the clinical histories of patients who were diagnosed with BC or CC at the State Cancer Center from January 2006 to December 2010 were analyzed. A total of 406 patients with BC and 328 patients with CC were registered. The most common clinical stage for both cancer types was IIB. The municipalities of San Pedro Lagunillas and El Nayar presented the highest prevalences of BC and CC, respectively. Our results suggest that women living in poorer and more marginalized regions have a higher possibility of developing BC and CC. Because BC and CC are preventable and treatable in their early stages, demographic information from population records for these cancers is helpful in determining the incidence rates and patterns and improving decision-making processes.

  15. Mutation and methylation analysis of the chromodomain-helicase-DNA binding 5 gene in ovarian cancer.

    PubMed

    Gorringe, Kylie L; Choong, David Yh; Williams, Louise H; Ramakrishna, Manasa; Sridhar, Anita; Qiu, Wen; Bearfoot, Jennifer L; Campbell, Ian G

    2008-11-01

    Chromodomain, helicase, DNA binding 5 (CHD5) is a member of a subclass of the chromatin remodeling Swi/Snf proteins and has recently been proposed as a tumor suppressor in a diverse range of human cancers. We analyzed all 41 coding exons of CHD5 for somatic mutations in 123 primary ovarian cancers as well as 60 primary breast cancers using high-resolution melt analysis. We also examined methylation of the CHD5 promoter in 48 ovarian cancer samples by methylation-specific single-stranded conformation polymorphism and bisulfite sequencing. In contrast to previous studies, no mutations were identified in the breast cancers, but somatic heterozygous missense mutations were identified in 3 of 123 ovarian cancers. We identified promoter methylation in 3 of 45 samples with normal CHD5 and in 2 of 3 samples with CHD5 mutation, suggesting these tumors may have biallelic inactivation of CHD5. Hemizygous copy number loss at CHD5 occurred in 6 of 85 samples as assessed by single nucleotide polymorphism array. Tumors with CHD5 mutation or methylation were more likely to have mutation of KRAS or BRAF (P = .04). The aggregate frequency of CHD5 haploinsufficiency or inactivation is 16.2% in ovarian cancer. Thus, CHD5 may play a role as a tumor suppressor gene in ovarian cancer; however, it is likely that there is another target of the frequent copy number neutral loss of heterozygosity observed at 1p36.

  16. Incidence and tumour stages of breast cancer in the region of Aachen, Germany.

    PubMed

    Seemayer, C A; Breuer, Elisabeth; Kroll, G; Markus-Sellhaus, S; Reineke, T H; Mittermayer, C

    2002-03-01

    We present epidemiological data of female breast cancer in the region of Aachen (Germany) including incidence and tumour stages for the period 1996-1997. Furthermore, we compare epidemiological data from Aachen with data from the directly neighbouring Dutch region South-Middle Limburg before and after the introduction of a national mammographic screening programme. The field study of breast cancer was undertaken at the Institute of Pathology and Comprehensive Cancer Center at the University of Aachen, supported by the Federal Ministry of Health (Germany), using data files from the Cancer Registry Aachen. The patient's consent to collect all data concerning her epidemiological and social situation as well as information on the outcome of disease was obtained in 83.4% of all cases. The remaining 16.6% of the cases without a patient's consent are based on histopathological reports. Only those patients are included who were documented as residing in the region of Aachen at the time of diagnosis. Tumour cases were counted according to International Agency for Research on Cancer rules and tumour stages are classified according to UICC guidelines. Incidence rates are calculated as crude value, adapted to the European and World Standard population (ESR, WSR), and the age specific incidence is presented in 5-year intervals. The cumulative risk is assessed for a certain life span by summarizing the age-specific incidences. The age-standardized breast cancer incidence rate in Aachen was 94 per 100 000 women in 1996 and 90 cases of invasive breast cancer per 100 000 women in 1997 according to the ESR. The cumulative risk of developing breast cancer in the life span ranging from 0 to 74 years is approximately 8%. The stage distribution of breast cancer reveals only 4% favourable carcinomata in situ, but 12% advanced T4 tumours. T1 and T2 tumour stages count for about 40% and T3 tumour stages about 4%. Incidence rates and the tumour stages of breast cancer in the region of

  17. Cancer Incidence Among Police Officers in a U.S. Northeast Region: 1976–2006

    PubMed Central

    Charles, Luenda E.; Burchfiel, Cecil M.; Andrew, Michael E.; Violanti, John M

    2015-01-01

    Police officers are exposed to occupational hazards which may put them at increased risk of cancer. We examined the incidence of cancer in a cohort of 2,234 white-male police officers in Buffalo, New York. The study population was followed for 31 years (1976–2006). The incidence of cancer, ascertained using a population-based tumor registry, was compared with 9 US regions using the Surveillance Epidemiology and End Results (SEER) program data. Four hundred and six officers (18.2%) developed cancer between 1976 and 2006. The risk of overall cancer among police officers was found to be similar to the general white-male population (Standardized Incidence Ratio [SIR] = 0.94, 95%, Confidence Interval [CI] = 0.85–1.03). An elevated risk of Hodgkin ‘s lymphoma was observed relative to the general population (SIR = 3.34, 95%, CI= 1.22–7.26). The risk of brain cancer, although only slightly elevated relative to the general population (SIR = 1.61, 95%, CI = 0.73–3.05), was significantly increased with 30 years or more of service (SIR = 2.92, 95%, CI = 1.07–6.36). Incidence ratios were significantly lower than expected for skin and bladder cancer. Police officers were at increased risk of Hodgkin’s lymphoma overall and of brain cancer after 30 years of service. PMID:22900461

  18. Assessing Needs and Assets for Building a Regional Network Infrastructure to Reduce Cancer Related Health Disparities

    PubMed Central

    Wells, Kristen J.; Lima, Diana S.; Meade, Cathy D.; Muñoz-Antonia, Teresita; Scarinci, Isabel; McGuire, Allison; Gwede, Clement K.; Pledger, W. Jack; Partridge, Edward; Lipscomb, Joseph; Matthews, Roland; Matta, Jaime; Flores, Idhaliz; Weiner, Roy; Turner, Timothy; Miele, Lucio; Wiese, Thomas E.; Fouad, Mona; Moreno, Carlos S.; Lacey, Michelle; Christie, Debra W.; Price-Haywood, Eboni G.; Quinn, Gwendolyn P.; Coppola, Domenico; Sodeke, Stephen O.; Green, B. Lee; Lichtveld, Maureen Y.

    2015-01-01

    Significant cancer health disparities exist in the United States and Puerto Rico. While numerous initiatives have been implemented to reduce cancer disparities, regional coordination of these efforts between institutions is often limited. To address cancer health disparities nationwide, a series of regional transdisciplinary networks through the Geographic Management Program (GMaP) and the Minority Biospecimen/Biobanking Geographic Management Program (BMaP) were established in six regions across the country. This paper describes the development of the Region 3 GMaP/BMaP network composed of over 100 investigators from nine institutions in five Southeastern states and Puerto Rico to develop a state-of-the-art network for cancer health disparities research and training. We describe a series of partnership activities that led to the formation of the infrastructure for this network, recount the participatory processes utilized to develop and implement a needs and assets assessment and implementation plan, and describe our approach to data collection. Completion, by all nine institutions, of the needs and assets assessment resulted in several beneficial outcomes for Region 3 GMaP/BMaP. This network entails ongoing commitment from the institutions and institutional leaders, continuous participatory and engagement activities, and effective coordination and communication centered on team science goals. PMID:24486917

  19. Cure fraction model with random effects for regional variation in cancer survival.

    PubMed

    Seppä, Karri; Hakulinen, Timo; Kim, Hyon-Jung; Läärä, Esa

    2010-11-30

    Assessing regional differences in the survival of cancer patients is important but difficult when separate regions are small or sparsely populated. In this paper, we apply a mixture cure fraction model with random effects to cause-specific survival data of female breast cancer patients collected by the population-based Finnish Cancer Registry. Two sets of random effects were used to capture the regional variation in the cure fraction and in the survival of the non-cured patients, respectively. This hierarchical model was implemented in a Bayesian framework using a Metropolis-within-Gibbs algorithm. To avoid poor mixing of the Markov chain, when the variance of either set of random effects was close to zero, posterior simulations were based on a parameter-expanded model with tailor-made proposal distributions in Metropolis steps. The random effects allowed the fitting of the cure fraction model to the sparse regional data and the estimation of the regional variation in 10-year cause-specific breast cancer survival with a parsimonious number of parameters. Before 1986, the capital of Finland clearly stood out from the rest, but since then all the 21 hospital districts have achieved approximately the same level of survival.

  20. Assessing needs and assets for building a regional network infrastructure to reduce cancer related health disparities.

    PubMed

    Wells, Kristen J; Lima, Diana S; Meade, Cathy D; Muñoz-Antonia, Teresita; Scarinci, Isabel; McGuire, Allison; Gwede, Clement K; Pledger, W Jack; Partridge, Edward; Lipscomb, Joseph; Matthews, Roland; Matta, Jaime; Flores, Idhaliz; Weiner, Roy; Turner, Timothy; Miele, Lucio; Wiese, Thomas E; Fouad, Mona; Moreno, Carlos S; Lacey, Michelle; Christie, Debra W; Price-Haywood, Eboni G; Quinn, Gwendolyn P; Coppola, Domenico; Sodeke, Stephen O; Green, B Lee; Lichtveld, Maureen Y

    2014-06-01

    Significant cancer health disparities exist in the United States and Puerto Rico. While numerous initiatives have been implemented to reduce cancer disparities, regional coordination of these efforts between institutions is often limited. To address cancer health disparities nation-wide, a series of regional transdisciplinary networks through the Geographic Management Program (GMaP) and the Minority Biospecimen/Biobanking Geographic Management Program (BMaP) were established in six regions across the country. This paper describes the development of the Region 3 GMaP/BMaP network composed of over 100 investigators from nine institutions in five Southeastern states and Puerto Rico to develop a state-of-the-art network for cancer health disparities research and training. We describe a series of partnership activities that led to the formation of the infrastructure for this network, recount the participatory processes utilized to develop and implement a needs and assets assessment and implementation plan, and describe our approach to data collection. Completion, by all nine institutions, of the needs and assets assessment resulted in several beneficial outcomes for Region 3 GMaP/BMaP. This network entails ongoing commitment from the institutions and institutional leaders, continuous participatory and engagement activities, and effective coordination and communication centered on team science goals. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Exome-Scale Discovery of Hotspot Mutation Regions in Human Cancer Using 3D Protein Structure.

    PubMed

    Tokheim, Collin; Bhattacharya, Rohit; Niknafs, Noushin; Gygax, Derek M; Kim, Rick; Ryan, Michael; Masica, David L; Karchin, Rachel

    2016-07-01

    The impact of somatic missense mutation on cancer etiology and progression is often difficult to interpret. One common approach for assessing the contribution of missense mutations in carcinogenesis is to identify genes mutated with statistically nonrandom frequencies. Even given the large number of sequenced cancer samples currently available, this approach remains underpowered to detect drivers, particularly in less studied cancer types. Alternative statistical and bioinformatic approaches are needed. One approach to increase power is to focus on localized regions of increased missense mutation density or hotspot regions, rather than a whole gene or protein domain. Detecting missense mutation hotspot regions in three-dimensional (3D) protein structure may also be beneficial because linear sequence alone does not fully describe the biologically relevant organization of codons. Here, we present a novel and statistically rigorous algorithm for detecting missense mutation hotspot regions in 3D protein structures. We analyzed approximately 3 × 10(5) mutations from The Cancer Genome Atlas (TCGA) and identified 216 tumor-type-specific hotspot regions. In addition to experimentally determined protein structures, we considered high-quality structural models, which increase genomic coverage from approximately 5,000 to more than 15,000 genes. We provide new evidence that 3D mutation analysis has unique advantages. It enables discovery of hotspot regions in many more genes than previously shown and increases sensitivity to hotspot regions in tumor suppressor genes (TSG). Although hotspot regions have long been known to exist in both TSGs and oncogenes, we provide the first report that they have different characteristic properties in the two types of driver genes. We show how cancer researchers can use our results to link 3D protein structure and the biologic functions of missense mutations in cancer, and to generate testable hypotheses about driver mechanisms. Our results

  2. Iodine deficiency and thyroid cancer trends in three regions of Thailand, 1990-2009.

    PubMed

    Mitro, Susanna D; Rozek, Laura S; Vatanasapt, Patravoot; Suwanrungruang, Krittika; Chitapanarux, Imjai; Srisukho, Songpol; Sriplung, Hutcha; Meza, Rafael

    2016-08-01

    Iodine deficiency may play a role in thyroid cancer carcinogenesis. Because Thailand has region-specific historical iodine deficiency, it is ideal to evaluate the potential impact of recent national iodine supplementation policies on thyroid cancer incidence trends. We examined thyroid cancer trends in Thailand from 1990 to 2009 in three geographically separated populations (Songkhla Province [south], Chiang Mai Province [north], and Khon Kaen Province [northeast]), each with a different historical prevalence of iodine deficiency. We used Joinpoint analysis and age-period-cohort (APC) models to investigate trends in thyroid cancer incidence. Pooled incidence of papillary cancers significantly increased (Males APC: 2.0, p<0.05; Females APC: 7.3 [1990-2001, p<0.05], -2.1 [2001-2009]) and incidence of follicular cancers significantly decreased (Males APC: -5.2, p<0.05; Females APC: -4.3 [1990-1998, p<0.05], 12.3 [1998-2001], -17.0 [2001-2005, p<0.05], 8.2 [2005-2009]) in both males and females between 1990 and 2009. The largest increases in papillary cancer incidence, and the largest decreases in follicular cancer incidence, occurred in historically iodine-deficient regions. Interestingly, the significant histological changes coincided with Thailand's most recent national iodination policy. The thyroid cancer trends in females were better explained by period effects than cohort effects. This study adds to the research indicating that papillary carcinoma incidence increases, and follicular carcinoma incidence decreases, as population-level iodine deficiency declines, and suggests that iodine exposure may affect late stages of thyroid carcinogenesis. However, our findings are limited by the ecological study design and lack of data prior to iodine supplementation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. [The perioperative period in cancer surgery: a critical moment! Is there a role for regional anesthesia in preventing cancer recurrence?].

