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Sample records for cancer loss-of-heterozygosity region

  1. 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...

  2. 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.

  3. A map of nuclear matrix attachment regions within the breast cancer loss-of-heterozygosity region on human chromosome 16q22.1.

    PubMed

    Shaposhnikov, Sergey A; Akopov, Sergey B; Chernov, Igor P; Thomsen, Preben D; Joergensen, Claus; Collins, Andrew R; Frengen, Eirik; Nikolaev, Lev G

    2007-03-01

    There is abundant evidence that the DNA in eukaryotic cells is organized into loop domains that represent basic structural and functional units of chromatin packaging. To explore the DNA domain organization of the breast cancer loss-of-heterozygosity region on human chromosome 16q22.1, we have identified a significant portion of the scaffold/matrix attachment regions (S/MARs) within this region. Forty independent putative S/MAR elements were assigned within the 16q22.1 locus. More than 90% of these S/MARs are AT rich, with GC contents as low as 27% in 2 cases. Thirty-nine (98%) of the S/MARs are located within genes and 36 (90%) in gene introns, of which 15 are in first introns of different genes. The clear tendency of S/MARs from this region to be located within the introns suggests their regulatory role. The S/MAR resource constructed may contribute to an understanding of how the genes in the region are regulated and of how the structural architecture and functional organization of the DNA are related. PMID:17188460

  4. 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.

  5. 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

  6. Loss of heterozygosity on chromosome arm 16q in breast cancer metastases.

    PubMed

    Driouch, K; Dorion-Bonnet, F; Briffod, M; Champéme, M H; Longy, M; Lidereau, R

    1997-07-01

    One of the main genetic abnormalities associated with breast carcinogenesis is the loss of genetic material from chromosome arm 16q. Different groups have identified two regions (16q22.1 and 16q24-ter) that are frequently deleted in primary tumors, suggesting the presence of tumor suppressor genes in these regions. Little is known about the late stages of tumor progression in this respect, and we, therefore, analyzed biopsy specimens of breast cancer metastases for deletions in these critical regions of 16q. We examined fine needle cytopunctures from 24 metastases, each with lymphocyte DNA, for allelic imbalance on 16q by means of polymerase chain reaction (PCR) with 15 highly polymorphic markers. All the metastatic samples showed deletion of at least one informative locus on 16q. The loss of heterozygosity (LOH) pattern often indicated the loss of a complete long arm of chromosome 16 (13 cases); nevertheless, in the remaining 11 samples, partial LOH patterns were observed. A small region of overlap (SR02) in 16q22.1 was frequently involved, whereas another (SR01) in 16q24-ter was affected in only two cases. A third region of LOH in 16q22.2-q23.2 was found in 6/11 samples. These results suggest that at least three different regions are involved in allelic imbalance on chromosome arm 16q in breast cancer. Loss of material from the third region could be a major event in the genesis of metastases. PMID:9219000

  7. Loss of heterozygosity at chromosome 16q in prostate adenocarcinoma: identification of three independent regions.

    PubMed

    Latil, A; Cussenot, O; Fournier, G; Driouch, K; Lidereau, R

    1997-03-15

    Loss of heterozygosity (LOH) on chromosome arm 16q is one of the most consistent genetic alterations in sporadic prostate cancer and may be involved in cancer development through inactivation of tumor suppressor genes. A candidate tumor suppressor gene on this chromosome arm, CDH1 at 16q22.1, is dysregulated in prostate cancer. However, no specific deletion map has been constructed from prostate tumors to determine whether CDH1 is the potential target gene for the observed LOH on 16q. To narrow down the region of 16q loss, we constructed a detailed deletion map that incorporates CDH1. We examined the pattern of allelic imbalance in prostate tissue from 22 patients with confined prostate tumors, 22 with local extracapsular extension, and 15 with metastatic forms, using 14 CA microsatellite repeats on 16q. Thirty-five of the 59 tumors tested showed LOH for at least one marker. We found evidence of 16q monosomy in 5 cases and partial allelic loss in 30. Our data provide evidence that three different target regions on 16q might be involved in the pathogenesis of prostate cancer. The first region is telomeric and lies at 16q24.3 between markers D16S520 and D16S413; the second, the most centromeric region in the 16q22.1 band, and limited by markers D16S347 and D16S318, is close to the CDH1 gene; the third, intermediate region, at 16q23.2, is bracketed by loci D16S518 and D16S507. The rate of LOH at 16q24.3 was significantly higher in metastatic forms (80%; 12 of 15) than localized forms (32%; 7 of 22), pointing to a gene related to invasiveness in prostate cancer. PMID:9067271

  8. Loss of heterozygosity at the BRCA1 locus in Tunisian women with sporadic breast cancer.

    PubMed

    Charef-Hamza, Sameh; Trimeche, Mounir; Ziadi, Sonia; Amara, Khaled; Gaddas, Naim; Mokni, Moncef; Sriha, Badreddine; Yacoubi, Tahar; Korbi, Sadok

    2005-06-28

    Breast cancer in Tunisia is characterized by a much higher incidence of aggressiveness compared with Western countries. The pattern of allelic loss at the BRCA1 locus in Tunisian women with breast carcinoma has not been studied. Therefore, the aim of this present preliminary study was mainly focused on loss of heterozygosity (LOH) analysis of the BRCA1 gene to determine if this tumor suppressor gene is involved in sporadic breast carcinoma among Tunisian women. We investigate allelic losses by analyzing three microsatellite markers in the BRCA1 region, in a panel of 21 human breast tumors. D17S1322 marker had the highest frequency of LOH (59%), followed by the D17S1323 (35%), and EDH-17B (20%). Collectively out of 21 informative cases 13 (62%) showed LOH at at least one BRCA1 locus. This data provides evidence that allelic loss at BRCA1 is a frequent event in sporadic breast tumorigenesis among Tunisian women, and suggests that the BRCA1 gene might play an important role as a tumor suppressor gene. PMID:15914269

  9. Imprinted survival genes preclude loss of heterozygosity of chromosome 7 in cancer cells.

    PubMed

    Boot, Arnoud; Oosting, Jan; de Miranda, Noel Fcc; Zhang, Yinghui; Corver, Willem E; van de Water, Bob; Morreau, Hans; van Wezel, Tom

    2016-09-01

    The genomes of a wide range of cancers, including colon, breast, and thyroid cancers, frequently show copy number gains of chromosome 7 and rarely show loss of heterozygosity. The molecular basis for this phenomenon is unknown. Strikingly, oncocytic follicular thyroid carcinomas can display an extreme genomic profile, with homozygosity of all chromosomes except for chromosome 7. The observation that homozygosity of chromosome 7 is never observed suggests that retention of heterozygosity is essential for cells. We hypothesized that cell survival genes are genetically imprinted on either of two copies of chromosome 7, which thwarts loss of heterozygosity at this chromosome in cancer cells. By employing a DNA methylation screen and gene expression analysis, we identified six imprinted genes that force retention of heterozygosity on chromosome 7. Subsequent knockdown of gene expression showed that CALCR, COPG2, GRB10, KLF14, MEST, and PEG10 were essential for cancer cell survival, resulting in reduced cell proliferation, G1 -phase arrest, and increased apoptosis. We propose that imprinted cell survival genes provide a genetic basis for retention of chromosome 7 heterozygosity in cancer cells. The monoallelically expressed cell survival genes identified in this study, and the cellular pathways that they are involved in, offer new therapeutic targets for the treatment of tumours showing retention of heterozygosity on chromosome 7. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27265324

  10. Copy neutral loss of heterozygosity is more frequent in older ovarian cancer patients

    PubMed Central

    Pedersen, Brent; Konstantinopoulos, Panagiotis A.; Spillman, Monique A.; De, Subhajyoti

    2013-01-01

    Loss of heterozygosity (LOH) is a common type of genomic alterations in ovarian cancer. Analyzing 74,415 copy neutral LOH events in 513 serous ovarian adenocarcinomas samples from the Cancer Genome Atlas, we report that the frequency of LOH events increases with age. Similar trend is observed for chromosome 17, which is frequently implicated in ovarian cancer. The results are consistent when we analyze data from the Boston High-grade serous cancer (HGSC) cohort. We further show that germ line and somatic mutations in BRCA1 (in chromosome 17) and BRCA2 (in chromosome 13) loci are not necessary to establish the pattern. We also report significant age-related changes in expression patterns for several genes in the homologous recombination (HR) pathway such as BRCA1, RAD50, RAD52, XRCC2, XRCC3, and MRE11A in these patient samples. Furthermore, we develop a metric for pathway-level imbalance, and show that increased imbalance in the HR pathway i.e. increase in expression of some HR genes and decrease in expression of others - is common, and correlates significantly with the frequency of LOH events in the patient samples. Taken together, it is highly likely that aging and deregulation of HR pathway contribute to the increased incidence of copy-neutral loss of heterozygosity in ovarian cancer patients. PMID:23716468

  11. Loss of heterozygosity and transcriptome analyses of a 1.2 Mb candidate ovarian cancer tumor suppressor locus region at 17q25.1-q25.2.

    PubMed

    Presneau, Nadège; Dewar, Ken; Forgetta, Vince; Provencher, Diane; Mes-Masson, Anne-Marie; Tonin, Patricia N

    2005-07-01

    Loss of heterozygosity (LOH) analysis was performed in epithelial ovarian cancers (EOC) to further characterize a previously identified candidate tumor suppressor gene (TSG) region encompassing D17S801 at chromosomal region 17q25.1. LOH of at least one informative marker was observed for 100 (71%) of 140 malignant EOC samples in an analysis of 6 polymorphic markers (cen-D17S1839-D17S785-D17S1817-D17S801-D17S751-D17S722-tel). The combined LOH analysis revealed a 453 kilobase (Kb) minimal region of deletion (MRD) bounded by D17S1817 and D17S751. Human and mouse genome assemblies were used to resolve marker inconsistencies in the D17S1839-D17S722 interval and identify candidates. The region contains 32 known and strongly predicted genes, 9 of which overlap the MRD. The reference genomic sequences share nearly identical gene structures and the organization of the region is highly collinear. Although, the region does not show any large internal duplications, a 1.5 Kb inverted duplicated sequence of 87% nucleotide identity was observed in a 13 Kb region surrounding D17S801. Transcriptome analysis by Affymetrix GeneChip and reverse transcription (RT)-polymerase chain reaction (PCR) methods of 3 well characterized EOC cell lines and primary cultures of normal ovarian surface epithelial (NOSE) cells was performed with 32 candidates spanning D17S1839-D17S722 interval. RT-PCR analysis of 8 known or strongly predicted genes residing in the MRD in 10 EOC samples, that exhibited LOH of the MRD, identified FLJ22341 as a strong candidate TSG. The proximal repeat sequence of D17S801 occurs 8 Kb upstream of the putative promoter region of FLJ22341. RT-PCR analysis of the EOC samples and cell lines identified DKFZP434P0316 that maps proximal to the MRD, as a candidate. While Affymetrix technology was useful for initially eliminating less promising candidates, subsequent RT-PCR analysis of well-characterized EOC samples was essential to prioritize TSG candidates for further study

  12. 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.

  13. Loss of heterozygosity on chromosomes 17 and 18 in breast carcinoma: two additional regions identified.

    PubMed Central

    Cropp, C S; Lidereau, R; Campbell, G; Champene, M H; Callahan, R

    1990-01-01

    The loss of heterozygosity (LOH) at specific regions of the human genome in tumor DNA is recognized as evidence for a tumor-suppressor gene located within the corresponding region of the homologous chromosome. Restriction fragment length polymorphism analysis of a panel of primary human breast tumor DNAs has led to the identification of two additional regions on chromosomes 17q and 18q that frequently are affected by LOH. Deletions of each of these regions have a significant correlation with clinical parameters that are associated with aggressive breast carcinomas. Previous restriction fragment length polymorphism analysis of this panel of tumors has uncovered several other frequently occurring mutations. LOH on chromosome 18q frequently occurs in tumors with concomitant LOH of loci on chromosomes 17p and 11p. Similarly, tumors having LOH on 17q also have LOH on chromosomes 1p and 3p. This suggests that certain combinations of mutations may collaborate in the development and malignant progression of breast carcinomas. Images PMID:1977164

  14. M6P/IGF2R loss of heterozygosity in head and neck cancer associated with poor patient prognosis

    PubMed Central

    Jamieson, Timothy A; Brizel, David M; Killian, J Keith; Oka, Yoshihiko; Jang, Hong-Seok; Fu, Xiaolong; Clough, Robert W; Vollmer, Robin T; Anscher, Mitchell S; Jirtle, Randy L

    2003-01-01

    Background The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes for a multifunctional receptor involved in lysosomal enzyme trafficking, fetal organogenesis, cytotoxic T cell-induced apoptosis and tumor suppression. The purpose of this investigation was to determine if the M6P/IGF2R tumor suppressor gene is mutated in human head and neck cancer, and if allelic loss is associated with poor patient prognosis. Methods M6P/IGF2R loss of heterozygosity in locally advanced squamous cell carcinoma of the head and neck was assessed with six different gene-specific nucleotide polymorphisms. The patients studied were enrolled in a phase 3 trial of twice daily radiotherapy with or without concurrent chemotherapy; median follow-up for surviving patients is 76 months. Results M6P/IGF2R was polymorphic in 64% (56/87) of patients, and 54% (30/56) of the tumors in these informative patients had loss of heterozygosity. M6P/IGF2R loss of heterozygosity was associated with a significantly reduced 5 year relapse-free survival (23% vs. 69%, p = 0.02), locoregional control (34% vs. 75%, p = 0.03) and cause specific survival (29% vs. 75%, p = 0.02) in the patients treated with radiotherapy alone. Concomitant chemotherapy resulted in a better outcome when compared to radiotherapy alone only in those patients whose tumors had M6P/IGF2R loss of heterozygosity. Conclusions This study provides the first evidence that M6P/IGF2R loss of heterozygosity predicts for poor therapeutic outcome in patients treated with radiotherapy alone. Our findings also indicate that head and neck cancer patients with M6P/IGF2R allelic loss benefit most from concurrent chemotherapy. PMID:12589712

  15. 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

  16. High incidence of microsatellite instability and loss of heterozygosity in three loci in breast cancer patients receiving chemotherapy: a prospective study

    PubMed Central

    2012-01-01

    Background The aim of the study was to evaluate potential chemotherapy-induced microsatellite instability, loss of heterozygosity, loss of expression in mismatch repair proteins and associations with clinical findings in breast cancer patients, especially resistance to chemotherapy and/or development of other tumors in the four years following chemotherapy treatment. Methods A comprehensive study of chemotherapy-related effects with a follow-up period of 48 months post treatment was conducted. A total of 369 peripheral blood samples were collected from 123 de novo breast cancer patients. Microsatellite instability and loss of heterozygosity in five commonly used marker loci (including Tp53-Alu of the tumor suppressor gene TP53) were analyzed in blood samples. Sampling was conducted on three occasions; 4–5 weeks prior to the first chemotherapy session (pre-treatment), to serve as a baseline, followed by two consecutive draws at 12 weeks intervals from the first collection. Mismatch repair protein expression was evaluated in cancer tissues using immunohistochemistry for three mismatch-repair related proteins. Results A total of 70.7% of the patients showed microsatellite instability for at least one locus, including 18.6% marked as high-positive and 52.1% as low-positive; 35.8% showed loss of heterozygosity in addition to microsatellite instability, while 29.3% exhibited microsatellite stability. The following incidence rates for microsatellite instability and loss of heterozygosity were detected: 39.1% positive for Tp53-Alu, 31.1% for locus Mfd41, and 25.3% for locus Mfd28. A higher occurrence of loss of heterozygosity was noted with alleles 399 and 404 of Tp53-Alu. The mismatch repair protein expression analysis showed that the chemotherapy caused a loss of 29.3% in hMLH1 expression, and 18.7% and 25.2% loss in hMSH2 and P53 expression, respectively. A strong correlation between low or deficient hMSH2 protein expression and occurrence of mismatch repair/loss

  17. Genotyping of the polymorphic N-acetyltransferase (NAT2) and loss of heterozygosity in bladder cancer patients.

    PubMed

    Schnakenberg, E; Ehlers, C; Feyerabend, W; Werdin, R; Hübotter, R; Dreikorn, K; Schloot, W

    1998-05-01

    Acetylation is one of the major routes in metabolism and detoxification of a large number of drugs, chemicals and carcinogens. Slow acetylators are said to be more susceptible to developing bladder cancer and because of investigations about tumor risk based on phenotyping procedures, it was our aim to study the distribution of allelic constellations of the N-acetyltransferase (NAT2) by genotyping patients with bladder cancer. We analysed NAT2 gene of blood and tumor DNA from 60 patients with primary bladder cancer and DNA of blood samples from 154 healthy individuals. Using ASO-PCR/RFLP techniques we identified 70% of patients with bladder cancer (n = 42) to be slow acetylators while genotyping of controls resulted in 61% with slow acetylators (n = 94). In addition, dividing bladder cancer patients in males and females the genotype NAT2*5B/NAT2*6A occured with much higher frequencies in males (OR = 4, 95%); CI = 1.8-8.9). Furthermore, investigating bladder cancer tissues we could detect loss of heterozygosity (LOH) in slow and rapid acetylator genotypes. In eleven out of 60 tumor samples (18.3%) we observed allelic loss at the NAT2 locus while in control DNA of blood from the same patients both alleles were still detectable. PMID:9660060

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

    PubMed

    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. Genetic variants in the HER2 gene: Influence on HER2 overexpression and loss of heterozygosity in breast cancer.

    PubMed

    Cresti, Nicola; Lee, Joanne; Rourke, Emma; Televantou, Despina; Jamieson, David; Verrill, Mark; Boddy, Alan V

    2016-03-01

    Human epidermal growth factor receptor 2 (HER2) overexpression in breast cancer is an indicator of poor prognosis and is the pre-requisite for treatment with the agents targeting this member of the epidermal growth factor receptor family. In order to determine the influence of these common single-nucleotide polymorphisms (SNPs) in the HER2 gene, genomic DNA was obtained from 361 patients with breast cancer, aged between 29 and 82 years. Samples of tumour tissue were obtained from 241 (66%) patients and material for extraction of DNA is isolated from surrounding normal tissue by laser capture microdissection. Genotyping was performed using the Taqman fluorogenic 5' nuclease assay. Of the 360 patients with definitive determination of HER2 status, 49% were positive. The Ile655Val SNP had no influence on the frequency of HER2 expression. However, the proline allele of the Ala1170Pro SNP was associated with a higher frequency of HER2 overexpression (56% versus 43%, p = 0.015). Where the germline genotype was homozygous, the tumour genotype was identical in every case and for both SNPs. In HER2-positive tumours, heterozygosity was maintained in only 15% and 18% of the Ile655Val and Ala1170Pro SNPs, respectively. This was lower than in the HER2-negative tumours (46% and 43%, respectively). Normal breast tissue (n = 23) retained the germline genotype in all but one case. The underlying link between the Ala1170Pro SNP and HER2 positivity is not known, nor is the significance of HER2 overexpression and loss of heterozygosity in breast cancer. However, these results illustrate the complexity of HER2 genotype and overexpression in this disease. PMID:26773371

  20. 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. PMID:26969202

  1. Loss of heterozygosity on the short arm of chromosome 17 is associated with high proliferative capacity and DNA aneuploidy in primary human breast cancer

    SciTech Connect

    Chen, Ling-Chun; Kurisu, W.; Smith, H.S. ); Neubauer, A.; Liu, E. ); Waldman, F.M.; Ljung, B.M.; Goodson, W. III; Goldman, E.S.; Balazs, M.; Mayall, B.H. ); Moore, D. II )

    1991-05-01

    Loss of heterozygosity (LOH) on the short arm of chromosome 17 (17p) was found in 27 of 52 (52%) previously untreated primary breast cancers. There was a significant correlation between this 17p allelic loss and two parameters associated with aggressive tumor behavior: high cellular proliferative fraction and DNA aneuploidy. These correlations with high cellular proliferative fraction and DNA aneuploidy were not found in tumors with LOH at nine other chromosome locations. The p53 gene, a putative tumor suppressor gene located at 17p13, was examined for aberrations to determine whether it is the target for the 17p LOH in breast cancer. Unlike other types of human cancer, there were no homozygous deletions or rearrangements of the p53 gene, and only 2 of 13 (15%) were mutated in the conserved region where mutational hot spots have been previously located. Therefore, the authors hypothesize that, in breast cancer, either loss of inactivation of gene(s) on chromosome 17p other than the p53 gene or a different mechanism of p53 gene inactivation may be responsible for the observed mechanism high labeling index and DNA aneuploidy associated with LOH at 17p.