    PubMed

    Beloeil, H; Nouette-Gaulain, K

    2012-06-01

    Surgical treatment of cancer is usually necessary but it can paradoxically aggravate the patient outcome by increasing the risk of recurrence. Many perioperative factors have been shown to contribute to the dissemination of the tumor: surgery itself, stress, inflammation, pain, anaesthetic drugs, blood transfusion, etc. The type of anaesthesia chosen in the cancer patient could then be crucial and influence the evolution of the disease. Experimental, preclinical and retrospective studies have suggested that a regional anesthesia associated or not with a general anesthesia for carcinologic surgery might reduce the risk of cancer recurrence. This text reviews the factors promoting the recurrence of tumors after carcinologic surgery and the potential possibilities of protection associated with the type of anaesthesia chosen.

  4. Serum Cadmium Levels in Pancreatic Cancer Patients from the East Nile Delta Region of Egypt

    PubMed Central

    Kriegel, Alison M.; Soliman, Amr S.; Zhang, Qing; El-Ghawalby, Nabih; Ezzat, Farouk; Soultan, Ahmed; Abdel-Wahab, Mohamed; Fathy, Omar; Ebidi, Gamal; Bassiouni, Nadia; Hamilton, Stanley R.; Abbruzzese, James L.; Lacey, Michelle R.; Blake, Diane A.

    2006-01-01

    The northeast Nile Delta region exhibits a high incidence of early-onset pancreatic cancer. It is well documented that this region has one of the highest levels of pollution in Egypt. Epidemiologic studies have suggested that cadmium, a prevalent pollutant in the northeast Nile Delta region, plays a role in the development of pancreatic cancer. Objective: We aimed to assess serum cadmium levels as markers of exposure in pancreatic cancer patients and noncancer comparison subjects from the same region in Egypt. Design and Participants: We assessed serum cadmium levels of 31 newly diagnosed pancreatic cancer patients and 52 hospital comparison subjects from Mansoura, Egypt. Evaluation/Measurements: Serum cadmium levels were measured using a novel immunoassay procedure. Results: We found a significant difference between the mean serum cadmium levels in patients versus comparison subjects (mean ± SD, 11.1 ± 7.7 ng/mL vs. 7.1 ± 5.0 ng/mL, respectively; p = 0.012) but not in age, sex, residence, occupation, or smoking status. The odds ratio (OR) for pancreatic cancer risk was significant for serum cadmium level [OR = 1.12; 95% confidence interval (CI), 1.04–1.23; p = 0.0089] and farming (OR = 3.25; 95% CI, 1.03–11.64; p = 0.0475) but not for age, sex, residence, or smoking status. Conclusions: The results from this pilot study suggest that pancreatic cancer in the East Nile Delta region is significantly associated with high levels of serum cadmium and farming. Relevance to Clinical Practice/Public Health: Future studies should further investigate the etiologic relationship between cadmium exposure and pancreatic carcinogenesis in cadmium-exposed populations. PMID:16393667

  5. Gastric cancer mortality trends in Spain, 1976-2005, differences by autonomous region and sex

    PubMed Central

    2009-01-01

    Background Gastric cancer is the second leading cause of oncologic death worldwide. One of the most noteworthy characteristics of this tumor's epidemiology is the marked decline reported in its incidence and mortality in almost every part of the globe in recent decades. This study sought to describe gastric cancer mortality time trends in Spain's regions for both sexes. Methods Mortality data for the period 1976 through 2005 were obtained from the Spanish National Statistics Institute. Cases were identified using the International Classification of Diseases 9th and 10th revision (codes 151 and C16, respectively). Crude and standardized mortality rates were calculated by geographic area, sex, and five-year period. Joinpoint regression analyses were performed to ascertain whether changes in gastric cancer mortality trends had occurred, and to estimate the annual percent change by sex and geographic area. Results Gastric cancer mortality decreased across the study period, with the downward trend being most pronounced in women and in certain regions situated in the interior and north of mainland Spain. Across the study period, there was an overall decrease of 2.90% per annum among men and 3.65% per annum among women. Generally, regions in which the rate of decline was sharpest were those that had initially registered the highest rates. However, the rate of decline was not constant throughout the study period: joinpoint analysis detected a shift in trend for both sexes in the early 1980s. Conclusion Gastric cancer mortality displayed in both sexes a downward trend during the study period, both nationally and regionally. The different trend in rates in the respective geographic areas translated as greater regional homogeneity in gastric cancer mortality by the end of the study period. In contrast, rates in women fell more than did those in men. The increasing differences between the sexes could indicate that some risk factors may be modifying the sex-specific pattern of

  6. The burden of HPV associated cancers in two regions in Nigeria 2012-2014.

    PubMed

    Jedy-Agba, E E; Dareng, E O; Adebamowo, S N; Odutola, M; Oga, E A; Igbinoba, F; Otu, T; Ezeome, E; Bray, F; Hassan, R; Adebamowo, C A

    2016-12-01

    HPV attributable cancers are the second most common infection-related cancers worldwide, with much higher burden in less developed regions. There are currently no country-specific estimates of the burden of these cancers in Nigeria just like many other low and middle income countries. In this study, we quantified the proportion of the cancer burden in Nigeria that is attributable to HPV infection from 2012 to 2014 using HPV prevalence estimated from previous studies and data from two population based cancer registries (PBCR) in Nigeria. We considered cancer sites for which there is strong evidence of an association with HPV infection based on the International Agency for Research on Cancer (IARC) classification. We obtained age and sex-specific estimates of incident cancers and using the World Standard Population, we derived age standardized incidence (ASR) rates for each cancer type by categories of sex, and estimated the population attributable fractions (PAF). The two PBCR reported 4336 new cancer cases from 2012 to 2014. Of these, 1627 (37.5%) were in males and 2709 (62.5%) in females. Some 11% (488/4336) of these cancers were HPV associated; 2% (38/1627) in men and 17% (450/2709) in women. Of the HPV associated cancers, 7.8% occurred in men and 92.2% in women. The ASRs for HPV associated cancers was 33.5 per 100,000; 2.3 and 31.2 per 100,000 in men and women respectively. The proportion of all cancers attributable to HPV infection ranged from 10.2 to 10.4% (442-453 of 4336) while the proportion of HPV associated cancers attributable to HPV infection ranged from 90.6% to 92.8% (442-453 of the 488 cases). In men, 55.3% to 68.4% of HPV associated cancers were attributable to HPV infection compared to 93.6% to 94.8% in women. The combined ASR for HPV attributable cancers ranged from 31.0 to 31.7 per 100,000. This was 1.4 to 1.7 per 100,000 in men and 29.6 to 30.0 per 100,000 in women. In women, cervical cancer (n=392, ASR 28.3 per 100,000) was the commonest HPV

  7. Trends in corrected lung cancer mortality rates in Brazil and regions

    PubMed Central

    Malta, Deborah Carvalho; de Abreu, Daisy Maria Xavier; de Moura, Lenildo; Lana, Gustavo C; Azevedo, Gulnar; França, Elisabeth

    2016-01-01

    ABSTRACT OBJECTIVE To describe the trend in cancer mortality rates in Brazil and regions before and after correction for underreporting of deaths and redistribution of ill-defined and nonspecific causes. METHODS The study used data of deaths from lung cancer among the population aged from 30 to 69 years, notified to the Mortality Information System between 1996 and 2011, corrected for underreporting of deaths, non-registered sex and age , and causes with ill-defined or garbage codes according to sex, age, and region. Standardized rates were calculated by age for raw and corrected data. An analysis of time trend in lung cancer mortality was carried out using the regression model with autoregressive errors. RESULTS Lung cancer in Brazil presented higher rates among men compared to women, and the South region showed the highest death risk in 1996 and 2011. Mortality showed a trend of reduction for males and increase for women. CONCLUSIONS Lung cancer in Brazil presented different distribution patterns according to sex, with higher rates among men and a reduction in the mortality trend for men and increase for women. PMID:27355467

  8. Analysis of the entire HLA region in susceptibility for cervical cancer: a comprehensive study

    PubMed Central

    Zoodsma, M; Nolte, I; Schipper, M; Oosterom, E; van der Steege, G; de Vries, E G E; te Meerman, G J; van der Zee, A G J

    2005-01-01

    Background: Infection with human papillomavirus (HPV) is the main cause of cervical cancer and its precursor lesion, cervical intraepithelial neoplasia (CIN). Variability in host immunogenetic background is important in determining the overall cellular immune response to HPV infections. Objective: To determine whether the HLA-DQ or HLA-DR genes, or others in their vicinity, are associated with cervical cancer. Methods: Markers covering the entire HLA region were genotyped in a large sample of CIN and cervical cancer patients and in controls (311 CIN, 695 cervical cancer, 115 family controls, and 586 unrelated controls). Results: Two markers were associated with susceptibility to cervical neoplasia, G511525 and MICA. G511525, close to the region containing the HLA-DQ and HLA-DR genes, was most strongly associated, showing a decrease in frequency of allele 221 from 6.7% to 3.3% in patients with squamous cell cancer (SCC). An association was found for MICA (allele 184) with SCC (odds ratio (OR) = 1.31 (95% confidence interval, 1.13 to 1.53); homozygotes, OR = 1.48 (1.06 to 2.06)). No associations were observed with adenocarcinoma or CIN. Conclusions: There is an association of the region containing the HLA-DQ and HLA-DR genes with the risk of developing squamous cell carcinoma. An increased risk was observed for carriers of allele 184 at the MICA locus, in particular for homozygotes, suggesting a recessive effect. PMID:16061555

  9. Personalization of loco-regional care for primary breast cancer patients (part 1).

    PubMed

    Toi, Masakazu; Winer, Eric P; Benson, John R; Inamoto, Takashi; Forbes, John F; von Minckwitz, Gunter; Robertson, John F R; Grobmyer, Stephen R; Jatoi, Ismail; Sasano, Hironobu; Kunkler, Ian; Ho, Alice Y; Yamauchi, Chikako; Chow, Louis W C; Huang, Chiun-Sheng; Han, Wonshik; Noguchi, Shinzaburo; Pegram, Mark D; Yamauchi, Hideko; Lee, Eun-Sook; Larionov, Alexey A; Bevilacqua, Jose L B; Yoshimura, Michio; Sugie, Tomoharu; Yamauchi, Akira; Krop, Ian E; Noh, Dong Young; Klimberg, V Suzanne

    2015-01-01

    ABSTRACT  Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the first of a two part conference scene, consensus recommendations for axillary management are presented and focus on the following topics: indications for completion axillary lymph node dissection in primary surgical patients with ≤2 macrometastases or any sentinel nodal deposits after PST; the timing of sentinel lymph node biopsy in the context of PST; use of axillary irradiation as a component of primary treatment plans and the role of intraoperative node assessment in the post-Z0011 era.

  10. TALEN mediated somatic mutagenesis in murine models of cancer

    PubMed Central

    Zhang, Shuyuan; Li, Lin; Kendrick, Sara L.; Gerard, Robert D.; Zhu, Hao

    2014-01-01

    Cancer genome sequencing has identified numerous somatic mutations whose biological relevance is uncertain. In this study, we used genome-editing tools to create and analyze targeted somatic mutations in murine models of liver cancer. TALEN were designed against β-catenin (Ctnnb1) and Apc, two commonly mutated genes in hepatocellular carcinoma (HCC), to generate isogenic HCC cell lines. Both mutant cell lines exhibited evidence of Wnt pathway dysregulation. We asked if these TALENs could create targeted somatic mutations after hydrodynamic transfection (HDT) into mouse liver. TALENs targeting β-catenin promoted endogenous HCC carrying the intended gain-of-function mutations. However, TALENs targeting Apc were not as efficient in inducing in vivo homozygous loss-of-function mutations. We hypothesized that hepatocyte polyploidy might be protective against TALEN-induced loss of heterozygosity (LOH), and indeed Apc gene editing was less efficient in tetraploid than in diploid hepatocytes. To increase efficiency, we administered adenoviral Apc TALENs and found that we could achieve a higher mutagenesis rate in vivo. Our results demonstrate that genome-editing tools can enable the in vivo study of cancer genes and faithfully recapitulate the mosaic nature of mutagenesis in mouse cancer models. PMID:25070752

  11. Limited capability of regional lymph nodes to eradicate metastatic cancer cells.

    PubMed

    Nagata, Hiroshi; Arai, Tsunenori; Soejima, Yusuke; Suzuki, Hidekazu; Ishii, Hiromasa; Hibi, Toshifumi

    2004-11-15

    The capacity of lymph nodes to eradicate cancer is a controversial issue. The purpose of this study was to determine the interplay between tumor growth and host resistance at early stages of lymph node metastasis. A metastasis model was made in the rat mesenteric lymph node, and migration of cancer cells was visualized in vivo. The lymph node was removed for histologic analysis and cytokine measurement. Migrant cancer cells were initially arrested in the marginal sinus. After an initial increase, the number of cancer cells in the marginal sinus declined until 48 hours after inoculation. Germinal centers and lymphoid cells in the medulla proliferated before 48 hours. ED3(+) macrophages incorporated apoptotic cancer cells, but significant cancer proliferation occurred after 4 days. Lymph nodes depleted of macrophages were massively invaded by cancer cells. Tumor necrosis factor alpha and interleukin (IL)-1beta in the nodes transiently increased after 1 hour and 3 hours, respectively, and were expressed in ED3(+) and ED2(+) macrophages, respectively. These changes were followed by a transient increase in IL-2. Interferon-gamma and IL-12 did not increase during the early stages of metastasis, but they decreased after 48 hours. In conclusion, the marginal sinus constitutes a mechanical barrier against cancer cell passage. Early pathological manifestations in the regional lymph node are consistent with those in cancer patients with improved survival. Parasinus macrophages play a role in the transient antimetastatic capability of the node, and cytokines secreted by these cells increased at the early stages of metastasis. Deterioration of cytokine induction may be responsible for subsequent cancer proliferation.