  2. 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

  3. Analysis of loss of heterozygosity in circulating DNA.

    PubMed

    Nakamura, Takeshi; Sunami, Eiji; Nguyen, Tuny; Hoon, Dave S B

    2009-01-01

    Analysis of genetic altera tion in circulating DNA can have clinical utility in predicting disease outcome. Loss of heterozygosity (LOH) of DNA microsatellites has been shown to occur commonly among all chromosomes in various cancers, such as melanoma, breast cancer, and lung cancer. In this protocol, we focused on the utility of LOH of microsatellite biomarkers for detection of analyzing circulating DNA. The protocol describes how PCR is performed on each patient's paired DNA samples (normal lymphocyte DNA and serum DNA) using specific microsatellite biomarkers followed by post-PCR product analysis using capillary array electrophoresis (CAE). The utility of CAE is due to its digitalization and accuracy of the post-PCR product results. PMID:19381958

  4. Loss of heterozygosity of the APC and MCC genes in squamous cell carcinoma of the head and neck

    SciTech Connect

    Nogueira, C.P.; Afridi, N.A.; Licameli, G.

    1994-09-01

    Squamous cell carcinoma of the head and neck offers a unique opportunity to study genetic mechanisms in human tumorigenesis. Two types of premalignant lesions can be identified clinically, suggesting a multistep process. The majority of the lesions are easy to identify and access. Despite these advantages, possible genetic models for these cancers remain relatively unexplored. Loss of heterozygosity of the tumor suppressor genes APC (adenomatous polyposis coli) and MCC (mutated in colon cancer) was investigated in 24 squamous cell carcinomas of the head and neck. Three sites were analyzed by assays based on the polymerase chain reaction: two RFLPs in the APC gene (Rsa I on exon 11; Ssp I on the 3{prime} untranslated region) and an insertion/deletion in exon 10 of the MCC gene. Sixty three percent of the individuals were informative for at least one marker. Loss of heterozygosity (LOH) was observed in 33% of the tumors, either at the APC or MCC locus. Two out of 11 informative tumors (18%) showed LOH on the APC gene. Three out of seven informative tumors (43%) showed LOH on the MCC gene. These results suggest that inactivation of the APC, MCC and/or a linked gene on chromosome 5q plays a important role in squamous cell carcinoma of the head and neck. The data is in agreement with another study, which detected 25% of loss of heterozygosity in the chromosomal region 5q by using microsatellite markers. These values are much lower than the ones observed in esophageal cancer, a closely related type of tumor, with the same etiology. This may be attributed to differences in the biology of these two cancers.

  5. 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.

  6. Loss of heterozygosity suggests multiple genetic alterations in pheochromocytomas and medullary thyroid carcinomas.

    PubMed Central

    Khosla, S; Patel, V M; Hay, I D; Schaid, D J; Grant, C S; van Heerden, J A; Thibodeau, S N

    1991-01-01

    Loss of heterozygosity (LOH) at specific loci may help localize tumor suppressor genes involved in the formation of various familial and sporadic tumors. In addition, the genetic loci for a number of familial tumor syndromes have been mapped by linkage analysis. To explore the possible role of tumor suppressor genes in endocrine tumors, we tested 41 pheochromocytomas (34 sporadic and 7 familial) and 11 medullary thyroid cancers (MTC) (10 sporadic and 1 familial) for LOH near a variety of potentially important genetic loci: (a) the multiple endocrine neoplasia type 2A (MEN 2A) locus on chromosome 10; (b) the von Hippel-Lindau locus on 3p; and (c) the p53 and neurofibromatosis 1 loci on 17. We also examined chromosomes 1p and 22q because previous studies in a small number of pheochromocytomas and MTCs suggested LOH in these regions. Background rates for LOH were assessed using several "random" probes. Finally, we examined a number of clinical and histologic characteristics of these tumors for possible correlations with specific genetic alterations. LOH in the region of the MEN 2A locus was uncommon (0% for MTCs, 5% for pheochromocytomas). However, we found significant allelic losses in pheochromocytomas on chromosomes 1p (42%), 3p (16%), 17p (24%), and 22q (31%). We also noted a correlation between LOH on 1p and urinary excretion of metanephrine by these patients (P = 0.02). LOH on 1p, 3p, and 17p also appeared to be associated with increased tumor volume. Analysis of the smaller number of MTCs demonstrated allelic losses on chromosomes 1p and 22q. Our results suggest that tumor formation and/or progression in pheochromocytomas and MTCs involves multiple genes, analogous with the model proposed for colon carcinoma. Images PMID:2022740

  7. 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

  8. Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis

    PubMed Central

    Jerez, Andres; Sugimoto, Yuka; Makishima, Hideki; Verma, Amit; Jankowska, Anna M.; Przychodzen, Bartlomiej; Visconte, Valeria; Tiu, Ramon V.; O'Keefe, Christine L.; Mohamedali, Azim M.; Kulasekararaj, Austin G.; Pellagatti, Andrea; McGraw, Kathy; Muramatsu, Hideki; Moliterno, Alison R.; Sekeres, Mikkael A.; McDevitt, Michael A.; Kojima, Seiji; List, Alan; Boultwood, Jacqueline; Mufti, Ghulam J.

    2012-01-01

    Loss of heterozygosity affecting chromosome 7q is common in acute myeloid leukemia and myelodysplastic syndromes, pointing toward the essential role of this region in disease phenotype and clonal evolution. The higher resolution offered by recently developed genomic platforms may be used to establish more precise clinical correlations and identify specific target genes. We analyzed a series of patients with myeloid disorders using recent genomic technologies (1458 by single-nucleotide polymorphism arrays [SNP-A], 226 by next-generation sequencing, and 183 by expression microarrays). Using SNP-A, we identified chromosome 7q loss of heterozygosity segments in 161 of 1458 patients (11%); 26% of chronic myelomonocytic leukemia patients harbored 7q uniparental disomy, of which 41% had a homozygous EZH2 mutation. In addition, we describe an SNP-A–isolated deletion 7 hypocellular myelodysplastic syndrome subset, with a high rate of progression. Using direct and parallel sequencing, we found no recurrent mutations in typically large deletion 7q and monosomy 7 patients. In contrast, we detected a markedly decreased expression of genes included in our SNP-A defined minimally deleted regions. Although a 2-hit model is present in most patients with 7q uniparental disomy and a myeloproliferative phenotype, haplodeficient expression of defined regions of 7q may underlie pathogenesis in patients with deletions and predominant dysplastic features. PMID:22553315

  9. Analysis of BRCA2 loss of heterozygosity in tumor tissue using droplet digital polymerase chain reaction.

    PubMed

    Cochran, Rory L; Cravero, Karen; Chu, David; Erlanger, Bracha; Toro, Patricia Valda; Beaver, Julia A; Zabransky, Daniel J; Wong, Hong Yuen; Cidado, Justin; Croessmann, Sarah; Parsons, Heather A; Kim, Minsoo; Wheelan, Sarah J; Argani, Pedram; Park, Ben Ho

    2014-07-01

    Loss-of-heterozygosity (LOH) analysis of archival tumor tissue can aid in determining the clinical significance of BRCA variants. Here we describe an approach for assessing LOH in formalin-fixed, paraffin-embedded (FFPE) tissues using variant-specific probes and droplet digital polymerase chain reaction (ddPCR). We evaluated LOH in 2 related breast cancer patients harboring a rare missense BRCA2 variant of unknown clinical significance (c.6966G>T; M2322I). Conventional PCR followed by Sanger sequencing suggested a change in allelic abundance in the FFPE specimens. However, we found no evidence of LOH as determined by the allelic ratio (wild type-variant) for BRCA2 in both patients' archival tumor specimens and adjacent normal control tissues using ddPCR. In summary, these experiments demonstrate the utility of ddPCR to quickly and accurately assess LOH in archival FFPE tumor tissue. PMID:24824029

  10. Genetic background influences loss of heterozygosity patterns in radiation-induced mouse thymic lymphoma

    PubMed Central

    Hang, Michael; Huang, Yurong; Snijders, Antoine M.; Mao, Jian-Hua

    2015-01-01

    Previous studies have revealed that p53 heterozygous (p53+/−) mice are extremely susceptible to radiation-induced tumorigenesis. To investigate whether genetic background influences radiation induced tumor susceptibility, we crossed p53+/− 129/Sv mice with genetically diverse strains to generate p53+/− F1 hybrids. The results showed that genetic background had a profound impact on tumor latency after exposure to gamma radiation, while the tumor spectrum did not change. We further characterized the thymic lymphomas that arose in the p53+/− mice by genome-wide loss of heterozygosity (LOH) analyses and found that genetic background strongly influenced the frequency of LOH and the loss of which parental allele on different chromosomes. Further research is needed to identify which genetic variations control the LOH patterns in radiation-induced thymic lymphomas and to evaluate its relevance to human cancers. PMID:25932465

  11. Exome sequencing-based copy-number variation and loss of heterozygosity detection: ExomeCNV

    PubMed Central

    Sathirapongsasuti, Jarupon Fah; Lee, Hane; Horst, Basil A. J.; Brunner, Georg; Cochran, Alistair J.; Binder, Scott; Quackenbush, John; Nelson, Stanley F.

    2011-01-01

    Motivation: The ability to detect copy-number variation (CNV) and loss of heterozygosity (LOH) from exome sequencing data extends the utility of this powerful approach that has mainly been used for point or small insertion/deletion detection. Results: We present ExomeCNV, a statistical method to detect CNV and LOH using depth-of-coverage and B-allele frequencies, from mapped short sequence reads, and we assess both the method's power and the effects of confounding variables. We apply our method to a cancer exome resequencing dataset. As expected, accuracy and resolution are dependent on depth-of-coverage and capture probe design. Availability: CRAN package ‘ExomeCNV’. Contact: fsathira@fas.harvard.edu; snelson@ucla.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:21828086

  12. 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

  13. Genomic alterations in nasopharyngeal carcinoma: loss of heterozygosity and Epstein-Barr virus infection.

    PubMed Central

    Mutirangura, A.; Tanunyutthawongese, C.; Pornthanakasem, W.; Kerekhanjanarong, V.; Sriuranpong, V.; Yenrudi, S.; Supiyaphun, P.; Voravud, N.

    1997-01-01

    Nasopharyngeal carcinoma is a subset of head and neck squamous cell cancers with unique endemic distribution and aetiological co-factors. Epstein-Barr virus has been revealed to be an important aetiological factor for most nasopharyngeal carcinomas. Nevertheless, additional genetic alterations may be involved in their development and progression. The aim of this study was to determine the likely chromosomal locations of tumour-suppressor genes related to Epstein-Barr virus-associated nasopharyngeal carcinoma. Fifty-six microsatellite polymorphic markers located on every autosomal arm were used to estimate the incidence of loss of heterozygosity in 27 Epstein-Barr virus-associated nasopharyngeal carcinomas. High frequencies of allelic loss were observed on chromosome 3p (75.0%) and 9p (87.0%). Chromosome 9q, 11q, 13q and 14q displayed loss in over 50%, while chromosome 3q, 6p, 16q, 19q and 22q exhibited loss in 35-50%. Furthermore, several other chromosomal arms demonstrated allelic loss in 20-35%. Additionally, 1 of the 27 cases showed microsatellite instability at multiple loci. These findings provide evidence of multiple genetic alterations during cancer development and clues for further studies of tumour-suppressor genes in Epstein-Barr virus-associated nasopharyngeal carcinoma. Images Figure 1 Figure 2 Figure 4 PMID:9310244

  14. Integrated analysis of copy number and loss of heterozygosity in primary breast carcinomas using high-density SNP array.

    PubMed

    Ching, Ho Ching; Naidu, Rakesh; Seong, Mun Kein; Har, Yip Cheng; Taib, Nur Aishah Mohd

    2011-09-01

    Breast cancer is a heterogeneous disease, marked by extensive chromosomal aberrations. In this study, we aimed to explicate the underlying chromosomal copy number (CN) alterations and loss of heterozygosity (LOH) implicated in a cohort of Malaysian hospital-based primary breast carcinoma samples using a single nucleotide polymorphism (SNP) array platform. The analysis was conducted by hybridizing the extracted DNA of 70 primary breast carcinomas and 37 normal peripheral blood samples to the Affymetrix 250K Sty SNP arrays. Locus-specific CN aberrations and LOH were statistically summarized using the binary segmentation algorithm and hidden Markov model. Selected genes from the SNP array analysis were also validated using quantitative real-time PCR. The merging of CN and LOH data fabricated distinctive integrated alteration profiles, which were comprised of finely demarcated minimal sites of aberrations. The most prevalent gains (≥ 30%) were detected at the 8q arm: 8q23.1, 8q23.3, 8q24.11, 8q24.13, 8q24.21, 8q24.22, 8q24.23 and 8q24.3, whilst the most ubiquitous losses (≥ 20%) were noted at the 8p12, 8p21.1, 8p21.2, 8p21.1-p21.2, 8p21.3, 8p22, 8p23.1, 8p23.1‑p23.2, 8p23.3, 17p11.2, 17p12, 17p11.2-p12, 17p13.1 and 17p13.2 regions. Copy-neutral LOH was characterized as the most prevailing LOH event, in which the most frequent distributions (≥ 30%) were revealed at 3p21.31, 5q33.2, 12q24.12, 12q24.12‑q24.13 and 14q23.1. These findings offer compre-hensive genome-wide views on breast cancer genomic changes, where the most recurrent gain, loss and copy-neutral LOH events were harboured within the 8q24.21, 8p21.1 and 14q23.1 loci, respectively. This will facilitate the uncovering of true driver genes pertinent to breast cancer biology and the develop-ment of prospective therapeutics. PMID:21687935

  15. 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 Central

    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. PMID:26247464

  16. 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

  17. Frequent loss of heterozygosity and altered expression of the candidate tumor suppressor gene 'FAT' in human astrocytic tumors

    PubMed Central

    2009-01-01

    Background We had earlier used the comparison of RAPD (Random Amplification of Polymorphic DNA) DNA fingerprinting profiles of tumor and corresponding normal DNA to identify genetic alterations in primary human glial tumors. This has the advantage that DNA fingerprinting identifies the genetic alterations in a manner not biased for locus. Methods In this study we used RAPD-PCR to identify novel genomic alterations in the astrocytic tumors of WHO grade II (Low Grade Diffuse Astrocytoma) and WHO Grade IV (Glioblastoma Multiforme). Loss of heterozygosity (LOH) of the altered region was studied by microsatellite and Single Nucleotide Polymorphism (SNP) markers. Expression study of the gene identified at the altered locus was done by semi-quantitative reverse-transcriptase-PCR (RT-PCR). Results Bands consistently altered in the RAPD profile of tumor DNA in a significant proportion of tumors were identified. One such 500 bp band, that was absent in the RAPD profile of 33% (4/12) of the grade II astrocytic tumors, was selected for further study. Its sequence corresponded with a region of FAT, a putative tumor suppressor gene initially identified in Drosophila. Fifty percent of a set of 40 tumors, both grade II and IV, were shown to have Loss of Heterozygosity (LOH) at this locus by microsatellite (intragenic) and by SNP markers. Semi-quantitative RT-PCR showed low FAT mRNA levels in a major subset of tumors. Conclusion These results point to a role of the FAT in astrocytic tumorigenesis and demonstrate the use of RAPD analysis in identifying specific alterations in astrocytic tumors. PMID:19126244

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

    ScienceCinema

    Mudge, Joanne [NCGR

    2013-03-22

    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.

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

    SciTech Connect

    Mudge, Joanne

    2012-06-01

    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.

  20. 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. PMID:24407298

  1. Comparative genomic hybridization in childhood acute lymphoblastic leukemia: correlation with interphase cytogenetics and loss of heterozygosity analysis.

    PubMed

    Scholz, I; Popp, S; Granzow, M; Schoell, B; Holtgreve-Grez, H; Takeuchi, S; Schrappe, M; Harbott, J; Teigler-Schlegel, A; Zimmermann, M; Fischer, C; Koeffler, H P; Bartram, C R; Jauch, A

    2001-01-15

    We used comparative genomic hybridization (CGH) to study DNA copy number changes in 71 children with acute lymphoblastic leukemia (ALL) including 50 B-lineage and 21 T-ALLs. Forty-two patients (59%) showed genomic imbalances whereby gains were more frequently observed than losses (127 vs. 29). Gains most commonly affected the entire chromosomes 21 and 10 (19.7% each), 6, 14, 18, X (15.5% each), 17 (14.1%) and 4 (11.3%). Highly hyperdiploid karyotypes (chromosome number >50) occurred more frequently in B-lineage than in T-lineage ALL (24% vs. 4.8%). In both cell lineages deletions were mainly detected on 9p (14.1%) and 12p (8.4%), and on 6q in T-lineage ALL (4.2%). These findings were compared with loss of heterozygosity (LOH) of 6q, 9p, 11q, and 12p previously performed in 56 of the 71 patients. Among 54 sites of LOH, CGH revealed losses of the respective chromosome arms in 17 LOH-positive regions (31.5%). G-banding analysis and interphase cytogenetics with subregional probes for 14 loci confirmed the presence of genomic imbalances as detected by CGH. We, therefore, conclude that, in the absence of cytogenetic data, CGH represents a suitable method for identifying hyperdiploid karyotypes as well as prognostically relevant deletions in ALL patients. PMID:11172898

  2. Carcinoma ex spiradenoma/cylindroma confirmed by immunohistochemical and molecular loss-of-heterozygosity profiling.

    PubMed

    Jukic, Drazen M; Drogowski, Laura M; Davie, James R

    2009-10-01

    We present a case of spiradenoma/cylindroma with admixed carcinoma of unknown origin, resolved using immunohistochemical and molecular loss-of-heterozygosity (LOH) profiling. The patient, a woman in her mid-70s, initially presented with separate mammary (ductal) carcinomas of the right and left breasts that were treated with radical mastectomies. For 9 years, the patient remained disease free until complaining of a slow-growing skin nodule on the lower back that was excised under clinical suspicion of metastatic mammary carcinoma. Histopathological exam revealed a benign eccrine spiradenoma/cylindroma and an intermixed carcinoma, with a differential diagnosis of either primary eccrine carcinoma or mammary carcinoma metastatic to the spiradenoma/cylindroma. Histological features and immunohistochemical staining favored eccrine carcinoma but not unequivocally; therefore, LOH profiles were performed on archival paraffin block tissue from the 3 neoplastic lesions (4 components). The mammary carcinomas showed disparate LOH at 5 of 7 (right breast) and 4 of 7 (left breast) informative genetic loci, establishing these carcinomas as separate primary neoplasms. Both the spiradenoma/cylindroma and eccrine carcinoma revealed no LOH at the tested loci, establishing the unknown carcinoma as an independent carcinoma arising within a spiradenoma/cylindroma. This neoplasm is referred to in the literature as carcinoma ex spiradenoma/cylindroma and spiradenocylindrocarcinoma. PMID:19684510