  12. Childhood cancer and parental use of tobacco: findings from the inter-regional epidemiological study of childhood cancer (IRESCC)

    PubMed Central

    Sorahan, T; McKinney, P A; Mann, J R; Lancashire, R J; Stiller, C A; Birch, J M; Dodd, H E; Cartwright, R A

    2001-01-01

    Parental smoking data have been re-abstracted from the interview records of the Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC) to test further the hypothesis that paternal cigarette smoking is a risk factor for the generality of childhood cancer. Reported cigarette smoking habits for the parents of 555 children diagnosed with cancer in the period 1980–1983 were compared, in two separate matched pairs analyses, with similar information for the parents of 555 children selected from GP lists (GP controls) and for the parents of 555 hospitalized children (hospital controls). When cases were compared with GP controls there was a statistically significant positive trend (P = 0.02) between the risk of childhood cancer and paternal daily consumption of cigarettes before the pregnancy; there was no significant trend for maternal smoking habit. When cases were compared with hospital controls there was a statistically significant negative trend (P< 0.001) between the risk of childhood cancer and maternal daily consumption of cigarettes before the pregnancy; there was no significant trend for paternal smoking habit. Neither of the significant trends could be explained by adjustment for socioeconomic grouping, ethnic origin or parental age at the birth of the child, or by simultaneous analysis of parental smoking habits. Relations between maternal consumption of cigarettes and birth weights suggested that (maternal) smoking data were equally reliable for case and control subjects, although comparisons with national data suggested that the hospital control parents were unusually heavy smokers. These findings give some support for the hypothesis that paternal cigarette smoking is a potential risk factor for the generality of childhood cancers. © 2001 Cancer Research Campaign http://www. bjcancer.com PMID:11139329

  13. [Nucleotide sequence of HLA-DQA1 promoter region (QAP) in a lung cancer patient].

    PubMed

    Qiu, C; Zhou, W; Song, C

    1996-06-01

    The HLA-DQA1 allele and nucleotide sequence of HLA-DQA1 promoter region (QAP) in a patient with IDDM complicated lung cancer have been identified by PCR/SSCP, PCR/SSCP and PCR/sequencing. The results showed that: (1) All of the lung cancer patient and his family members carried HLA-DQA1* 0301/0501 alleles. (2) a single base substitution G-->A at position -155 and deletion CAA at position -161 to -163 occurred in the patient. These results suggest that the mutation of HLA-DQA1 promoter region may modulate HLA-DQA1 gene expression by trans-acting factors binding to variant cis-acting elements and may be responsible for pathogenesis of lung cancer.

  14. Associations of Diabetes Mellitus with Site-Specific Cancer Mortality in the Asia-Pacific Region

    PubMed Central

    Lam, Eugene K.K.; Batty, G. David; Huxley, Rachel R.; Martiniuk, Alexandra L.C.; Barzi, Federica; Lam, Tai Hing; Lawes, Carlene M.M.; Giles, Graham G.; Welborn, Tim; Ueshima, Hirotsugu; Tamakoshi, Akiko; Woo, Jean; Kim, Hyeon Chang; Fang, Xianghua; Czernichow, Sébastien; Woodward, Mark

    2014-01-01

    Background Owing to the increasing prevalence of obesity and diabetes in Asia, and the paucity of studies, we examined the influence of raised blood glucose and diabetes on cancer mortality risk. Methods Thirty-six cohort Asian and Australasian studies provided 367,361 participants (74% from Asia); 6% had diabetes at baseline. Associations between diabetes and site-specific cancer mortality were estimated using time-dependent Cox models, stratified by study and sex, and adjusted for age. Results During a median follow-up of 4.0 years, there were 5,992 deaths due to cancer (74% Asian; 41% female). Participants with diabetes had 23% greater risk of mortality from all-cause cancer compared with those without: hazard ratio (HR) 1.23 (95% CI 1.12, 1.35). Diabetes was associated with mortality due to cancer of the liver (HR 1.51, 95% CI 1.19, 1.91), pancreas (HR 1.78, 95% CI 1.20, 2.65), and, less strongly, colorectum (HR 1.32, 95% CI 0.98, 1.78). There was no evidence of sex- or region-specific differences in these associations. The population attributable fractions for cancer mortality due to diabetes were generally higher for Asia compared with non-Asian populations. Conclusion Diabetes is associated with increased mortality from selected cancers in Asian and non-Asian populations. PMID:20705912

  15. Incidence analyses of bladder cancer in the Nile delta region of Egypt.

    PubMed

    Fedewa, Stacey A; Soliman, Amr S; Ismail, Kadry; Hablas, Ahmed; Seifeldin, Ibrahim A; Ramadan, Mohamed; Omar, Hoda G; Nriagu, Jerome; Wilson, Mark L

    2009-10-01

    Bladder cancer is the most common malignancy among Egyptian males and previously has been attributed to Schistosoma infection, a major risk factor for squamous cell carcinoma (SCC). Recently, transitional cell carcinoma (TCC) incidence has been increasing while SCC has declined. To investigate this shift, we analyzed the geographical patterns of all bladder cancers cases recorded in Egypt's Gharbiah Population-Based Cancer Registry from 1999 through 2002. Data on tumor grade, stage, and morphology, as well as smoking, community of residence, age and sex, were collected on 1209 bladder cancer cases. Age-adjusted incidence rates were calculated for males, females, and the total population for the eight administrative Districts and 316 communities in Gharbiah. Incidence Rate Ratios (IRR) and 95% confidence intervals (CI) were computed using Poisson Regression. The male age-adjusted incidence rate (IR) in Gharbiah Province was 13.65/100,000 person years (PY). The District of Kotour had the highest age-adjusted IR 28.96/100,000 among males. The District of Kotour also had the highest IRR among all Districts, IRR=2.15 95% CI (1.72, 2.70). Kotour's capital city had the highest bladder cancer incidence among the 316 communities (IR=73.11/100,000 PY). Future studies on sources and types of environmental pollution and exposures in relation to the spatial patterns of bladder cancer, particularly in Kotour District, may improve our understating of risk factors for bladder cancer in the region.

  16. Incidence analyses of bladder cancer in the Nile delta region of Egypt

    PubMed Central

    Fedewa, Stacey A.; Soliman, Amr S.; Ismail, Kadry; Hablas, Ahmed; Seifeldin, Ibrahim A.; Ramadan, Mohamed; Omar, Hoda G.; Nriagu, Jerome; Wilson, Mark L.

    2009-01-01

    Bladder cancer is the most common malignancy among Egyptian males and previously has been attributed to Schistosoma infection, a major risk factor for squamous cell carcinoma (SCC). Recently, transitional cell carcinoma (TCC) incidence has been increasing while SCC has declined. To investigate this shift, we analyzed the geographical patterns of all bladder cancers cases recorded in Egypt’s Gharbiah Population-Based Cancer Registry from 1999 through 2002. Data on tumor grade, stage, and morphology, as well as smoking, community of residence, age and sex, were collected on 1,209 bladder cancer cases. Age-adjusted incidence rates were calculated for males, females, and the total population for the eight administrative Districts and 316 communities in Gharbiah. Incidence Rate Ratios (IRR) and 95% Confidence Intervals (CI) were computed using Poisson Regression. The male age-adjusted incidence rate (IR) in Gharbiah Province was 13.65/100,000 person years (PY). The District of Kotour had the highest age-adjusted IR 28.96/100,000 among males. The District of Kotour also had the highest IRR among all Districts, IRR=2.15 95% CI (1.72, 2.70). Kotour’s capital city had the highest bladder cancer incidence among the 316 communities (IR=73.11/100,000 PY). Future studies on sources and types of environmental pollution and exposures in relation to the spatial patterns of bladder cancer, particularly in Kotour District, may improve our understating of risk factors for bladder cancer in the region. PMID:19762298

  17. No role for human papillomavirus infection in oral cancers in a region in southern India.

    PubMed

    Laprise, Claudie; Madathil, Sreenath A; Allison, Paul; Abraham, Priya; Raghavendran, Anantharam; Shahul, Hameed P; ThekkePurakkal, Akhil-Soman; Castonguay, Geneviève; Coutlée, François; Schlecht, Nicolas F; Rousseau, Marie-Claude; Franco, Eduardo L; Nicolau, Belinda

    2016-02-15

    Oral cancer is a major public health issue in India with ∼ 77,000 new cases and 52,000 deaths yearly. Paan chewing, tobacco and alcohol use are strong risk factors for this cancer in India. Human papillomaviruses (HPVs) are also related to a subset of head and neck cancers (HNCs). We examined the association between oral HPV and oral cancer in a sample of Indian subjects participating in a hospital-based case-control study. We recruited incident oral cancer cases (N = 350) and controls frequency-matched by age and sex (N = 371) from two main referral hospitals in Kerala, South India. Sociodemographic and behavioral data were collected by interviews. Epithelial cells were sampled using Oral CDx® brushes from the oral cancer site and the normal mucosa. Detection and genotyping of 36 HPV genotypes were done using a polymerase chain reaction protocol. Data collection procedures were performed by qualified dentists via a detailed protocol with strict quality control, including independent HPV testing in India and Canada. HPV DNA was detected in none of the cases or controls. Associations between oral cancer and risk factors usually associated with HPV infection, such as oral sex and number of lifetime sexual partners, were examined by logistic regression and were not associated with oral cancer. Lack of a role for HPV infection in this study may reflect cultural or religious characteristics specific to this region in India that are not conducive to oral HPV transmission. A nationwide representative prevalence study is needed to investigate HPV prevalence variability among Indian regions. © 2015 UICC.

  18. Analysis of regional bone scan index measurements for the survival of patients with prostate cancer.

    PubMed

    Kalderstam, Jonas; Sadik, May; Edenbrandt, Lars; Ohlsson, Mattias

    2014-07-10

    A bone scan is a common method for monitoring bone metastases in patients with advanced prostate cancer. The Bone Scan Index (BSI) measures the tumor burden on the skeleton, expressed as a percentage of the total skeletal mass. Previous studies have shown that BSI is associated with survival of prostate cancer patients. The objective in this study was to investigate to what extent regional BSI measurements, as obtained by an automated method, can improve the survival analysis for advanced prostate cancer. The automated method for analyzing bone scan images computed BSI values for twelve skeletal regions, in a study population consisting of 1013 patients diagnosed with prostate cancer. In the survival analysis we used the standard Cox proportional hazards model and a more advanced non-linear method based on artificial neural networks. The concordance index (C-index) was used to measure the performance of the models. A Cox model with age and total BSI obtained a C-index of 70.4%. The best Cox model with regional measurements from Costae, Pelvis, Scapula and the Spine, together with age, got a similar C-index (70.5%). The overall best single skeletal localisation, as measured by the C-index, was Costae. The non-linear model performed equally well as the Cox model, ruling out any significant non-linear interactions among the regional BSI measurements. The present study showed that the localisation of bone metastases obtained from the bone scans in prostate cancer patients does not improve the performance of the survival models compared to models using the total BSI. However a ranking procedure indicated that some regions are more important than others.

  19. Mutation and Methylation Analysis of the Chromodomain-Helicase-DNA Binding 5 Gene in Ovarian Cancer12

    PubMed Central

    Gorringe, Kylie L; Choong, David YH; Williams, Louise H; Ramakrishna, Manasa; Sridhar, Anita; Qiu, Wen; Bearfoot, Jennifer L; Campbell, Ian G

    2008-01-01

    Chromodomain, helicase, DNA binding 5 (CHD5) is a member of a subclass of the chromatin remodeling Swi/Snf proteins and has recently been proposed as a tumor suppressor in a diverse range of human cancers. We analyzed all 41 coding exons of CHD5 for somatic mutations in 123 primary ovarian cancers as well as 60 primary breast cancers using high-resolution melt analysis. We also examined methylation of the CHD5 promoter in 48 ovarian cancer samples by methylation-specific single-stranded conformation polymorphism and bisulfite sequencing. In contrast to previous studies, no mutations were identified in the breast cancers, but somatic heterozygous missense mutations were identified in 3 of 123 ovarian cancers. We identified promoter methylation in 3 of 45 samples with normal CHD5 and in 2 of 3 samples with CHD5 mutation, suggesting these tumors may have biallelic inactivation of CHD5. Hemizygous copy number loss at CHD5 occurred in 6 of 85 samples as assessed by single nucleotide polymorphism array. Tumors with CHD5 mutation or methylation were more likely to have mutation of KRAS or BRAF (P = .04). The aggregate frequency of CHD5 haploinsufficiency or inactivation is 16.2% in ovarian cancer. Thus, CHD5 may play a role as a tumor suppressor gene in ovarian cancer; however, it is likely that there is another target of the frequent copy number neutral loss of heterozygosity observed at 1p36. PMID:18953434

  20. Regional Delivery of Chimeric Antigen Receptor (CAR) T-Cells for Cancer Therapy.

    PubMed

    Sridhar, Praveen; Petrocca, Fabio

    2017-07-18

    Chimeric Antigen Receptor (CAR) T-cells are T-cells with recombinant receptors targeted to tumor antigens. CAR-T cell therapy has emerged as a mode of immunotherapy and is now being extensively explored in hematologic cancer. In contrast, CAR-T cell use in solid tumors has been hampered by multiple obstacles. Several approaches have been taken to circumvent these obstacles, including the regional delivery of CAR-T cells. Regional CAR-T cell delivery can theoretically compensate for poor T-cell trafficking and tumor antigen specificity while avoiding systemic toxicity associated with intravenous delivery. We reviewed completed clinical trials for the treatment of glioblastoma and metastatic colorectal cancer and examined the data in these studies for safety, efficacy, and potential advantages that regional delivery may confer over systemic delivery. Our appraisal of the available literature revealed that regional delivery of CAR-T cells in both glioblastoma and hepatic colorectal metastases was generally well tolerated and efficacious in select instances. We propose that the regional delivery of CAR-T cells is an area of potential growth in the solid tumor immunotherapy, and look towards future clinical trials in head and neck cancer, mesothelioma, and peritoneal carcinomatosis as the use of this technique expands.

  1. Regional Delivery of Chimeric Antigen Receptor (CAR) T-Cells for Cancer Therapy

    PubMed Central

    Sridhar, Praveen; Petrocca, Fabio

    2017-01-01

    Chimeric Antigen Receptor (CAR) T-cells are T-cells with recombinant receptors targeted to tumor antigens. CAR-T cell therapy has emerged as a mode of immunotherapy and is now being extensively explored in hematologic cancer. In contrast, CAR-T cell use in solid tumors has been hampered by multiple obstacles. Several approaches have been taken to circumvent these obstacles, including the regional delivery of CAR-T cells. Regional CAR-T cell delivery can theoretically compensate for poor T-cell trafficking and tumor antigen specificity while avoiding systemic toxicity associated with intravenous delivery. We reviewed completed clinical trials for the treatment of glioblastoma and metastatic colorectal cancer and examined the data in these studies for safety, efficacy, and potential advantages that regional delivery may confer over systemic delivery. Our appraisal of the available literature revealed that regional delivery of CAR-T cells in both glioblastoma and hepatic colorectal metastases was generally well tolerated and efficacious in select instances. We propose that the regional delivery of CAR-T cells is an area of potential growth in the solid tumor immunotherapy, and look towards future clinical trials in head and neck cancer, mesothelioma, and peritoneal carcinomatosis as the use of this technique expands. PMID:28718815

  2. [Loco-regional chemotherapy at the outpatient clinic for gastric cancer patients with home enteral nutrition].