  3. Loss of heterozygosity drives clonal diversity of Phytophthora capsici in China.

    PubMed

    Hu, Jian; Diao, Yongzhao; Zhou, Yuxin; Lin, Dong; Bi, Yang; Pang, Zhili; Trout Fryxell, Rebecca; Liu, Xili; Lamour, Kurt

    2013-01-01

    Phytophthora capsici causes significant loss to pepper (Capsicum annum) in China and our goal was to develop single nucleotide polymorphism (SNP) markers for P. capsici and characterize genetic diversity nationwide. Eighteen isolates of P. capsici from locations worldwide were re-sequenced and candidate nuclear and mitochondrial SNPs identified. From 2006 to 2012, 276 isolates of P. capsici were recovered from 136 locations in 27 provinces and genotyped using 45 nuclear and 2 mitochondrial SNPs. There were two main mitochondrial haplotypes and 95 multi-locus genotypes (MLGs) identified. Genetic diversity was geographically structured with a high level of genotypic diversity in the north and on Hainan Island in the south, suggesting outcrossing contributes to diversity in these areas. The remaining areas of China are dominated by four clonal lineages that share mitochondrial haplotypes, are almost exclusively the A1 or A2 mating type and appear to exhibit extensive diversity based on loss of heterozygosity (LOH). Analysis of SNPs directly from infected peppers confirmed LOH in field populations. One clonal lineage is dominant throughout much of the country. The overall implications for long-lived genetically diverse clonal lineages amidst a widely dispersed sexual population are discussed. PMID:24349339

  4. Copy neutral loss of heterozygosity in 20q in chronic lymphocytic leukemia/small lymphocytic lymphoma

    PubMed Central

    Pei, Jianming; Robu, Valentin; Feder, Madelyn; Cheung, Mitchell; Neumann-Domer, Erin; Talarchek, Jacqueline; Dulaimi, Essel; Millenson, Michael M.; Testa, Joseph R.

    2014-01-01

    Single nucleotide polymorphism (SNP)-based chromosome microarray analysis was used to uncover copy neutral loss of heterozygosity (LOH) in the long arm of chromosome 20 in blood or bone marrow specimens from three patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). All three patients presented with lymph node enlargement. While one of the patients has had a complicated clinical course, the other two have a more indolent disease. Sequence analysis of the tumor suppressor gene ASXL1, which is located in 20q and is commonly mutated in malignant myeloid diseases and occasionally in CLL/SLL specimens, revealed no mutations in our three patients with copy neutral LOH in 20q. The possible contribution of other imprinted microRNAs and antisense genes residing in 20q to the pathogenesis of a subset of CLL/SLL patients is discussed. These findings illustrate the value of SNP arrays for the detection of novel recurrent genomic alterations that may contribute to CLL/SLL onset or progression. PMID:24704113

  5. 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.

  6. Tight association of loss of merlin expression with loss of heterozygosity at chromosome 22q in sporadic meningiomas.

    PubMed

    Ueki, K; Wen-Bin, C; Narita, Y; Asai, A; Kirino, T

    1999-12-01

    Mutations of NF2, the gene for neurofibromatosis 2, are detected in 20-30% of sporadic meningiomas, and almost all mutations lead to loss of merlin expression. However, loss of heterozygosity (LOH) at chromosome 22q is found at a much higher frequency, up to 50-70%, and the possibility of another tumor suppressor gene in this region has not been excluded. Furthermore, a recent report proposed that abnormal activation of a protease micro-calpain can be an alternative pathway for merlin loss in meningiomas and schwannomas. To determine the correlation of merlin loss with NF2 genetic alteration or micro-calpain activation, we performed a molecular genetic analysis of 50 sporadic meningiomas and also examined the expression status of merlin and active form micro-calpain. LOH assay of five microsatellite markers franking NF2 revealed LOH in 22 cases, and single-strand conformation polymorphism assay detected six frameshift mutations, two splicing mutations, one nonsense mutation, and one missense mutation, all accompanied by 22q LOH. In addition, a multiplex PCR assay indicated homozygous deletion of NF2 in two cases. Interestingly, a marked decrease of merlin expression was seen exclusively in the 22 cases with 22q LOH. Activated micro-calpain expression was observed in 28 cases at various levels but showed no correlation with merlin status. These data strongly support the notion that NF2 is the sole target of 22q LOH in meningiomas and that loss of merlin expression is always caused by genetic alteration of NF2, following the classic "two hit" theory. PMID:10606247

  7. 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.

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

    PubMed Central

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

    1994-01-01

    Neuroblastomas often show loss of heterozygosity of the chromosomal region 1p36 (LOH 1p), probably reflecting loss of a tumor-suppressor gene. Here we 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. Images Figure 1 Figure 2 Figure 3 PMID:8037211

  9. Loss of heterozygosity on chromosome 10q23 and mutation of the phosphatase and tensin homolog deleted from chromosome 10 tumor suppressor gene in Korean hepatocellular carcinoma patients.

    PubMed

    Bae, Jei-Jun; Rho, Jin-Woo; Lee, Tae-Jin; Yun, Sung-Su; Kim, Hong-Jin; Choi, Joon-Hyuk; Jeong, Daewon; Jang, Byeong-Churl; Lee, Tae-Yoon

    2007-10-01

    Loss of heterozygosity (LOH) in the 10q23 chromosomal region was analyzed in 18 tissue samples from Korean hepatocellular carcinoma (HCC) patients. LOH at the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) region (D10S215, AFMa086wg9 and D10S541) was found in 8 of the 18 (44.4%) HCCs. LOH (20%) and microsatellite instability (26.7%) were also frequently found at the D10S2177 locus, which is located on the telomere side of the PTEN region. LOH was found in other loci, such as AFM280we1 and D10S2281. The presence of LOH in regions other than the PTEN region on chromosome 10q23 suggested the presence of additional tumor suppressor gene(s). PTEN mutation was found in only a subset of HCCs: A single base insertion at the end of the 5'-end splice signal (AG-GUAAGUU) in intron 5 and a silent mutation in exon 6 (codon 188, CTG-Val to CTA). Our data collectively suggest that the genetic alterations of chromosome 10q23, including the PTEN gene, could be important in hepatocarcinogenesis in the Korean population. PMID:17786367

  10. Patterns of loss of heterozygosity in breast carcinoma during neoadjuvant chemotherapy.

    PubMed

    Oudin, Claire; Bonnetain, Frank; Boidot, Romain; Végran, Frédérique; Soubeyrand, Marie-Sophie; Arnould, Laurent; Riedinger, Jean-Marc; Lizard-Nacol, Sarab

    2007-05-01

    There is evidence indicating that resistance to some chemotherapy drugs is related to enhanced repair of DNA lesions. Microsatellite instability (MSI) and loss of heterozy-gosity (LOH) reflect genetic instability and are associated with specific DNA repair pathways. Despite the strong implication of genetic instability in breast cancer its association with chemotherapy is unknown. Thus, we analyzed microsatellite alterations with 12 markers in locally advanced breast carcinomas in relation to neoadjuvant epirubicin-cyclophosphamide-containing chemotherapy (FEC-100) and compared it to a docetaxol-based (Tax-Epi) regimen. Samples were obtained before, during and after treatments. In pre-treated samples, MSI was detected only in 2 cases (7%) whereas LOH was found in 23 of the 34 (68%) carcinomas including 10 belonging to the FEC-100 group and 13 to Tax-Epi one. LOH frequency decreased from the first course of both regimens, but differences between the patterns of LOH during treatment were found. Persistent LOH was more frequent in FEC-100 group (71% vs. 41%) that was detected only in biopsies belonging to non-responder patients. Persistent LOH were clustered at particular loci located at regions containing common fragile sites (FHIT and FRA6E). Analysis of baseline LOH with 6 markers located at 3p indicates discontinuous patterns reflecting double-strand break (DSB) lesions. These results agree with a drug-dependent link between genetic instability and chemoresistance and show that FEC-100 treatment is associated with DSB accumulation manifested as LOH in tumor cells resistant to chemotherapy in breast carcinoma. PMID:17390016

  11. 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. PMID:23445872

  12. Identification of germline DICER1 mutations and loss of heterozygosity in familial Wilms tumour.

    PubMed

    Palculict, Timothy Blake; Ruteshouser, E Cristy; Fan, Yu; Wang, Wenyi; Strong, Louise; Huff, Vicki

    2016-06-01

    Wilms tumour (WT), a paediatric renal cancer, is the most common childhood kidney cancer. The aetiology of WT is heterogeneous with multiple genes known to result in WT tumorigenesis. However, these genes are rarely associated with familial Wilms tumour (FWT). To identify mutations predisposing to FWT, we performed whole-genome sequencing using genomic DNA from three affected/obligate carriers in a large WT family, followed by Sanger sequencing of candidate gene mutations in 47 additional WT families to determine their frequency in FWT. As a result, we identified two novel germline DICER1 mutations (G803R and R800Xfs5) co-segregating in two families, thus expanding the number of reported WT families with unique germline DICER1 mutations. The one large family was found to include individuals with multiple DICER1 syndrome phenotypes, including four WT cases. Interestingly, carriers of the DICER1 mutation displayed a greatly increased frequency of WT development compared with the penetrance observed in previously published pedigrees. Also uniquely, in one tumour this DICER1 mutant allele (G803R) was reduced to homozygosity in contrast to the somatic hotspot mutations typically observed in tumours in DICER1 families. PMID:26566882

  13. 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.