    PubMed

    Maruyama, Michio; Nagahama, Takeshi; Sugano, Norihide; Satoh, Eigo; Maruyama, Shouji; Tanami, Hideo; Chiba, Tetsuma; Murakata, Ayano; Mitsuhashi, Yosuke; Uehira, Daisuke; Akazawa, Naoya; Suzuki, Keiichirou

    2011-11-01

    In over the 10 years from 2000-2010, 21 gastric cancer patients received loco-regional chemotherapy with home enteral nutrition (HEN) at an outpatient clinic because of insufficient oral intake. These loco-regional chemotherapy regimens consisted of 5 intra-aortic chemotherapies, 4 hepato-arterial infusions and 12 intra-peritoneal chemotherapies. Five out of 8 cases that had measurable lesions showed PR, and 3 cases revealed PD. The patients received HEN with peptide central formula, 400-1,200 kcal/day in night time. The average duration of HEN was 12.9 months. The post-operative nutritional management was needed for continuation and securing of outpatient chemotherapy. The author reported an experience of the outpatient loco-regional chemotherapy with HEN for the gastric cancer patients who could not eat a sufficient volume of food.

  3. [Oncolor: a comprehensive cancer network in the Lorraine Region of France].

    PubMed

    Sommelet, Danièle; Bey, Pierre

    2006-02-01

    Legislation governing patients' rights and health care quality (March 2002) provided for the creation of healthcare networks intended to improve the management of patients with complex and/or chronic diseases. As defined in the Cancer Plan, activated in March 2003, an oncological healthcare network covers a particular French region, with the aim of offering patients equal access to the best available care and accompaniment, based on caregiver coordination, shared multidisciplinary tools, and communication. ONCOLOR, the regional cancer network launched in the Lorraine region in 1993, complies with these objectives. Nevertheless, its future development depends on continued dynamism, durable financial support, and regular evaluation of the benefits for patients and caregivers. The key words are professionalism and consensus.

  4. Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes.

    PubMed

    Zheng, Christina L; Wang, Nicholas J; Chung, Jongsuk; Moslehi, Homayoun; Sanborn, J Zachary; Hur, Joseph S; Collisson, Eric A; Vemula, Swapna S; Naujokas, Agne; Chiotti, Kami E; Cheng, Jeffrey B; Fassihi, Hiva; Blumberg, Andrew J; Bailey, Celeste V; Fudem, Gary M; Mihm, Frederick G; Cunningham, Bari B; Neuhaus, Isaac M; Liao, Wilson; Oh, Dennis H; Cleaver, James E; LeBoit, Philip E; Costello, Joseph F; Lehmann, Alan R; Gray, Joe W; Spellman, Paul T; Arron, Sarah T; Huh, Nam; Purdom, Elizabeth; Cho, Raymond J

    2014-11-20

    Somatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs) arising in an XPC(-/-) background. XPC(-/-) cells lack global genome nucleotide excision repair (GG-NER), thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk.

  5. Transcription restores DNA repair to heterochromatin, determining regional mutation rates in cancer genomes

    PubMed Central

    Zheng, Christina L.; Wang, Nicholas J.; Chung, Jongsuk; Moslehi, Homayoun; Sanborn, J. Zachary; Hur, Joseph S.; Collisson, Eric A.; Vemula, Swapna S.; Naujokas, Agne; Chiotti, Kami E.; Cheng, Jeffrey B.; Fassihi, Hiva; Blumberg, Andrew J.; Bailey, Celeste V.; Fudem, Gary M.; Mihm, Frederick G.; Cunningham, Bari B.; Neuhaus, Isaac M.; Oh, Dennis H.; Cleaver, James E.; LeBoit, Philip E.; Costello, Joseph F.; Lehmann, Alan R.; Gray, Joe W.; Spellman, Paul T.; Arron, Sarah T.; Huh, Nam; Purdom, Elizabeth; Cho, Raymond J.

    2014-01-01

    Summary Somatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs) arising in an XPC−/− background. XPC−/− cells lack global genome nucleotide excision repair (GG-NER), thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this novel relationship between transcription, chromatin state and DNA repair, revealing a new, personalized determinant of cancer risk. PMID:25456125

  6. Accuracy of FDG-PET to diagnose lung cancer in a region of endemic granulomatous disease.

    PubMed

    Deppen, Stephen; Putnam, Joe B; Andrade, Gabriela; Speroff, Theodore; Nesbitt, Jonathan C; Lambright, Eric S; Massion, Pierre P; Walker, Ron; Grogan, Eric L

    2011-08-01

    The 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) is used to evaluate suspicious pulmonary lesions due to its diagnostic accuracy. The southeastern United States has a high prevalence of infectious granulomatous lung disease, and the accuracy of FDG-PET may be reduced in this population. We examined the diagnostic accuracy of FDG-PET in patients with known or suspected non-small cell lung cancer treated at our institution. A total of 279 patients, identified through our prospective database, underwent an operation for known or suspected lung cancer. Preoperative FDG-PET in 211 eligible patients was defined by standardized uptake value greater than 2.5 or by description ("moderate" or "intense") as avid. Sensitivity, specificity, positive and negative predictive values, likelihood ratios, and decision diagrams were calculated for FDG-PET in all patients and in patients with indeterminate nodules. In all eligible patients (n=211), sensitivity and specificity of FDG-PET were 92% and 40%, respectively. Positive and negative predictive values were 86% and 55%. Overall FDG-PET accuracy to diagnose lung cancer was 81%. Preoperative positive likelihood ratio for FDG-PET diagnosis of lung cancer in this population was 1.5 compared with previously published values of 7.1. In 113 indeterminate lesions, 65% had lung cancer and the sensitivity and specificity were 89% and 40%, respectively. Twenty-four benign nodules (60%) had false positive FDG-PET scans. Twenty-two of 43 benign nodules (51%) were granulomas. In a region with endemic granulomatous diseases, the specificity of FDG-PET for diagnosis of lung cancer was 40%. Clinical decisions and future clinical predictive models for lung cancer must accommodate regional variation of FDG-PET scan results. Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  7. Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer.

    PubMed

    O'Mara, Tracy A; Glubb, Dylan M; Painter, Jodie N; Cheng, Timothy; Dennis, Joe; Attia, John; Holliday, Elizabeth G; McEvoy, Mark; Scott, Rodney J; Ashton, Katie; Proietto, Tony; Otton, Geoffrey; Shah, Mitul; Ahmed, Shahana; Healey, Catherine S; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; Fasching, Peter A; Hein, Alexander; Beckmann, Matthias W; Ekici, Arif B; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Dürst, Matthias; Runnebaum, Ingo; Hillemanns, Peter; Dörk, Thilo; Lambrechts, Diether; Depreeuw, Jeroen; Annibali, Daniela; Amant, Frederic; Zhao, Hui; Goode, Ellen L; Dowdy, Sean C; Fridley, Brooke L; Winham, Stacey J; Salvesen, Helga B; Njølstad, Tormund S; Trovik, Jone; Werner, Henrica M J; Tham, Emma; Liu, Tao; Mints, Miriam; Bolla, Manjeet K; Michailidou, Kyriaki; Tyrer, Jonathan P; Wang, Qin; Hopper, John L; Peto, Julian; Swerdlow, Anthony J; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang-Claude, Jenny; Couch, Fergus J; Giles, Graham G; Kristensen, Vessela N; Cox, Angela; Pharoah, Paul D P; Dunning, Alison M; Tomlinson, Ian; Easton, Douglas F; Thompson, Deborah J; Spurdle, Amanda B

    2015-10-01

    Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86×10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76×10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types.

  8. Trends in Breast Cancer Epidemiology in Chelyabinsk Region, 2006-2015

    PubMed

    Aksenova, Irina A; Moore, Malcolm A; Domozhirova, Alla S

    2017-04-01

    Breast cancer among women occupies a leading position in the profile of cancer incidence in most parts of the world. The present study of the incidence and prevalence of breast cancer was carried out using data from the Chelyabinsk population cancer registry for 2006-2015. A stable growth trend in the incidence over time was noted overall, as well as major differences in the figures for women of different ethnicities (Russian, Tatar, Bashkir), by far the highest incidences being observed for Russian women. Urban rates were generally higher than in rural sites and a shift towards older age at presentation was seen between 2006 and 2015. At the same time a slight decrease in mortality was noted, from 42.4% to 33.5% relative to incidence, with a decrease in the proportion of stage IV cancers. This might have been related to increasing use of mammography screening.The data have obvious connotations for primary prevention and particularly for measures adopted for secondary prevention in detection of the disease in its early stages, facilitating reduction in associated mortality. Improvement in screening rates is thus a high priority for more effective management of breast cancer in the region. Creative Commons Attribution License

  9. Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer

    PubMed Central

    O’Mara, Tracy A; Glubb, Dylan M; Painter, Jodie N; Cheng, Timothy; Dennis, Joe; Attia, John; Holliday, Elizabeth G; McEvoy, Mark; Scott, Rodney J; Ashton, Katie; Proietto, Tony; Otton, Geoffrey; Shah, Mitul; Ahmed, Shahana; Healey, Catherine S; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; Fasching, Peter A; Hein, Alexander; Beckmann, Matthias W; Ekici, Arif B; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Dürst, Matthias; Runnebaum, Ingo; Hillemanns, Peter; Dörk, Thilo; Lambrechts, Diether; Depreeuw, Jeroen; Annibali, Daniela; Amant, Frederic; Zhao, Hui; Goode, Ellen L; Dowdy, Sean C; Fridley, Brooke L; Winham, Stacey J; Salvesen, Helga B; Njølstad, Tormund S; Trovik, Jone; Werner, Henrica MJ; Tham, Emma; Liu, Tao; Mints, Miriam; Bolla, Manjeet K; Michailidou, Kyriaki; Tyrer, Jonathan P; Wang, Qin; Hopper, John L; Peto, Julian; Swerdlow, Anthony J; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang-Claude, Jenny; Couch, Fergus J; Giles, Graham G; Kristensen, Vessela N; Cox, Angela; Pharoah, Paul D P; Dunning, Alison M; Tomlinson, Ian; Easton, Douglas F; Thompson, Deborah J; Spurdle, Amanda B

    2015-01-01

    Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3,633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6,607 EC cases and 37,925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P = 1.86 × 10−5), which was stronger for cancers of endometrioid subtype (P = 3.76 × 10−6). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types. PMID:26330482

  10. Mortality trend of gallbladder cancer in Araucanía Region, Chile, 2004-2014.

    PubMed

    Muñoz, Paula; Vidal, Carolina; Moya, Patricia; Hoffmeister, Lorena

    2017-08-30

    Chile has the highest mortality rate for gallbladder cancer in the Andean region. The areas most affected by this cancer are found in southern Chile. To describe the mortality rate trends for gallbladder cancer in the Araucanía region between 2004 and 2014. Ecological observational descriptive study. The cases were identified by the codes ICD-10: C-23. The population at risk was obtained from the projections of the National Institute of Statistics of Chile. The mortality rate was modeled using the Poisson regression method, including age, time, and interaction between the two variables. The annual percentage change (APC) was used as a summary measure. In 2014, the Araucanía region had a standardized mortality rate of 10.36 per 100,000 inhabitants, while in the country it was 6.13 per 100,000. At the country level, the temporal evolution of mortality due to gallbladder cancer presented an annual percentage change of 9.1% (incidence rate ratio = 0.91 p-value <0.05), while in Araucanía the decrease was 7 % (incidence rate ratio = 0.93 p-value= 0.16), which is not statistically significant. The mortality rate was 2.68 times higher in women than in Araucanía men (p-value <0.05), a result similar to that of the country. At the national level, the trend according to age group shows a decrease for all groups, being the one of greater magnitude in those people from 45 to 54 years with an annual percent change of -5.36%, these results are not observed in the Araucanía. Mortality from gallbladder cancer shows a decreasing trend in the period studied for the whole country; however, this is not so for the Araucanía region, which maintains a higher mortality rate than that of the country.

  11. [Ethnic aspects of hereditary breast cancer in the region of Siberia].

    PubMed

    Cherdyntseva, N V; Pisareva, L F; Ivanova, A A; Panferova, Ye V; Malinovskaya, E A; Odintsova, I N; Doroshenko, A V; Gervas, P A; Slonimskaya, E M; Shivit-ool, A A; Dvornichenko, V V; Choinzonov, Ye L

    2014-01-01

    Ethnic diversity of the population in the region of Siberia suggests the existence of different germline mutations in the BRCA1/2 genes associated with breast and ovarian cancer in different ethnic populations, but spectrum of these mutations has not been studied. Our aim was to evaluate the frequency of the most common mutations BRCA1/2 (BRCA1 5382insC, BRCA1 185delAG, BRCA1 4153delAG, BRCAI T300G, BRCA2 6174delT) in women diagnosed with breast cancer among indigenous people and newcomers living in Siberia. We tested 1281 genomic DNA samples for the presence of BRCA1 5382insC mutation in patients diagnosed with breast cancer considering no family history. 72 patients having hereditary cancer signs were tested for the mutations BRCA1 185delAG, BRCA1 4153delAG, BRCA1 T300G, BRCA2 6174delT. Out of 765 patients of Slavic ethnic group, 27 women (3.5%) were carriers of allele BRCA1 5382insC. The frequencies of mutations in patients with signs of hereditary cancer were: 8.3% in group of young patients (under 40 years), 20.0% in patients with bilateral cancer and 5.7% in patients with family history of breast or ovarian cancers. We tested 516 BC patients residing on the territory of the Buryat-Aginsky district, Republics of Tyva and Altai. Out of them, there were 197 patients among the indigenous population (buryats, tuvinians, altaians), and 319 patients among newcomers (Slavic ethnics). Mutations BRCA1 5382insC were detected only in women from Slavic ethnic groups. The frequency of BRCA1 5382insC mutation was 6% in the group where family history was excluded and 14% in the group of patients with characteristics of family cancer. Allele BRCA1 5382insC was not found in indigenous breast cancer patients, although 59 patients had signs of hereditary cancer. In women from Slavic ethnic group, the BRCA1 185delAG, BRCA1 4153delAG and BRCA1 T300G mutations were detected in 9.1% of cases and were not found in patients among the indigenous population. studies of mutations in the

  12. ANX7, a candidate tumor suppressor gene for prostate cancer

    PubMed Central

    Srivastava, Meera; Bubendorf, Lukas; Srikantan, Vasantha; Fossom, Linda; Nolan, Lisa; Glasman, Mirta; Leighton, Ximena; Fehrle, Wilfred; Pittaluga, Stefania; Raffeld, Mark; Koivisto, Pasi; Willi, Niels; Gasser, Thomas C.; Kononen, Juha; Sauter, Guido; Kallioniemi, Olli P.; Srivastava, Shiv; Pollard, Harvey B.

    2001-01-01

    The ANX7 gene is located on human chromosome 10q21, a site long hypothesized to harbor a tumor suppressor gene(s) (TSG) associated with prostate and other cancers. To test whether ANX7 might be a candidate TSG, we examined the ANX7-dependent suppression of human tumor cell growth, stage-specific ANX7 expression in 301 prostate specimens on a prostate tissue microarray, and loss of heterozygosity (LOH) of microsatellite markers at or near the ANX7 locus. Here we report that human tumor cell proliferation and colony formation are markedly reduced when the wild-type ANX7 gene is transfected into two prostate tumor cell lines, LNCaP and DU145. Consistently, analysis of ANX7 protein expression in human prostate tumor microarrays reveals a significantly higher rate of loss of ANX7 expression in metastatic and local recurrences of hormone refractory prostate cancer as compared with primary tumors (P = 0.0001). Using four microsatellite markers at or near the ANX7 locus, and laser capture microdissected tumor cells, 35% of the 20 primary prostate tumors show LOH. The microsatellite marker closest to the ANX7 locus showed the highest rate of LOH, including one homozygous deletion. We conclude that the ANX7 gene exhibits many biological and genetic properties expected of a TSG and may play a role in prostate cancer progression. PMID:11287641

  13. Recent trends in racial and regional disparities in cervical cancer incidence and mortality in United States

    PubMed Central

    Kim, Sangmi

    2017-01-01

    Background Although black women experienced greater cervical cancer incidence and mortality rate reduction in recent years, they continue to have higher incidence rates than whites. Great variations also exist among geographic regions of the US, with the South having both the highest incidence and mortality rates compared to other regions. The present study explores the question of whether living in the South is associated with greater racial disparity in cervical cancer incidence and mortality by examining race- and region-specific rates and the trend between 2000 and 2012. Methods The Surveillance, Epidemiology, and End Results (SEER) 18 Program data was used. Cervical cancer incidence and mortality rates, annual percent changes, and disparity ratios were calculated using SEER*Stat software and Joinpoint regression for four groups: US14-Non-Hispanic White (NHW), US14-Non-Hispanic Black (NHB), South-NHW, and South-NHB, where South included 4 registries from Georgia and Louisiana and US14 were 14 US registries except the four South registries. Results The average age-adjusted cervical cancer incidence rate was the highest among South-NHBs (11.1) and mortality rate was the highest among US14-NHBs (5.4). In 2012, the degree of racial disparities between South-NHBs and South-NHWs was greater in terms of mortality rates (NHB:NHW = 1.80:1.35) than incidence rates (NHB:NHW = 1.45:1.15). While mortality disparity ratios decreased from 2000–2012 for US14-NHB (APC: -1.9(-2.3,-1.4), mortality disparity ratios for South-NHWs (although lower than NHBs) increased compared to US14-NHW. Incidence rates for NHBs continued to increase with increasing age, whereas rates for NHWs decreased after age 40. Mortality rates for NHBs dramatically increased at age 65 compared to a relatively stable trend for NHWs. The increasing racial disparity with increasing age in terms of cervical cancer incidence rates became more pronounced when corrected for hysterectomy prevalence. Conclusions

  14. Locally constrained active contour: a region-based level set for ovarian cancer metastasis segmentation

    NASA Astrophysics Data System (ADS)

    Liu, Jianfei; Yao, Jianhua; Wang, Shijun; Linguraru, Marius George; Summers, Ronald M.

    2014-03-01

    Accurate segmentation of ovarian cancer metastases is clinically useful to evaluate tumor growth and determine follow-up treatment. We present a region-based level set algorithm with localization constraints to segment ovarian cancer metastases. Our approach is established on a representative region-based level set, Chan-Vese model, in which an active contour is driven by region competition. To reduce over-segmentation, we constrain the level set propagation within a narrow image band by embedding a dynamic localization function. The metastasis intensity prior is also estimated from image regions within the level set initialization. The localization function and intensity prior force the level set to stop at the desired metastasis boundaries. Our approach was validated on 19 ovarian cancer metastases with radiologist-labeled ground-truth on contrast-enhanced CT scans from 15 patients. The comparison between our algorithm and geodesic active contour indicated that the volume overlap was 75+/-10% vs. 56+/-6%, the Dice coefficient was 83+/-8% vs. 63+/-8%, and the average surface distance was 2.2+/-0.6mm vs. 4.4+/-0.9mm. Experimental results demonstrated that our algorithm outperformed traditional level set algorithms.

  15. Loco-regional treatment in metastatic breast cancer patients: is there a survival benefit?

    PubMed

    Ly, Bevan H; Nguyen, Nam P; Vinh-Hung, Vincent; Rapiti, Elisabetta; Vlastos, Georges

    2010-02-01

    A number of studies have recently demonstrated a survival benefit in stage IV breast cancer patients following surgical resection of the primary tumor. Here, we investigate the relationship between loco-regional treatment and survival in patients with metastatic breast cancer and evaluate the impact of different loco-regional treatments. We conducted a systematic review of the literature using PubMed to analyze studies with the following criteria: Type of loco-regional treatment (surgery alone or combined with radiation, radiotherapy), overall survival, progression-free survival, selection factors for local treatment, and complication rates. Thirteen studies evaluated the effect of loco-regional treatment on overall survival with overall median survival increasing from a range of 12.6-28.3 months among patients without surgery to a range of 25-42 months among patients with surgery. In addition, six studies reported a 3-year survival benefit of 28-95% and 17-79% in women with and without locoregional therapy respectively. Two studies did not find any improvement in overall survival. One study found an improvement in 5-year breast cancer-specific survival of 27% with negative surgical margins versus 12% with no surgery. Three studies reported an advantage in progression-free survival in the treatment group compared with the non-treatment group. Loco-regional treatment for breast cancer patients with distant metastases at diagnosis is an important issue because of possible improvement of survival or disease-free survival. The possibility of surgery and/or radiotherapy following induction chemotherapy should be weighed and left to individual practice. Participation in randomized controlled trials should be encouraged.

  16. Inconsistent selection and definition of local and regional endpoints in breast cancer research.

    PubMed

    Moossdorff, M; van Roozendaal, L M; Schipper, R-J; Strobbe, L J A; Voogd, A C; Tjan-Heijnen, V C G; Smidt, M L

    2014-12-01

    Results in breast cancer research are reported using study endpoints. Most are composite endpoints (such as locoregional recurrence), consisting of several components (for example local recurrence) that are in turn composed of specific events (such as skin recurrence). Inconsistent endpoint selection and definition might lead to unjustified conclusions when comparing study outcomes. This study aimed to determine which locoregional endpoints are used in breast cancer studies, and how these endpoints and their components are defined. PubMed was searched for breast cancer studies published in nine leading journals in 2011. Articles using endpoints with a local or regional component were included and definitions were compared. Twenty-three different endpoints with a local or regional component were extracted from 44 articles. Most frequently used were disease-free survival (25 articles), recurrence-free survival (7), local control (4), locoregional recurrence-free survival (3) and event-free survival (3). Different endpoints were used for similar outcomes. Of 23 endpoints, five were not defined and 18 were defined only partially. Of these, 16 contained a local and 13 a regional component. Included events were not specified in 33 of 57 (local) and 27 of 50 (regional) cases. Definitions of local components inconsistently included carcinoma in situ and skin and chest wall recurrences. Regional components inconsistently included specific nodal sites and skin and chest wall recurrences. Breast cancer studies use many different endpoints with a locoregional component. Definitions of endpoints and events are either not provided or vary between trials. To improve transparency, facilitate trial comparison and avoid unjustified conclusions, authors should report detailed definitions of all endpoints. © 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.

  17. Public knowledge on cancer and its determinants among Saudis in the Riyadh Region of Saudi Arabia.

    PubMed

    Ravichandran, Kandasamy; Mohamed, Gamal; Al-Hamdan, Nasser Abdulrahman

    2010-01-01

    Earlier studies on cancer knowledge/awareness from Saudi Arabia have been few and mostly limited to knowledge of and attitude towards breast cancer. The objectives of the present cross sectional study were to determine the levels of knowledge concerning cancer and to identify associated factors. This study was carried out among 1,407 Saudis who were either patients or their escorts, attending selected hospitals in Riyadh region and aged 15 years or more. Required information was obtained by interview using a piloted Arabic questionnaire. Associations between different variables and respondents knowledge were evaluated by Chi square test. Multiple logistic regression analyses were performed to examine the potential impact of the variables. This study population consisted of 688 males and 719 females. Approximately two thirds of participants (67.6%) had never heard of any cancer warning signals, but 80.7% believed some cancers can be cured if detected early, 27.1% believed cancer means end of life and 74.2% believed cancer will appear overnight. The majority of the respondents (65.1%) received information about cancer from television/radio. Although 1,159 had high level knowledge (scored 50.0% and more), only 233 individuals scored 75.0% and more. Significant differences in the knowledge level across age groups, educational levels and marital status were observed. Females had higher level knowledge than males. Odds of having high level knowledge about cancer was 5.27 times higher among those who had undergone any of the tests (breast self examination, mammography, occult blood, Papanicolau smear) compared to those who had none of those tests (95% CI: 1.87-14.8). Those who had heard about any cancer warning signal were more knowledgeable (OR=1.55; 95% CI: 1.10-2.19) than those who hadn't. The other most important determinants of knowledge level included age, and attending a primary health care centre. Our results suggest that the knowledge of cancer is poor among the

  18. Changing Trends of Skin Cancer: A Tertiary Care Hospital Study in Malwa Region of Punjab

    PubMed Central

    Banipal, Raja Paramjeet Singh; Bhatti, Deepak John; Yadav, Hanuman Prasad

    2016-01-01

    Introduction Skin cancer constitutes a small but significant proportion of patients with cancer. Although the presence of eumelanin in dark skin is protective against the development of skin cancer, it is increasingly being diagnosed in the Indian population. Aim To study the profile of skin cancer patients presenting to a tertiary hospital in Malwa area of Punjab, India. Materials and Methods Retrospective study was done to analyse the profile of skin cancer patients who attended the institution over one year from 1st December 2013 to 30th November 2014. A comprehensive review of aetiology and related risk factors was done to correlate the environmental factors with high skin cancer prevalence in this region. Results Skin cancer constituted (3.18%) 84 out of 2638 patients registered with cancer of all types. The age of the patients was 62±14.2 years and ranged from 27 to 92 yrs. Basal cell carcinoma (BCC) was the most common histological type(46/84, 54.76%) followed by squamous cell carcinoma (SCC) (31/84, 36.91%) and malignant melanoma (MM) (7/84, 8.33%). Male: female ratio was found to be 0.79:1. BCC showed higher female preponderance (p<0.05). Head and Neck was the commonest site involved (p<0.05). Majority (88%) of patients were from rural area. 92% of patients were directly into the profession of agriculture with history of prolonged exposure to sunlight. Conclusion Skin cancer constitutes a small but significant proportion of patients with cancers. This study highlights a paradoxically increasing trend of BCC and female preponderance. Head and neck is the most common site involved. Exposure to Ultra Violet B (UVB) radiation and higher levels of arsenic in drinking water has been reported to be associated with skin cancers. Limited studies show that levels of arsenic and pesticides were higher in the samples of drinking water in Malwa area of Punjab. Therefore a multipronged strategy to provide safe drinking water supply and discouraging the indiscriminate

  19. Genetic testing for breast-ovarian cancer susceptibility: a regional trial.

    PubMed

    Loader, S; Levenkron, J C; Rowley, P T

    1998-01-01

    To evaluate receptivity to testing for a genetic susceptibility to breast-ovarian cancer, information is needed on the response when the offer is open to all qualifying women in a given region. To qualify in this trial, a woman who had not had breast or ovarian cancer had to have at least two first-degree relatives or one first- and one second-degree relative with breast and/or ovarian cancer, whereas a woman who had had breast or ovarian cancer had to have at least one first-degree relative with breast or ovarian cancer and a first- or second-degree relative without cancer willing to be tested. Of 140 women qualifying and interested enough to return questionnaires requesting baseline information, 111 were referred by their physician and 29 were identified from a regional tumor registry. Of these 140, 112 came for pretest education and 98 of these chose to be tested. Thus, the acceptance rate was 70% for all those returning baseline questionnaires, but 88% for those interested enough to come for pretest education. The most common reasons for accepting testing were to take extra precautions if a mutation were found (42.9%) and to determine if offspring were at risk (24.5%). The most common reasons for declining were anxiety and absence of specific interventions. Factors predicting who chose testing were years of education (p < 0.005) and family closeness (p < 0.02). Fourteen deleterious BRCA1 or BRCA2 mutations were found in 13 of the 87 families actually tested. If the criteria for testing had been three or more affected family members rather than two or more, the number of families tested would have been reduced by 46%, but the number of families found to have a deleterious mutation would have been reduced by only 9%.

  20. Accuracy of FDG-PET to diagnose lung cancer in a region of endemic granulomatous disease

    PubMed Central

    Deppen, Stephen; Putnam, Joe B.; Andrade, Gabriela; Speroff, Theodore; Nesbitt, Jonathan C.; Lambright, Eric S.; Massion, Pierre P.; Walker, Ron; Grogan, Eric L.