  14. Phenotypic Consequences of a Spontaneous Loss of Heterozygosity in a Common Laboratory Strain of Candida albicans.

    PubMed

    Ciudad, Toni; Hickman, Meleah; Bellido, Alberto; Berman, Judith; Larriba, Germán

    2016-07-01

    By testing the susceptibility to DNA damaging agents of several Candida albicans mutant strains derived from the commonly used laboratory strain, CAI4, we uncovered sensitivity to methyl methanesulfonate (MMS) in CAI4 and its derivatives, but not in CAF2-1. This sensitivity is not a result of URA3 disruption because the phenotype was not restored after URA3 reintroduction. Rather, we found that homozygosis of a short region of chromosome 3R (Chr3R), which is naturally heterozygous in the MMS-resistant-related strains CAF4-2 and CAF2-1, confers MMS sensitivity and modulates growth polarization in response to MMS. Furthermore, induction of homozygosity in this region in CAF2-1 or CAF4-2 resulted in MMS sensitivity. We identified 11 genes by SNP/comparative genomic hybridization containing only the a alleles in all the MMS-sensitive strains. Four candidate genes, SNF5, POL1, orf19.5854.1, and MBP1, were analyzed by generating hemizygous configurations in CAF2-1 and CAF4-2 for each allele of all four genes. Only hemizygous MBP1a/mbp1b::SAT1-FLIP strains became MMS sensitive, indicating that MBP1a in the homo- or hemizygosis state was sufficient to account for the MMS-sensitive phenotype. In yeast, Mbp1 regulates G1/S genes involved in DNA repair. A second region of homozygosis on Chr2L increased MMS sensitivity in CAI4 (Chr3R homozygous) but not CAF4-2 (Chr3R heterozygous). This is the first example of sign epistasis in C. albicans. PMID:27206717

  15. 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. PMID:22712506

  16. 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.

  17. 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

  18. Ploidy status and copy number aberrations in primary glioblastomas defined by integrated analysis of allelic ratios, signal ratios and loss of heterozygosity using 500K SNP Mapping Arrays

    PubMed Central

    Gardina, Paul J; Lo, Ken C; Lee, Walter; Cowell, John K; Turpaz, Yaron

    2008-01-01

    Background Genomic hybridization platforms, including BAC-CGH and genotyping arrays, have been used to estimate chromosome copy number (CN) in tumor samples by detecting the relative strength of genomic signal. The methods rely on the assumption that the predominant chromosomal background of the samples is diploid, an assumption that is frequently incorrect for tumor samples. In addition to generally greater resolution, an advantage of genotyping arrays over CGH arrays is the ability to detect signals from individual alleles, allowing estimation of loss-of-heterozygosity (LOH) and allelic ratios to enhance the interpretation of copy number alterations. Copy number events associated with LOH potentially have the same genetic consequences as deletions. Results We have utilized allelic ratios to detect patterns that are indicative of higher ploidy levels. An integrated analysis using allelic ratios, total signal and LOH indicates that many or most of the chromosomes from 24 glioblastoma tumors are in fact aneuploid. Some putative whole-chromosome losses actually represent trisomy, and many apparent sub-chromosomal losses are in fact relative losses against a triploid or tetraploid background. Conclusion These results suggest a re-interpretation of previous findings based only on total signal ratios. One interesting observation is that many single or multiple-copy deletions occur at common putative tumor suppressor sites subsequent to chromosomal duplication; these losses do not necessarily result in LOH, but nonetheless occur in conspicuous patterns. The 500 K Mapping array was also capable of detecting many sub-mega base losses and gains that were overlooked by CGH-BAC arrays, and was superior to CGH-BAC arrays in resolving regions of complex CN variation. PMID:18928532

  19. Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML.

    PubMed

    Stirewalt, D L; Pogosova-Agadjanyan, E L; Tsuchiya, K; Joaquin, J; Meshinchi, S

    2014-01-01

    Patients with high FLT3 internal tandem duplication allelic ratios (FLT3/ITD-ARs) have a poor prognosis. Single-nucleotide polymorphism/comparative genomic hybridization, single-cell PCR and colony-forming assays were used to evaluate genotypic evolution of high FLT3/ITD-ARs in 85 acute myeloid leukemia (AML) patients. Microarrays were used to examine molecular pathways disrupted in leukemic blasts with high FLT3/ITD-ARs. Copy-neutral loss of heterozygosity (CN-LOH) was identified at the FLT3 locus in diagnostic samples with high FLT3/ITD-ARs (N=11), but not in samples with low FLT3/ITD-ARs (N=24), FLT3-activating loop mutations (N=11) or wild-type FLT3 (N=39). Single-cell assays showed that homozygous FLT3/ITD genotype was present in subsets of leukemic blasts at diagnosis but became the dominant clone at relapse. Less differentiated CD34(+)/CD33(-) progenitor colonies were heterozygous for FLT3/ITD, whereas more differentiated CD34(+)/CD33(+) progenitor colonies were homozygous for FLT3/ITD. Expression profiling revealed that samples harboring high FLT3/ITD-ARs aberrantly expressed genes within the recombination/DNA repair pathway. Thus, the development of CN-LOH at the FLT3 locus, which results in high FLT3/ITD-ARs, likely represents a late genomic event that occurs after the acquisition of the FLT3/ITD. Although the etiology underlying the development of CN-LOH remains to be clarified, the disruption in recombination/DNA repair pathway, which is present before the development of LOH, may have a role. PMID:24786392

  20. Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML

    PubMed Central

    Stirewalt, D L; Pogosova-Agadjanyan, E L; Tsuchiya, K; Joaquin, J; Meshinchi, S

    2014-01-01

    Patients with high FLT3 internal tandem duplication allelic ratios (FLT3/ITD-ARs) have a poor prognosis. Single-nucleotide polymorphism/comparative genomic hybridization, single-cell PCR and colony-forming assays were used to evaluate genotypic evolution of high FLT3/ITD-ARs in 85 acute myeloid leukemia (AML) patients. Microarrays were used to examine molecular pathways disrupted in leukemic blasts with high FLT3/ITD-ARs. Copy-neutral loss of heterozygosity (CN-LOH) was identified at the FLT3 locus in diagnostic samples with high FLT3/ITD-ARs (N=11), but not in samples with low FLT3/ITD-ARs (N=24), FLT3-activating loop mutations (N=11) or wild-type FLT3 (N=39). Single-cell assays showed that homozygous FLT3/ITD genotype was present in subsets of leukemic blasts at diagnosis but became the dominant clone at relapse. Less differentiated CD34+/CD33− progenitor colonies were heterozygous for FLT3/ITD, whereas more differentiated CD34+/CD33+ progenitor colonies were homozygous for FLT3/ITD. Expression profiling revealed that samples harboring high FLT3/ITD-ARs aberrantly expressed genes within the recombination/DNA repair pathway. Thus, the development of CN-LOH at the FLT3 locus, which results in high FLT3/ITD-ARs, likely represents a late genomic event that occurs after the acquisition of the FLT3/ITD. Although the etiology underlying the development of CN-LOH remains to be clarified, the disruption in recombination/DNA repair pathway, which is present before the development of LOH, may have a role. PMID:24786392

  1. Effects of a Topically Applied Bioadhesive Berry Gel on Loss of Heterozygosity Indices in Premalignant Oral Lesions

    PubMed Central

    Shumway, Brian S.; Kresty, Laura A.; Larsen, Peter E.; Zwick, Jared C.; Lu, Bo; Fields, Henry W.; Mumper, Russell J.; Stoner, Gary D.; Mallery, Susan R.

    2012-01-01

    Purpose The aim of this study was to assess the effects of topical application of a 10% (w/w) freeze-dried black raspberry (FBR) gel on oral intraepithelial neoplasia (IEN) variables that included histologic diagnoses and loss of heterozygosity (LOH) indices. Microsatellite instability and/or LOH at tumor suppressor gene – associated chromosomal loci have been associated with a higher risk for oral IEN progression to oral squamous cell carcinoma. Previously, our laboratories have shown that FBRs are well tolerated and possess potent antioxidant, apoptotic, and differentiation-inducing properties. Experimental Design Each participant with IEN served as their own internal control. Before treatment, all lesions were photographed, and lesional tissue was hemisected to obtain a pretreatment diagnosis and baseline biochemical and molecular variables. Gel dosing (0.5 g applied four times daily for 6 weeks) was initiated 1 week after the initial biopsy. Genomic DNA was isolated from laser-captured basilar and suprabasilar surface epithelial cells followed by PCR amplification using primer sets that targeted known and presumed tumor suppressor gene loci associated with INK4a/ARF, p53, and FHIT. Allelic imbalance was determined by sequence analysis using normal participant tissues to establish microsatellite marker peak patterns and allele sizes. Results Confirming earlier phase I data, none of the 27 participants developed FBR gel – associated toxicities. Furthermore, our results show histologic regression in a subset of patients as well as statistically significant reduction in LOH at tumor suppressor gene – associated loci. Conclusions These preliminary data suggest that further evaluation of berry gels for oral IEN chemoprevention is warranted. PMID:18413833

  2. Microsatellite analysis of loss of heterozygosity on chromosomes 9q, 11p and 17p in medulloblastomas.

    PubMed

    Albrecht, S; von Deimling, A; Pietsch, T; Giangaspero, F; Brandner, S; Kleihues, P; Wiestler, O D

    1994-02-01

    Medulloblastoma (MB) is a primitive neuroectodermal tumour of the cerebellum whose pathogenesis is poorly understood. Previous studies suggest a role for loci on chromosomes 11p and 17p in the pathogenesis of MB. Evidence for another potential MB locus has recently emerged from studies on Gorlin syndrome (GS), an autosomal dominant syndrome with multiple basal cell carcinomas, epithelial jaw cysts, and skeletal anomalies. Since GS can be associated with MB, we examined sporadic (non-GS) cases of MB for evidence of loss of heterozygosity (LOH) on chromosome 9 where a putative GS locus has been localized to band q31. Nineteen paired blood and MB DNA specimens from 16 patients (11 primary tumours, two primary with recurrent tumours, one primary tumour and cell line, two cell lines) were studied by PCR analysis of microsatellites at D9S55 (9p12), D9S15 (9q13-q21.1), D9S127 (9q21.1-21.3), D9S12 (9q22.3), D9S58 (9q22.3-q31), D9S109 (9q31), D9S53 (9q31), GSN (9q33), D9S60 (9q33-q34), D9S65 (9q33-q34), ASS (9q34), D9S67 (9q34.3), TH (11p15.5), D11S490 (11q23.3), D17S261 (17p11.2-12), D17S520 (17p12), TP53 (17p13.1), D17S5 (17p13.3), D17S515 (17q22-qter), and by RFLP analysis at the WT-1 locus (11p13). Only two tumours had LOH on 9q. One was non-informative at D9S15, D9S65, and GSN but showed LOH at D9S127, D9S12, D9S58, D9S109, D9S53, D9S60, ASS, and D9S67. The other was uninterpretable at D9S65 and non-informative at D9S15, D9S58, D9S53, and D9S67 but exhibited LOH at D9S127, D9S12, D9S109, GSN, D9S60, and ASS. Both these cases were informative at D9S55 without LOH.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8208343