    2011-01-01

    Background 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) is used to evaluate suspicious pulmonary lesions due to its diagnostic accuracy. The southeastern United States has a high prevalence of infectious granulomatous lung disease, and the accuracy of FDGPET may be reduced in this population. We examined the diagnostic accuracy of FDG-PET in patients with known or suspected NSCLC treated at our institution. Methods 279 patients identified through our prospective database, underwent an operation for known or suspected lung cancer. Preoperative FDG-PET in 211 eligible patients was defined by standardized uptake value, SUV > 2.5 or by description (“moderate” or “intense”) as avid. Sensitivity, specificity, positive and negative predictive values, likelihood ratios, and decision diagrams were calculated for FDG-PET in all patients and in patients with indeterminate nodules. Results In all eligible patients (n=211), sensitivity and specificity of FDG-PET were 92% and 40%. Positive and negative predictive values were 86% and 55%. Overall FDG-PET accuracy to diagnose lung cancer was 81%. Preoperative positive likelihood ratio for FDG-PET diagnosis of lung cancer in this population was 1.5 compared to previously published values of 7.1. In 113 indeterminate lesions, 65% had lung cancer and the sensitivity and specificity were 89% and 40% respectively. 24 benign nodules (60%) had false positive FDG-PET scans. 22 of 43 benign nodules (51%) were granulomas. Conclusions In a region with endemic granulomatous diseases, the specificity of FDG-PET for diagnosis of lung cancer was 40%. Clinical decisions and future clinical predictive models for lung cancer must accommodate regional variation of FDG-PET scan results. PMID:21592456

  1. ChromSorter PC: A database of chromosomal regions associated with human prostate cancer

    PubMed Central

    Etim, Ann; Zhou, Guohui; Wen, Xinyu; Liu, Hang; Ruotti, Victor; Twigger, Simon; Jin, Weihong; Matysiak, Brian; Mathis, Jedidiah; Tonellato, Peter J; Datta, Milton W

    2004-01-01

    Background Our increasing use of genetic and genomic strategies to understand human prostate cancer means that we need access to simplified and integrated information present in the associated biomedical literature. In particular, microarray gene expression studies and associated genetic mapping studies in prostate cancer would benefit from a generalized understanding of the prior work associated with this disease. This would allow us to focus subsequent laboratory studies to genomic regions already related to prostate cancer by other scientific methods. We have developed a database of prostate cancer related chromosomal information from the existing biomedical literature. The input material was based on a broad literature search with subsequent hand annotation of information relevant to prostate cancer. Description The database was then analyzed for identifiable trends in the whole scale literature. We have used this database, named ChromSorter PC, to present graphical summaries of chromosomal regions associated with prostate cancer broken down by age, ethnicity and experimental method. In addition we have placed the database information on the human genome using the Generic Genome Browser tool that allows the visualization of the data with respect to user generated datasets. Conclusions We have used this database as an additional dataset for the filtering of genes identified through genetics and genomics studies as warranting follow-up validation studies. We would like to make this dataset publicly available for use by other groups. Using the Genome Browser allows for the graphical analysis of the associated data . Additional material from the database can be obtained by contacting the authors (mdatta@mcw.edu). PMID:15113398

  2. Relationship between microRNA genes incidence and cancer-associated genomic regions in canine tumors: a comprehensive bioinformatics study.

    PubMed

    Zamani-Ahmadmahmudi, Mohamad

    2016-03-01

    The role of microRNAs (miRNAs) in human cancer biology has been confirmed on a genome-wide scale through the high incidence of these genes in cancer-associated regions. We analyzed the association between canine miRNA genes and cancer-associated regions (deleted and amplified regions) using previously published array of comparative genomic hybridization data on 268 canine cancer samples-comprising osteosarcoma, breast cancer, leukemia, and colorectal cancer. We also assessed this relationship apropos the incidence of miRNA genes in the CpG islands of the canine genome assembly. The association was evaluated using the mixed-effects Poisson regression analysis. Our analyses revealed that 135 miRNA genes were exactly located in the aberrated regions: 77 (57 %) in the loss and 58 (43 %) in amplified regions. Our findings indicated that the miRNA genes were located more frequently in the deleted regions as well as in the CpG islands than in all other regions. Additionally, with the exception of leukemia, the amplified regions significantly contained higher numbers of miRNA genes than did all the other regions.

  3. Association between adjuvant regional radiotherapy and cognitive function in breast cancer patients treated with conservation therapy

    PubMed Central

    Shibayama, Osamu; Yoshiuchi, Kazuhiro; Inagaki, Masatoshi; Matsuoka, Yutaka; Yoshikawa, Eisho; Sugawara, Yuriko; Akechi, Tatsuo; Wada, Noriaki; Imoto, Shigeru; Murakami, Koji; Ogawa, Asao; Akabayashi, Akira; Uchitomi, Yosuke

    2014-01-01

    Although protracted cognitive impairment has been reported to occur after radiotherapy even when such therapy is not directed to brain areas, the mechanism remains unclear. This study investigated whether breast cancer patients exposed to local radiotherapy showed lower cognitive function mediated by higher plasma interleukin (IL)-6 levels than those unexposed. We performed the Wechsler Memory Scale-Revised (WMS-R) and measured plasma IL-6 levels for 105 breast cancer surgical patients within 1 year after the initial therapy. The group differences in each of the indices of WMS-R were investigated between cancer patients exposed to adjuvant regional radiotherapy (n = 51) and those unexposed (n = 54) using analysis of covariance. We further investigated a mediation effect by plasma IL-6 levels on the relationship between radiotherapy and the indices of WMS-R using the bootstrapping method. The radiotherapy group showed significantly lower Immediate Verbal Memory Index and Delayed Recall Index (P = 0.001, P = 0.008, respectively). Radiotherapy exerted an indirect effect on the lower Delayed Recall Index of WMS-R through elevation of plasma IL-6 levels (bootstrap 95% confidence interval = −2.6626 to −0.0402). This study showed that breast cancer patients exposed to adjuvant regional radiotherapy in conservation therapy might have cognitive impairment even several months after their treatment. The relationship between the therapy and the cognitive impairment could be partially mediated by elevation of plasma IL-6 levels. PMID:24756915

  4. Genomic shotgun array: a procedure linking large-scale DNA sequencing with regional transcript mapping.

    PubMed

    Li, Ling-Hui; Li, Jian-Chiuan; Lin, Yung-Feng; Lin, Chung-Yen; Chen, Chung-Yung; Tsai, Shih-Feng

    2004-02-11

    To facilitate transcript mapping and to investigate alterations in genomic structure and gene expression in a defined genomic target, we developed a novel microarray-based method to detect transcriptional activity of the human chromosome 4q22-24 region. Loss of heterozygosity of human 4q22-24 is frequently observed in hepatocellular carcinoma (HCC). One hundred and eighteen well-characterized genes have been identified from this region. We took previously sequenced shotgun subclones as templates to amplify overlapping sequences for the genomic segment and constructed a chromosome-region-specific microarray. Using genomic DNA fragments as probes, we detected transcriptional activity from within this region among five different tissues. The hybridization results indicate that there are new transcripts that have not yet been identified by other methods. The existence of new transcripts encoded by genes in this region was confirmed by PCR cloning or cDNA library screening. The procedure reported here allows coupling of shotgun sequencing with transcript mapping and, potentially, detailed analysis of gene expression and chromosomal copy of the genomic sequence for the putative HCC tumor suppressor gene(s) in the 4q candidate region.

  5. Complementary alternative medicine use amongst breast cancer patients in the Northern region of peninsular Malaysia.

    PubMed

    Knight, Aishah; Hwa, Yen Siew; Hashim, Hasnah

    2015-01-01

    Breast cancer is a common cancer affecting women in Malaysia and the use of complementary/ alternative medicine (CAM) has been associated with delays in getting treatment. The aim of the study was to explore the use of CAM and the influencing factors in the Northern region of Peninsular Malaysia. This was a cross-sectional descriptive study on a convenience sample of 100 Malaysian breast cancer survivors. The reported use of CAM among the breast cancer survivors was lower than in other studies but the types of CAM used had a similar pattern with nutrition supplements/vitamins being the most common. The factors that positively influenced the use of complimentary/traditional therapy were income and getting information from television or radio. Survivors with access to internet/blogs appear to have lower odds of using complimentary/traditional therapy compared to the respondents who reported no such access. Information transmitted via television and radio appears to have a positive influence on CAM use by breast cancer patients compared to other information sources and it is important to ensure that such information is accurate and impartial.

  6. [Trend pattern of the incidence of thyroid cancer in Murcia Region (Spain) from 1984 to 2008].

    PubMed

    Chirlaque, María Dolores; Moldenhauer, Fernando; Salmerón, Diego; Navarro, Carmen

    2014-01-01

    To study the trend pattern of the incidence of thyroid cancer. We selected incident cases of thyroid cancer occurring in the Region of Murcia (Spain) in 1984-2008. The variables gathered were age, sex, date of diagnosis, and morphology. We calculated incidence rates and the annual percentage of change using Bayesian age-period-cohort models. During the study period, 1414 cases were diagnosed, representing an increase in adjusted rates from 2.9/100000 in 1984-1988 to 7.3 in 2004-2008. The incidence was 3.5 times higher in women than in men and the most frequent morphology was papillary carcinoma (67.7%). An increasing trend was found in both genders; these increments were more pronounced in papillary carcinoma. In women, the incidence increased with age, calendar year, and in those born in 1945-1963. The incidence of papillary microcarcinoma increased four-fold in women. Thyroid cancer used to be a rare cancer but has become an emerging tumor. The greatest changes were found in papillary thyroid cancer, including a gradual increase in the proportion of microcarcinoma. Copyright © 2014 SESPAS. Published by Elsevier Espana. All rights reserved.

  7. Risks of Lung Cancer due to Radon Exposure among the Regions of Korea.

    PubMed

    Lee, Hye Ah; Lee, Won Kyung; Lim, Dohee; Park, Su Hyun; Baik, Sun Jung; Kong, Kyoung Ae; Jung-Choi, Kyunghee; Park, Hyesook

    2015-05-01

    Radon is likely the second most common cause of lung cancer after smoking. We estimated the lung cancer risk due to radon using common risk models. Based on national radon survey data, we estimated the population-attributable fraction (PAF) and the number of lung cancer deaths attributable to radon. The exposure-age duration (EAD) and exposure-age concentration (EAC) models were used. The regional average indoor radon concentration was 37.5 95 Bq/m(3). The PAF for lung cancer was 8.3% (European Pooling Study model), 13.5% in males and 20.4% in females by EAD model, and 19.5% in males and 28.2% in females by EAC model. Due to differences in smoking by gender, the PAF of radon-induced lung cancer deaths was higher in females. In the Republic of Korea, the risk of radon is not widely recognized. Thus, information about radon health risks is important and efforts are needed to decrease the associated health problems.

  8. Edmonton Regional Palliative Care Program: impact on patterns of terminal cancer care

    PubMed Central

    Bruera, E; Neumann, C M; Gagnon, B; Brenneis, C; Kneisler, P; Selmser, P; Hanson, J

    1999-01-01

    The Edmonton Regional Palliative Care Program was established in July 1995 to measure the access of patients with terminal cancer to palliative care services, decrease the number of cancer-related deaths in acute care facilities and increase the participation of family physicians in the care of terminally ill patients. In this retrospective study the authors compared the pattern of care and site of deaths before establishment of the program (1992/93) and during its second year of operation (1996/97). Significantly more cancer-related deaths occurred in acute care facilities in 1992/93 than in 1996/97 (86% [1119/1304] v. 49% [633/1279]) (p < or = 0.001). The number of inpatient days decreased, from 24,566 in 1992/93 to 6960 in 1996/97. More cancer patients saw a palliative care consult team in 1996/97 than in 1992/93 (82% v. 22%). The shift from deaths in acute care facilities to palliative hospices suggests that the establishment of an integrated palliative care program has increased access of patients with terminal cancer to palliative care. PMID:10463053

  9. Allelic expression imbalance polymorphisms in susceptibility chromosome regions and the risk and survival of breast cancer.

    PubMed

    Lin, Wei; Lin, Hong-Da; Guo, Xing-Yi; Lin, Ying; Su, Feng-Xi; Jia, Wei-Hua; Tang, Lu-Ying; Zheng, Wei; Long, Ji-Rong; Ren, Ze-Fang

    2017-01-01

    Allelic expression imbalance (AEI) has been applied to indicate potential function of genetic variants. Combining earlier results from global differential allele-specific expression analysis and genome wide association studies (GWASs), we select the single nuclear polymorphisms (SNPs) exhibiting AEI phenomenon located in breast cancer susceptibility chromosome regions, and evaluate their associations with breast cancer risk and survival. We examined the genotypes of 10 AEI SNPs in 1551 incident breast cancer cases and 1605 age-frequency matched controls from Guangzhou, China. In total, 1168 cases were followed up. MUC16 rs2591592 (AT/AA vs. TT) was associated with an increased risk of premenopausal breast cancer (OR [95%CI]: 1.30 [1.07, 1.57]); SLAMF1 rs1061217 (CT/TT vs. CC) decreased the risk of breast cancer among overweight women (OR [95%CI]: 0.74 [0.57, 0.96]) but increased the risk among normal-weight women (OR [95%CI]: 1.15 [1.01, 1.39]); ZNF331 rs8109631 (AG/AA vs. GG) and CHRAC1 rs10216653 (GC/GG vs. CC) were associated with progression free survival among breast cancer patients with negative ER/PR status and higher clinical stage (HRs [95%CIs]: 2.39 [1.14, 5.00], 1.85 [1.03, 3.32], and 0.49 [0.30, 0.80], respectively). ZNF331 rs8109631 and CHRAC1 rs10216653 were further found to represent several functional SNPs through bioinformatic analysis. In conclusion, our findings demonstrated suggestive associations of AEI polymorphisms with breast cancer risk (MUC16 rs2591592 and SLAMF1 rs1061217) and prognosis (ZNF331 rs8109631 and CHRAC1 rs10216653). © 2016 Wiley Periodicals, Inc.

  10. Regional Contrast-Enhanced Ultrasonography (CEUS) Characteristics of Breast Cancer and Correlation with Microvessel Density (MVD).

    PubMed

    Leng, Xiaoling; Huang, Guofu; Ma, Fucheng; Yao, Lanhui

    2017-07-14

    BACKGROUND The aim of this study was to investigate the perfusion characteristics of different breast lesion regions in contrast-enhanced ultrasonography (CEUS). MATERIAL AND METHODS A total of 161 malignant and benign breast lesion cases were subjected to CEUS. Perfusion parameters were analyzed and compared between the central and peripheral lesion regions, and surrounding tissue. Mass section was marked with methylene blue. Samples were subjected to immunohistochemistry, and microvessel density (MVD) was calculated. RESULTS There were significant differences in perfusion performance between the central and peripheral lesion regions, and surrounding tissue. In the malignant tumors, the fast-in and fast-out pattern was the most common type in the peripheral region (57.98%), while the slow-in and slow-out patterns were the major types in the central region and surrounding tissue (49.58% and 57.98%, respectively). Compared with the surrounding tissue, the peripheral region in the cancers exhibited hyperechoic enhancement and fast-in and slow-out pattern, with large area under the curve (AUC), while the central region showed isoechoic enhancement and equally-in and slow-out pattern, with large AUC. In the benign lesions, the peripheral region exhibited hyperechoic enhancement and fast-in and fast-out pattern, with small AUC, while the central region showed isoechoic enhancement and equally-in and -out pattern, with the same AUC value. Moreover, the perfusion parameters in the central and peripheral regions were significantly associated with MVD. CONCLUSIONS It is more objective to evaluate the perfusion performance of breast lesions with the reference of surrounding tissue. Compared with the central region, the peripheral region could better reflect the perfusion characteristics of malignant lesions.

  11. Evaluation of the interval cancer rate and its determinants on the Girona Health Region's early breast cancer detection program.

    PubMed

    Renart-Vicens, Gemma; Puig-Vives, Montserrat; Albanell, Joan; Castañer, Francesc; Ferrer, Joana; Carreras, Miquel; Tarradas, Joan; Sala, Maria; Marcos-Gragera, Rafael

    2014-08-01

    The main aim of this study is to estimate the rate of false negative and true IC on the Program for the Early Detection of Breast Cancer (PEDBC) run by the Girona Health Region (GHR) and compare the clinicopathological characteristics of these tumors with those detected within the same program. A retrospective cohort study including all women participating on the Girona PEDBC between 2000 and 2006, with negative mammography screening. The IC included are those detected between the first and second round of screening and between the second and third round. We identified a total of 43 IC, representing an incidence rate of 0.70 cases per 1,000 screened women. Of the 43 probable IC, we were able to classify a total of 22 (51.2%) cases. Of these 22 cases, 54.5% were classified as true interval tumors, 13.6% false negatives, 18.2% occult tumors and the remaining 13.6% minimal sign.We found significant differences in some clinicopathological characteristics of the IC comparing with the tumors detected within the program during the same period. The IC rate for the PEDBC is within the expected parameters, with a high proportion of cases of true interval cancers (54.5%) and a low proportion of false negatives (13.6%). The results show that the proportional incidence of IC is within the limits set by European Guidelines. Furthermore, it has been confirmed that IC display more aggressive clinicopathological characteristics than screening breast cancers.

  12. Knowledge about cervical cancer and barriers of screening program among women in Wufeng County, a high-incidence region of cervical cancer in China.

    PubMed

    Jia, Yao; Li, Shuang; Yang, Ru; Zhou, Hang; Xiang, Qunying; Hu, Ting; Zhang, Qinghua; Chen, Zhilan; Ma, Ding; Feng, Ling

    2013-01-01

    Cervical cancer screening is an effective method for reducing the incidence and mortality of cervical cancer, but the screening attendance rate in developing countries is far from satisfactory, especially in rural areas. Wufeng is a region of high cervical cancer incidence in China. This study aimed to investigate the issues that concern cervical cancer and screening and the factors that affect women's willingness to undergo cervical cancer screening in the Wufeng area. A cross-sectional survey of women was conducted to determine their knowledge about cervical cancer and screening, demographic characteristics and the barriers to screening. Women who were willing to undergo screenings had higher knowledge levels. "Anxious feeling once the disease was diagnosed" (47.6%), "No symptoms/discomfort" (34.1%) and "Do not know the benefits of cervical cancer screening" (13.4%) were the top three reasons for refusing cervical cancer screening. Women who were younger than 45 years old or who had lower incomes, positive family histories of cancer, secondary or higher levels of education, higher levels of knowledge and fewer barriers to screening were more willing to participate in cervical cancer screenings than women without these characteristics. Efforts are needed to increase women's knowledge about cervical cancer, especially the screening methods, and to improve their perceptions of the screening process for early detection to reduce cervical cancer incidence and mortality rates.

  13. Knowledge about Cervical Cancer and Barriers of Screening Program among Women in Wufeng County, a High-Incidence Region of Cervical Cancer in China

    PubMed Central

    Zhou, Hang; Xiang, Qunying; Hu, Ting; Zhang, Qinghua; Chen, Zhilan; Ma, Ding; Feng, Ling

    2013-01-01

    Purpose Cervical cancer screening is an effective method for reducing the incidence and mortality of cervical cancer, but the screening attendance rate in developing countries is far from satisfactory, especially in rural areas. Wufeng is a region of high cervical cancer incidence in China. This study aimed to investigate the issues that concern cervical cancer and screening and the factors that affect women’s willingness to undergo cervical cancer screening in the Wufeng area. Participants and Methods A cross-sectional survey of women was conducted to determine their knowledge about cervical cancer and screening, demographic characteristics and the barriers to screening. Results Women who were willing to undergo screenings had higher knowledge levels. “Anxious feeling once the disease was diagnosed” (47.6%), “No symptoms/discomfort” (34.1%) and “Do not know the benefits of cervical cancer screening” (13.4%) were the top three reasons for refusing cervical cancer screening. Women who were younger than 45 years old or who had lower incomes, positive family histories of cancer, secondary or higher levels of education, higher levels of knowledge and fewer barriers to screening were more willing to participate in cervical cancer screenings than women without these characteristics. Conclusion Efforts are needed to increase women’s knowledge about cervical cancer, especially the screening methods, and to improve their perceptions of the screening process for early detection to reduce cervical cancer incidence and mortality rates. PMID:23843976

  14. Genomic Changes in Normal Breast Tissue in Women at Normal Risk or at High Risk for Breast Cancer

    PubMed Central

    Danforth, David N.

    2016-01-01

    Sporadic breast cancer develops through the accumulation of molecular abnormalities in normal breast tissue, resulting from exposure to estrogens and other carcinogens beginning at adolescence and continuing throughout life. These molecular changes may take a variety of forms, including numerical and structural chromosomal abnormalities, epigenetic changes, and gene expression alterations. To characterize these abnormalities, a review of the literature has been conducted to define the molecular changes in each of the above major genomic categories in normal breast tissue considered to be either at normal risk or at high risk for sporadic breast cancer. This review indicates that normal risk breast tissues (such as reduction mammoplasty) contain evidence of early breast carcinogenesis including loss of heterozygosity, DNA methylation of tumor suppressor and other genes, and telomere shortening. In normal tissues at high risk for breast cancer (such as normal breast tissue adjacent to breast cancer or the contralateral breast), these changes persist, and are increased and accompanied by aneuploidy, increased genomic instability, a wide range of gene expression differences, development of large cancerized fields, and increased proliferation. These changes are consistent with early and long-standing exposure to carcinogens, especially estrogens. A model for the breast carcinogenic pathway in normal risk and high-risk breast tissues is proposed. These findings should clarify our understanding of breast carcinogenesis in normal breast tissue and promote development of improved methods for risk assessment and breast cancer prevention in women. PMID:27559297

  15. Prognostic significance of extranodal extension of regional lymph node metastasis in papillary thyroid cancer.

    PubMed

    Wu, Ming-Hsun; Shen, Wen T; Gosnell, Jessica; Duh, Quan-Yang

    2015-09-01

    The presence and location of regional lymph node metastasis affect the prognosis of patients with thyroid cancer. Lymph node classification of the current TNM system may be inadequate because it insufficiently characterizes the nature and severity of lymph node metastasis that may influence prognosis. We retrospectively studied 240 patients with papillary thyroid cancer and node metastases who had undergone total thyroidectomy, lymph node dissection, and postoperative (131) I treatment at the University Cancer Center between 1994 and 2004. We reviewed the status of regional lymph node metastasis, including the location, number, largest size, and extranodal tumor extension and analyzed their effect on the prognosis of the patients. There were 172 women and 68 men, with a median age of 38 years and median tumor size of 1.9 cm. Thirty-five percent had only central compartment (N1a) nodal metastasis and 65% had involvement of both central and lateral compartments (N1b). There were a median of 4 nodes containing metastasis with a median largest diameter of 1.2 cm. Sixty patients (25%) had extranodal extension of cancer. Multivariate analysis showed that patient age (p = .0017; hazard ratio [HR], 2.156), >3 lymph node metastasis (p = .0316; HR, 1.806), and extranodal extension (p < .0001; HR, 4.027) were independent predictors of disease recurrence. Patient age (p = .0034; HR, 22.068), vascular invasion (p = .01; HR, 8.2), and extranodal extension (p = .022; HR, 12.597) were independent predictors of disease-specific survival (DSS). The DSS and recurrence-free survival curve between patients with and without extranodal extension differ significantly (p < .0001). For those older than 45 years, the 10-year recurrence was 11 of 43 patients for those without extranodal extension and 24 of 27 patients for those with extranodal extension (p < .001). Among patients with stage 4a/4b, those with extranodal extension had a significantly worse DSS

  16. Tumor Suppressors Status in Cancer Cell Line Encyclopedia

    PubMed Central

    Sonkin, Dmitriy; Hassan, Mehedi; Murphy, Denis J.; Tatarinova, Tatiana V.

    2013-01-01

    Tumor suppressors play a major role in the etiology of human cancer, and typically achieve a tumor promoting effect upon complete functional inactivation. Bi-allelic inactivation of tumor suppressors may occur through genetic mechanisms (such as loss-of-function mutation, copy number (CN) loss, or loss-of-heterozygosity (LOH)), epigenetic mechanisms (such as promoter methylation or histone modification), or a combination of the two. We report systematically derived status of 69 known or putative tumor suppressors, across 799 samples of the Cancer Cell Line Encyclopedia. In order to generate such resource we constructed a novel comprehensive computational framework for the assessment of tumor suppressor functional “status”. This approach utilizes several orthogonal genomic data types, including mutation data, copy number, LOH and expression. Through correlation with additional data types (compound sensitivity and gene set activity) we show that this integrative method provides a more accurate assessment of tumor suppressor status than can be inferred by expression, copy number, or mutation alone. This approach has the potential for a more realistic assessment of tumor suppressor genes for both basic and translational oncology research. PMID:23639312

  17. Tumor suppressors status in cancer cell line Encyclopedia.

    PubMed

    Sonkin, Dmitriy; Hassan, Mehedi; Murphy, Denis J; Tatarinova, Tatiana V

    2013-08-01

    Tumor suppressors play a major role in the etiology of human cancer, and typically achieve a tumor-promoting effect upon complete functional inactivation. Bi-allelic inactivation of tumor suppressors may occur through genetic mechanisms (such as loss of function mutation, copy number (CN) loss, or loss of heterozygosity (LOH)), epigenetic mechanisms (such as promoter methylation or histone modification), or a combination of the two. We report systematically derived status of 69 known or putative tumor suppressors, across 799 samples of the Cancer Cell Line Encyclopedia. In order to generate such resource we constructed a novel comprehensive computational framework for the assessment of tumor suppressor functional "status". This approach utilizes several orthogonal genomic data types, including mutation data, copy number, LOH and expression. Through correlation with additional data types (compound sensitivity and gene set activity) we show that this integrative method provides a more accurate assessment of tumor suppressor status than can be inferred by expression, copy number, or mutation alone. This approach has the potential for a more realistic assessment of tumor suppressor genes for both basic and translational oncology research.

  18. Current Status of Adjuvant Therapy for Colon Cancer

    PubMed Central

    André, Thierry; Afchain, Pauline; Barrier, Alain; Blanchard, Pierre; Larsen, Annette K.; Tournigand, Christophe; Louvet, Christophe; de Gramont, Aimery

    2007-01-01

    Due to its frequency and persistently high mortality, colorectal cancer represents a major public health problem. The use of adjuvant chemotherapy has improved prognosis in stage III disease, but much work remains to be done in optimizing adjuvant treatment, including refinement of ability to predict disease course and response to chemotherapy. The FOLFOX4 regimen is now considered standard treatment for stage III disease. Combinations of irinotecan and 5-fluorouracil (5-FU) have not proven to be more effective than 5-FU/folinic acid (FA). Oral fluoropyrimidines (eg, capecitabine, UFT + FA) now offer an alternative to intravenous 5-FU. Adjuvant chemotherapy for stage II colorectal cancer is more controversial. Use of adjuvant chemotherapy does not appear to be justified in patients with no particular risk factors (T3N0 with no poor prognosis factor). In contrast, the risk:benefit ratio in patients with one or more poor prognostic factors (T4 tumor, occlusion or perforation, poorly differentiated tumor, vascular invasion, or < 10 lymph nodes examined) appears to favor adjuvant treatment with FOLFOX4. Ongoing adjuvant trials are evaluating bevacizumab and cetuximab combined with 5-FU and oxaliplatin, and are examining the utility of such potential predictive markers as tumor microsatellite instability and loss of heterozygosity. Duration of therapy and prevention of oxaliplatin neurotoxicity are other critical areas for future research. PMID:19262714

  19. [Cancer mortality of residents near a steel factory in Udine (Friuli Venezia Giulia Region, Northern Italy)].