  3. 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

  4. Glucose-dependent insulinotropic peptide receptor overexpression in adrenocortical hyperplasia in MEN1 syndrome without loss of heterozygosity at the 11q13 locus

    PubMed Central

    Costa, Marcia Helena Soares; Domenice, Sorahia; Toledo, Rodrigo Almeida; Lourenço, Delmar Muniz; Latronico, Ana Claudia; Pinto, Emilia Modolo; Toledo, Sergio Pereira Almeida; Mendonca, Berenice Bilharinho; Fragoso, Maria Candida Barisson Villares

    2011-01-01

    BACKGROUND: The molecular mechanisms involved in the genesis of the adrenocortical lesions seen in MEN1 syndrome (ACL-MEN1) remain poorly understood; loss of heterozygosity at 11q13 and somatic mutations of MEN1 are not usually found in these lesions. Thus, additional genes must be involved in MEN1 adrenocortical disorders. Overexpression of the glucose-dependent insulinotropic peptide receptor has been shown to promote adrenocortical tumorigenesis in a mice model and has also been associated with ACTH-independent Cushing syndrome in humans. However, to our knowledge, the status of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions in MEN1 has not been previously investigated. OBJECTIVE: To evaluate glucose-dependent insulinotropic peptide receptor expression in adrenocortical hyperplasia associated with MEN1 syndrome. MATERIALS/METHODS: Three adrenocortical tissue samples were obtained from patients with previously known MEN1 germline mutations and in whom the presence of a second molecular event (a new MEN1 somatic mutation or an 11q13 loss of heterozygosity) had been excluded. The expression of the glucose-dependent insulinotropic peptide receptor was quantified by qPCR using the ΔΔCT method, and β-actin was used as an endogenous control. RESULTS: The median of glucose-dependent insulinotropic peptide receptor expression in the adrenocortical lesions associated with MEN1 syndrome was 2.6-fold (range 1.2 to 4.8) higher than the normal adrenal controls (p = 0.02). CONCLUSION: The current study represents the first investigation of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions without 11q13 loss of heterozygosity in MEN1 syndrome patients. Although we studied a limited number of cases of MEN1 adrenocortical lesions retrospectively, our preliminary data suggest an involvement of glucose-dependent insulinotropic peptide receptor overexpression in the etiology of adrenocortical

  5. 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.

  6. Clonal evolution and clinical significance of copy number neutral loss of heterozygosity of chromosome arm 6p in acquired aplastic anemia.

    PubMed

    Betensky, Marisol; Babushok, Daria; Roth, Jacquelyn J; Mason, Philip J; Biegel, Jaclyn A; Busse, Tracy M; Li, Yimei; Lind, Curt; Papazoglou, Anna; Monos, Dimitri; Podsakoff, Gregory; Bessler, Monica; Olson, Timothy S

    2016-01-01

    Acquired aplastic anemia (aAA) results from the T cell-mediated autoimmune destruction of hematopoietic stem cells. Factors predicting response to immune suppression therapy (IST) or development of myelodysplastic syndrome (MDS) are beginning to be elucidated. Our recent data suggest most patients with aAA treated with IST develop clonal somatic genetic alterations in hematopoietic cells. One frequent acquired abnormality is copy-number neutral loss of heterozygosity on chromosome 6p (6p CN-LOH) involving the human leukocyte antigen (HLA) locus. We hypothesized that because 6p CN-LOH clones may arise from selective pressure to escape immune surveillance through deletion of HLA alleles, the development of 6p CN-LOH may affect response to IST. We used single nucleotide polymorphism array genotyping and targeted next-generation sequencing of HLA alleles to assess frequency of 6p CN-LOH, identity of HLA alleles lost through 6p CN-LOH, and impact of 6p CN-LOH on response to IST. 6p CN-LOH clones were present in 11.3% of patients, remained stable over time, and were not associated with development of MDS-defining cytogenetic abnormalities. Notably, no patient with 6p CN-LOH treated with IST achieved a complete response. In summary, clonal 6p CN-LOH in aAA defines a unique subgroup of patients that may provide insights into hematopoietic clonal evolution. PMID:26702937

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

    PubMed Central

    Bepler, G; Garcia-Blanco, M A

    1994-01-01

    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. Images PMID:8202519

  8. 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

  9. Calcification on CT is a simple and valuable preoperative indicator of 1p/19q loss of heterozygosity in supratentorial brain tumors that are suspected grade II and III gliomas.

    PubMed

    Saito, Taiichi; Muragaki, Yoshihiro; Maruyama, Takashi; Komori, Takashi; Tamura, Manabu; Nitta, Masayuki; Tsuzuki, Shunsuke; Kawamata, Takakazu

    2016-07-01

    Gliomas with 1p/19q loss of heterozygosity (LOH) are known to be associated with longer patient survival and higher sensitivity to treatment than tumors without 1p/19q LOH. This study was designed to clarify whether the preoperative finding of calcification on CT was correlated with 1p/19q LOH in patients with suspected WHO grade II and III gliomas. This study included 250 adult patients who underwent resection for primary supratentorial tumors at Tokyo Women's Medical University Hospital. The tumors were suspected, based on MRI findings, to be WHO grade II or III gliomas. The presence of calcification on the patients' CT images was qualitatively evaluated before treatment. After surgery, the resected tumors were examined to determine their 1p/19q status and mutations of IDH1 and p53. The presence of calcification was significantly correlated with 1p/19q LOH (P < 0.0001), with a positive predictive value of 91 %. The tumors of all the 78 patients with calcification were diagnosed as oligodendroglial tumors. Seventy of these patients showed classic oligodendroglial features, while 8 patients showed non-classic features. Calcification on CT is a simple and valuable preoperative indicator of 1p/19q LOH in supratentorial brain tumors that are suspected to be WHO grade II and III gliomas. PMID:26849373

  10. Three distinct commonly deleted regions of chromosome arm 16q in human primary and metastatic prostate cancers.

    PubMed

    Suzuki, H; Komiya, A; Emi, M; Kuramochi, H; Shiraishi, T; Yatani, R; Shimazaki, J

    1996-12-01

    Human prostate cancers frequently show loss of heterozygosity (LOH) at loci on the long arm of chromosome 16 (16q). In this study, we analyzed prostate cancer specimens from 48 patients (Stage B, 20 cases; Stage C, 10 cases; cancer death, 18 cases) for allelic loss on 16q, using either restriction fragment length polymorphism (RFLP)- or polymerase chain reaction (PCR)-based methods. Allelic losses were observed in 20 (42%) of 48 cases, all of which were informative with at least one locus. Detailed deletion mapping identified three distinct commonly deleted regions on this chromosome arm: q22.1-q22.3, q23.2-q24.1, and q24.3-qter. On the basis of a published sex-averaged framework map, the estimated sizes of the commonly deleted regions were 4.7 (16q22.1-q22.3), 17.2 (16q23.2-q24.1) and 8.4 cM (16q24.3-qter). Allelic losses on 16q were observed more frequently in the cancer-death cases (11 of 18; 61%) than in early-stage tumor cases (9 of 30; 30%; P < 0.05). In 7 of 11 patients from whom DNA was available from metastatic cancers as well as from normal tissues and primary tumors, the primary cancer foci had no detectable abnormality of 16q, but the metastatic tumors showed LOH. These results suggest that inactivation of tumor suppressor genes on 16q plays an important role in the progression of prostate cancer. We also analyzed exons 5-8 of the E-cadherin gene, located at 16q22.1, in tumor DNA by means of PCR-single strand conformation polymorphism and direct sequencing, but we detected no somatic mutations in this candidate gene. PMID:8946204

  11. No germline mutations in the dimerization domain of MXI1 in prostate cancer clusters. The CRC/BPG UK Familial Prostate Cancer Study Collaborators. Cancer Research Campaign/British Prostate Group.

    PubMed Central

    Edwards, S. M.; Dearnaley, D. P.; Ardern-Jones, A.; Hamoudi, R. A.; Easton, D. F.; Ford, D.; Shearer, R.; Dowe, A.; Eeles, R. A.

    1997-01-01

    There is evidence that predisposition to cancer has a genetic component. Genetic models have suggested that there is at least one highly penetrant gene predisposing to this disease. The oncogene MXI1 on chromosome band 10q24-25 is mutated in a proportion of prostate tumours and loss of heterozygosity occurs at this site, suggesting the location of a tumour suppressor in this region. To investigate the possibility that MXI1 may be involved in inherited susceptibility to prostate cancer, we have sequenced the HLH and ZIP regions of the gene in 38 families with either three cases of prostate cancer or two affected siblings both diagnosed below the age of 67 years. These are the areas within which mutations have been described in some sporadic prostate cancers. No mutations were found in these two important coding regions and we therefore conclude that MXI1 does not make a major contribution to prostate cancer susceptibility. PMID:9376279

  12. Detailed deletion mapping in sporadic breast cancer at chromosomal region 17p13 distal to the TP53 gene: association with clinicopathological parameters.