    PubMed

    Castriotta, Luigi; Casetta, Anica; Barbone, Fabio

    2016-01-01

    to evaluate the association between distance of residence from a steel factory, a point source of air pollution within an industrial area in Udine (Friuli Venezia Giulia Region, Northern Italy), and cancer mortality. retrospective study. To evaluate the association between mortality rates and distance from the source, a Stone test analysis for all cases occurred in the entire area was conducted. The significance level was determined using Monte Carlo simulations. a GIS mapped residential history of Friuli Venezia Giulia population was completed. Among residents within 5 km from the principal industrial plant of the area from 1989 to 2012, deaths caused by cancer were selected. Furthermore, according to the prevalent wind direction, an analysis was conducted also in a subgroup of residents located into the South-Western quadrant. A set of 8 bands with increasing distance from the point-source was defined. The total population was 37,473 inhabitants. in each band, observed and expected cancer-related deaths (calculated on the basis of mortality rates in the entire area) and standardized mortality ratios (SMRs) were computed to test for decline in risk of mortality at different distances from the main chimney. Stone test, in which a decline in risk of disease with an increase in distance from the source of pollution is tested, was used. the risk for all cancers and lung cancer was higher than expected. For male residents located within 2 km into the South-Western quarter there were 21 observed deaths from lung cancer vs. 13 expected (SMR: 1.62; p-value=0.02). despite the fact that in the whole area cancer mortality is not increased, this study seems to support evidence of an excess of cancer deaths, especially lung cancer among males, near a steel factory. However, the study has limitations because of the small number of cases and the lack of individual exposure data and information about confounders (e.g., smoke habits and professional exposure). Therefore, a

  20. Prognostic Factors for Local, Loco-regional and Systemic Recurrence in Early-stage Breast Cancer.

    PubMed

    Kümmel, A; Kümmel, S; Barinoff, J; Heitz, F; Holtschmidt, J; Weikel, W; Lorenz-Salehi, F; du Bois, A; Harter, P; Traut, A; Blohmer, J U; Ataseven, B

    2015-07-01

    Aim: The risk of recurrence in breast cancer depends on factors such as treatment but also on the intrinsic subtype. We analyzed the risk factors for local, loco-regional and systemic recurrence, evaluated the differences and analyzed the risk of recurrence for different molecular subtypes. Material and Methods: A total of 3054 breast cancer patients who underwent surgery followed by adjuvant treatment at HSK hospital or Essen Mitte Hospital between 1998 and 2011 were analyzed. Based on immunohistochemical parameters, cancers were divided into the following subgroups: luminal A, luminal B (HER2-), luminal B (HER2+), HER2+ and TNBC (triple negative breast cancer). Results: 67 % of tumors were classified as luminal A, 13 % as luminal B (HER2-), 6 % as luminal B (HER2+), 3 % as HER2+ and 11 % as TNBC. After a median follow-up time of 6.6 years there were 100 local (3.3 %), 32 loco-regional (1 %) and 248 distant recurrences (8 %). Five-year recurrence-free survival for the overall patient collective was 92 %. On multivariate analysis, positive nodal status, TNBC subtype and absence of radiation therapy were found to be independent risk factors for all forms of recurrence. Age < 50 years, tumor size, luminal B (HER2-) subtype and breast-conserving therapy were additional risk factors for local recurrence. Compared to the luminal A subtype, the risk of systemic recurrence was higher for all other subtypes; additional risk factors for systemic recurrence were lymphatic invasion, absence of systemic therapy and mastectomy. Conclusion: Overall, the risk of local and loco-regional recurrence was low. In addition to nodal status, subgroup classification was found to be an important factor affecting the risk of recurrence.

  1. The status of lead and cadmium in soils of high prevalenct gastrointestinal cancer region of Isfahan.

    PubMed

    Mohajer, Reza; Salehi, Mohammad Hassan; Mohammadi, Jahangard; Emami, Mohammad Hassan; Azarm, Taleb

    2013-03-01

    Cadmium and lead compounds are classified as human carcinogens by several regulatory agencies. Twenty five percent of all cancer-related deaths are attributed to gastrointestinal cancers (GI Ca). We investigated the levels of 2 different heavy metals (Cd and Pb) in the soils of the Lenjanat region, Isfahan province, Central Iran where intensive agriculture is surrounded by different industries like steel and cement-making factories and mining and gastrointestinal cancers are very common in this province. Two hundred topsoil samples (0-20 cm depth) were collected from agricultural and non-agricultural soils of the region and were analyzed for heavy metals. The metal contents were determined by flame atomic absorption spectrometry. The findings of this study showed that frequency of gastrointestinal cancers in the study area have been increased in the recent years. Results of soil samples in this region showed that the mean concentration of Pb and Cd were more than 16 and 1 mg kg(-1), respectively. The total Cd concentration in most of the samples exceeded the suggested Swiss thresholds (0.8 mg kg(-1)) but the mean value of Pb concentration in soil was less than the threshold of 50 mg kg(-1) set by Swiss Federal Office of Environmental, Forest and Landscape. Compared to the threshold values for heavy metals (Cd and Pb) in soils, data showed that the studied fields were contaminated especially by Cd. High heavy metals content in the soils seems to play an important etiological role in the carcinogenesis. Excessive accumulation of heavy metals in agricultural soils may not only result in soil contamination, but also lead to elevated heavy metal uptake by crops, and thus affect food quality and safety. Thus, analyzing heavy metals content in crops, water and dust could provide us a better insight to solve the problem.

  2. The status of lead and cadmium in soils of high prevalenct gastrointestinal cancer region of Isfahan

    PubMed Central

    Mohajer, Reza; Salehi, Mohammad Hassan; Mohammadi, Jahangard; Emami, Mohammad Hassan; Azarm, Taleb

    2013-01-01

    Background: Cadmium and lead compounds are classified as human carcinogens by several regulatory agencies. Twenty five percent of all cancer-related deaths are attributed to gastrointestinal cancers (GI Ca). We investigated the levels of 2 different heavy metals (Cd and Pb) in the soils of the Lenjanat region, Isfahan province, Central Iran where intensive agriculture is surrounded by different industries like steel and cement-making factories and mining and gastrointestinal cancers are very common in this province. Materials and methods: Two hundred topsoil samples (0-20 cm depth) were collected from agricultural and non-agricultural soils of the region and were analyzed for heavy metals. The metal contents were determined by flame atomic absorption spectrometry. Results: The findings of this study showed that frequency of gastrointestinal cancers in the study area have been increased in the recent years. Results of soil samples in this region showed that the mean concentration of Pb and Cd were more than 16 and 1 mg kg−1, respectively. The total Cd concentration in most of the samples exceeded the suggested Swiss thresholds (0.8 mg kg−1) but the mean value of Pb concentration in soil was less than the threshold of 50 mg kg−1 set by Swiss Federal Office of Environmental, Forest and Landscape. Compared to the threshold values for heavy metals (Cd and Pb) in soils, data showed that the studied fields were contaminated especially by Cd. Conclusion: High heavy metals content in the soils seems to play an important etiological role in the carcinogenesis. Excessive accumulation of heavy metals in agricultural soils may not only result in soil contamination, but also lead to elevated heavy metal uptake by crops, and thus affect food quality and safety. Thus, analyzing heavy metals content in crops, water and dust could provide us a better insight to solve the problem. PMID:23930117

  3. Alternating expression levels of WWOX tumor suppressor and cancer-related genes in patients with bladder cancer

    PubMed Central

    PŁUCIENNIK, ELŻBIETA; NOWAKOWSKA, MAGDALENA; STĘPIEN, ANNA; WOŁKOWICZ, MATEUSZ; STAWIŃSKI, ADAM; RÓŻAŃSKI, WALDEMAR; LIPIŃSKI, MAREK; BEDNAREK, ANDRZEJ K

    2014-01-01

    The aim of the present study was to determine the roles of the WWOX tumor suppressor and cancer-related genes in bladder tumor carcinogenesis. Reverse transcription-quantitative polymerase chain reaction was used to analyze the status of WWOX promoter methylation (using MethylScreen™ technology) and loss of heterozygosity (LOH) in papillary urothelial cancer tissues. The associations between the expression levels of the following tumorigenesis-related genes were also assessed: The WWOX tumor suppressor gene, the MKI67 proliferation gene, the BAX, BCL2 and BIRC5 apoptotic genes, the EGFR signal transduction gene, the VEGF vascular endothelial growth factor gene, and the CCND1 and CCNE1 cell cycle genes. The results reveal a high frequency of LOH in intron 1 in the WWOX gene, as well as an association between reduced WWOX expression levels and increased promoter methylation. In addition, the present study demonstrates that in bladder tumors, apoptosis is inhibited by increased expression levels of the BCL2 gene. A correlation between the proliferation indices of the MKI67 and the BIRC5 genes was also revealed. Furthermore, the expression levels of VEGF were identified to be positively associated with those of the EGFR gene. PMID:25295115

  4. Regional variation in thyroid cancer incidence in Belgium is associated with variation in thyroid imaging and thyroid disease management.

    PubMed

    Van den Bruel, Annick; Francart, Julie; Dubois, Cecile; Adam, Marielle; Vlayen, Joan; De Schutter, Harlinde; Stordeur, Sabine; Decallonne, Brigitte

    2013-10-01

    Increased thyroid cancer incidence is at least partially attributed to increased detection and shows considerable regional variation. We investigated whether regional variation in cancer incidence was associated with variations in thyroid disease management. We conducted a retrospective population-based cohort study that involved linking data from the Belgian Health Insurance database and the Belgian Cancer Registry to compare thyroid-related procedures between regions with high and low cancer incidence. Primary outcome measures were rates of TSH testing, imaging, fine-needle aspiration cytology (FNAC), and thyroid surgery. Secondary study outcomes were proportions of subjects with thyrotoxicosis and nodular disease treated with surgery, of subjects treated with surgery preceded by FNAC or with synchronous lymph node dissection, and of thyroid cancer diagnosis after surgery. The rate of TSH testing was similar, but the rate of imaging was lower in the low incidence region. The rate of FNAC was similar, whereas the rate of surgery was lower in the low incidence region (34 [95% CI 33; 35 ] vs 80 [95% CI 79; 81 ] per 100,000 person years in the high incidence region; P < .05). In the low incidence region compared to the high incidence region, surgery represented a less chosen therapy for euthyroid nodular disease patients (47% [95% CI 46; 48] vs 69% [95% CI 68; 70]; P < .05), proportionally more surgery was preceded by FNAC, more cancer was diagnosed after total thyroidectomy, and thyroid cancer patients had more preoperative FNAC and synchronous lymph node dissection. Regional variation in thyroid cancer incidence, most marked for low-risk disease, is associated with different usage of thyroid imaging and surgery, supporting variable detection as a key determinant in geographic variation.

  5. Incidence variation of prostate and cervical cancer according to socioeconomic level in the Girona Health Region.

    PubMed

    Vicens, Gemma Renart; Zafra, Marc Saez; Moreno-Crespi, Judit; Ferrer, Bernat C Serdà; Marcos-Gragera, Rafael

    2014-10-17

    The main aim of this study, using a spatial-temporal model, is to analyse the link between a deprivation index and the incidence of prostate and cervical cancer in the Girona Health Region (GHR). This is a population-based study which includes all the inhabitants in the GHR in the period 1993-2006. In order to assess prostate/cervical cancer risk, Besag, York and Mollie (BYM)'s spatial-temporal version of the model was used and four random effects were introduced: (non-spatial) unstructured variability, spatial dependency, temporal dependency and spatial-temporal interaction. As an explanatory variable, a deprivation index was introduced at the census tract level. Furthermore, the percentage of the population between 45-64 years of age and over-65 was also considered as explanatory variables. In the case of prostate cancer, all the variables which were introduced into the model showed a significant correlation with the relative risk, except for the second quintile of the deprivation index. Furthermore, as the index increased the correlation became negative and lower. Thus, the correlation between the relative risk and the two age bands proved to be lower, the higher the age was. In the case of cervical cancer, only the correlation between the over-65 age band and the relative risk was found to be statistically significant and positive. In the case of prostate cancer, the results obtained in the GHR are in line with similar analyses. However, in the case of cervical cancer, no significant relationship between incidences in this location or economic status was found.

  6. [Role of loco-regional treatments for patients with breast cancer liver metastases].

    PubMed

    Raimondi, Cristina; Danova, Marco; Chatzileontiadou, Sofia; Palmeri, Laura; Vercelli, Alessandro; Palmeri, Sergio

    2009-09-01

    Breast cancer liver metastases (BCLM) are not uncommon (about 18% of cases): although some patients have been reported as still living after 25 months, median survival after hormonal- or chemotherapy is 6-14 months. In recent years, new chemotherapy regimens and molecular targeted therapies have given medical oncologists reason to believe that metastatic disease can be eradicated, or at least controlled for prolonged periods. In an attempt to improve survival, consideration has also been given to loco-regional treatments such as hepatic resection and radio-frequency ablation, which have been associated with better outcomes in selected patients. This review considers the role of two loco-regional approaches in a multidisciplinary perspective in the treatment of single or multiple breast cancer metastases limited to the liver. An expanded role for hepatic resection and ablation is being investigated. We assessed available data in the literature to determine their role on survival outcomes. They suggest that loco-regional treatments might be of significant benefit in a selected group of women with BCLM, but the role of these local treatments in multimodality treatment of liver metastases remains controversial. It can generally be said that loco-regional treatments can improve overall survival, with no mortality and less than 20% morbidity in patients at low surgical risk; however, they should only be considered cytoreductive treatments and, as such, always need to be integrated with systemic therapy.

  7. Molecular and cellular alterations in tobacco smoke-associated larynx cancer.

    PubMed

    Szyfter, K; Szmeja, Z; Szyfter, W; Hemminki, K; Banaszewski, J; Jaskuła-Sztul, R; Louhelainen, J

    1999-09-30

    Tumours of head and neck belong to the most frequent types of cancer world-wide. In Poland, mortality from larynx cancer among males has been continuously increasing during the last decades up to 8.4 deaths per 100,000 men in 1993, which exceeds epidemiological records from other countries. The aetiology of laryngeal cancer is strongly associated with exposure to carcinogens present in tobacco smoke. The review describes a sequence of molecular and cellular events from carcinogenic exposure, DNA adduct formation, detection of mutations in the p53 gene, loss of heterozygosity (LOH) in chromosomal loci encoding the p53 and p16 genes, and loss of control of the cell cycle. The section concerning DNA adducts includes a discussion of the role of such confounders as exogenous exposure, the age and sex of the subject, and disease progression. The significance of genetic factors as individual risk determinants is discussed in relation to bleomycin-induced chromosome instability and in connection with the occurrence of defects in genes encoding detoxifying enzymes. The question concerning the substantial difference between men and women in larynx cancer morbidity and mortality remains open, even when the significantly higher adduct formation in male DNA compared with female material was taken into account. Preliminary experiments suggest a role of the frequently observed loss of the Y-chromosome.

  8. Estimating cancer survival and clinical outcome based on genetic tumor progression scores.

    PubMed

    Rahnenführer, Jörg; Beerenwinkel, Niko; Schulz, Wolfgang A; Hartmann, Christian; von Deimling, Andreas; Wullich, Bernd; Lengauer, Thomas

    2005-05-15

    In cancer research, prediction of time to death or relapse is important for a meaningful tumor classification and selecting appropriate therapies. Survival prognosis is typically based on clinical and histological parameters. There is increasing interest in identifying genetic markers that better capture the status of a tumor in order to improve on existing predictions. The accumulation of genetic alterations during tumor progression can be used for the assessment of the genetic status of the tumor. For modeling dependences between the genetic events, evolutionary tree models have been applied. Mixture models of oncogenetic trees provide a probabilistic framework for the estimation of typical pathogenetic routes. From these models we derive a genetic progression score (GPS) that estimates the genetic status of a tumor. GPS is calculated for glioblastoma patients from loss of heterozygosity measurements and for prostate cancer patients from comparative genomic hybridization measurements. Cox proportional hazard models are then fitted to observed survival times of glioblastoma patients and to times until PSA relapse following radical prostatectomy of prostate cancer patients. It turns out that the genetically defined GPS is predictive even after adjustment for classical clinical markers and thus can be c