    PubMed

    Seitz, S; Poppe, K; Fischer, J; Nothnagel, A; Estévez-Schwarz, L; Haensch, W; Schlag, P M; Scherneck, S

    2001-07-01

    Chromosome 17p is among the most frequently deleted regions in a variety of human malignancies including breast cancer. This study has further refined the localization of a putative tumour suppressor gene (TSG) at 17p13 distal to the TP53 gene in breast carcinomas. It was found that 73% (37 of 51) of the breast tumours exhibited loss of heterozygosity (LOH) at one or more loci at 17p13. The allelic loss patterns of these tumours suggest the presence of at least seven commonly deleted regions on 17p13. The three most frequently deleted regions were mapped at chromosomal location 17p13.3-17p13.2 between the markers D17S831 and D17S1845 (56% LOH), at 17p13.1 between D17S1810 and D17S1832 (53% LOH), and at 17p13.1 between D17S938 and TP53 (55% LOH). A significant correlation was found between loss at 17p13 and tumour grade, size, proliferative activity, and oestrogen receptor (ER) status. Losses at 17p13 were seen more frequently in large and poorly differentiated tumours with high proliferative activity. These data support and extend previous reports on the presence of a putative TSG(s) at chromosomal region 17p13 distal to the TP53 gene and show that different subsets of LOH are associated with more aggressive tumour behaviour. PMID:11439364

  13. YAC contigs covering an 8-megabase region of 3p deleted in the small-cell lung cancer cell line U2020

    SciTech Connect

    Todd, S.; Bolin, R.; Drabkin, H.A.

    1995-01-01

    Somatic deletions of chromosome 3p occur at high frequencies in cancers of kidney, breast, cervix, head and neck, nasopharynx, and lung. The frequency of 3p deletion in lung cancer approaches 100% among small cell lesions and 70 to 80% in non-small cell lesions. This evidence strongly implies that one or more tumor suppressor genes of potentially widespread significance reside within the deleted region(s). Precise definition of the deleted target region(s) has been difficult due to the extensive area(s) lost and use of markers with low informativeness. However, improved definition remains essential to permit isolation of putative tumor suppressor genes from 3p. The identification of several small, homozygous 3p deletions in lung cancer cell lines has provided a critical resource that will assist this search. The U2020 cell line contains a small homozygous deletion that maps to a very proximal region of 3p and includes the marker D3S3. We previously identified a subset of DNA markers located within the deleted region and determined their relative order by pulsed-field gel mapping studies. In the present report, we describe the development of YAC contigs that span the majority of the deleted region and link up to flanking markers on both sides. The centromere proximal portion of the contig crosses the breakpoint from an X;3 translocation located within 3p12 providing both location and orientation to the map. PCR-based (CA){sub n} microsatellite polymorphisms have been localized within and flanking the deletion region. These markers should greatly facilitate loss-of-heterozygosity studies of this region in human cancer. The contig provides a direct means for isolation of putative tumor suppressor genes from this segment of 3p. 51 refs., 3 figs., 3 tabs.

  14. P17.01CHROMOSOME ARM 9P LOSS OF HETEROZYGOSITY IS A MARKER OF SHORTER SURVIVAL IN 1P/19Q CO-DELETED ANAPLASTIC OLIGODENDROGLIOMA. A POLA NETWORK STUDY

    PubMed Central

    Alentorn, A.; Dehais, C.; Carpentier, C.; Mokhtari, K.; Ducray, F.; Figarella-Branger, D.; Delattre, J.; Idbaih, A.; (POLA)”, POLA Network “Prise en charge des OLigodendrogliomes Anaplasiques

    2014-01-01

    Anaplastic or WHO grade III oligodendrogliomas (AO) are a heterogeneous subgroup of diffuse glial tumors in adults. Three major histomolecular subtypes with clinical relevance have been individualized: (i) 1p/19q co-deleted AO -80% of cases-, (ii) non 1p/19q co-deleted and IDH mutated AO -10% of cases- and (iii) non 1p/19q co-deleted and IDH wild-typeAO -10% of cases-. 1p/19q co-deleted AO, and to a lesser extent IDH mutated AO, have better prognosis and better response to treatment with a median survival of more than 10 years, as shown in two phase III international trials. We have recently shown that loss of heterozygosity (LOH) in chromosome arm 9p, with copy number loss -CL LOH- or without -Copy Neutral LOH- is a frequent event in AO. Interestingly, 9p CN LOH, inducing gene under-expression, has biological significance. In the present study, we address the prognostic value of 9p loss in 1p/19q co-deleted AO. In the present study, 228 AO exhibiting 1p/19q co-deletion were included. All tumors were centrally reviewed in the setting of the French national network for high-grade oligodendroglial tumors (POLA network) that recruits prospectively newly diagnosed anaplastic oligodendroglial tumors. Tumor DNA was analyzed using high-resolution single nucleotide polymorphism array analysis. In the entire series, 70/228 (1/3) harbored 9p loss including CN-LOH, homozygous loss or CL-LOH. 9p loss was associated with a worse prognosis in 1p19q co-deleted AO in univariate analysis (3-years OS of 98% vs. 74%, p < 0.001) whereas PFS at three years was not significantly different (3-years PFS of 88% vs. 66% p = 0.1). After adjustment for age, KPS, and treatment, multivariate analysis demonstrated 9p loss to be an independent prognostic factor for OS, p-value = 0.03, HR = 4.9 [1.2-16], but not for PFS. 1p19q co-deleted AO harboring 9p loss have shorter overall survival compared to their non 9p-lost counterparts in this prospective cohort. Further studies are needed to validate

  15. Absence of somatic alterations of the EB1 gene adenomatous polyposis coli-associated protein in human sporadic colorectal cancers.

    PubMed Central

    Jaïs, P.; Sabourin, J. C.; Bombled, J.; Rougier, P.; Lasser, P.; Duvillard, P.; Bénard, J.; Bressac-de Paillerets, B.

    1998-01-01

    The human EB1 gene product was recently found, by a yeast two-hybrid screening, to be associated with the carboxy terminus of the APC (adenomatous polyposis coli) protein, the product of a tumour-suppressor gene thought to act as a gatekeeper in colorectal carcinogenesis. Because virtually all of the APC mutations result in the synthesis of carboxy-terminal truncated proteins, mutant APC proteins are expected to lose their ability to interact with EB1 gene product. Thus, the interaction between APC and EB1 proteins may be important for the tumour-suppressor activity of APC protein, and raises the hypothesis that EB1 is also involved in sporadic colorectal tumorigenesis. To investigate this hypothesis, somatic mutations in the entire coding sequence of EB1 cDNA were searched by reverse transcriptase single-strand conformational polymorphism (SSCP) analysis in 21 sporadic colorectal cancers and seven adenomas. None of these tumours contained somatic mutation, whereas a silent cDNA variant was identified in 14% of alleles. Furthermore, to investigate whether EB1 locus was included within a region subjected to losses of heterozygosity, four polymorphism markers surrounding EB1 locus were surveyed. Only one out of 28 colorectal tumours contained a loss of heterozygosity at the D20S107 marker. In conclusion, the present findings strongly suggest that EB1 gene is not involved in somatic colorectal carcinogenesis. Images Figure 2 Figure 3 PMID:9823979

  16. High frequency of allelic imbalance at chromosome region 16q22-23 in human breast cancer: correlation with high PgR and low S phase.

    PubMed

    Skirnisdottir, S; Eiriksdottir, G; Baldursson, T; Barkardottir, R B; Egilsson, V; Ingvarrson, S

    1995-04-21

    The loss of genetic material from a specific chromosome region in tumors suggests that presence of tumor-suppressor genes. Loss of heterozygosity (LOH) or allelic imbalance (AI) on the long arm of chromosome 16 is a known event in sporadic breast cancer. To locate the commonly deleted regions, and therefore (a) candidate tumor-suppressor gene(s), a deletion map of chromosome 16 was made, using 10 microsatellite markers on 150 sporadic breast tumors. The 3 smallest regions of overlap (SRO) were detected on the long arm of chromosome 16. Allelic imbalance was observed with at least one marker in 67% of the tumors. One marker, D16S421, at the 16q22-23 region, showed the highest allelic imbalance, 58%. Tumors with and without AI on 16q were tested for correlation with clinico-pathological features of the tumors such as estrogen- and progesterone-receptor content (ER and PgR), age at diagnosis, tumor size, node status, histological type, S-phase fraction, AI on chromosome 3p, and ploidy. A correlation was found between AI on 16q and high PgR content, also low S-phase fraction (99% confidence limits). A comparison of tumors with and without AI at the D16S421 marker locus revealed a slight correlation with high PgR content. The survival data showed no difference between patients with AI on 16q and those with a normal allele pattern on the long arm of chromosome 16. PMID:7615353

  17. 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

  18. Allele-Specific Amplification in Cancer Revealed by SNP Array Analysis

    PubMed Central

    2005-01-01

    Amplification, deletion, and loss of heterozygosity of genomic DNA are hallmarks of cancer. In recent years a variety of studies have emerged measuring total chromosomal copy number at increasingly high resolution. Similarly, loss-of-heterozygosity events have been finely mapped using high-throughput genotyping technologies. We have developed a probe-level allele-specific quantitation procedure that extracts both copy number and allelotype information from single nucleotide polymorphism (SNP) array data to arrive at allele-specific copy number across the genome. Our approach applies an expectation-maximization algorithm to a model derived from a novel classification of SNP array probes. This method is the first to our knowledge that is able to (a) determine the generalized genotype of aberrant samples at each SNP site (e.g., CCCCT at an amplified site), and (b) infer the copy number of each parental chromosome across the genome. With this method, we are able to determine not just where amplifications and deletions occur, but also the haplotype of the region being amplified or deleted. The merit of our model and general approach is demonstrated by very precise genotyping of normal samples, and our allele-specific copy number inferences are validated using PCR experiments. Applying our method to a collection of lung cancer samples, we are able to conclude that amplification is essentially monoallelic, as would be expected under the mechanisms currently believed responsible for gene amplification. This suggests that a specific parental chromosome may be targeted for amplification, whether because of germ line or somatic variation. An R software package containing the methods described in this paper is freely available at http://genome.dfci.harvard.edu/~tlaframb/PLASQ. PMID:16322765

  19. 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.

  20. Myopodin, a synaptopodin homologue, is frequently deleted in invasive prostate cancers.

    PubMed

    Lin, F; Yu, Y P; Woods, J; Cieply, K; Gooding, B; Finkelstein, P; Dhir, R; Krill, D; Becich, M J; Michalopoulos, G; Finkelstein, S; Luo, J H

    2001-11-01

    Prostate cancer is one of the leading causes of cancer-related deaths for men in the United States. Like other malignancies, prostate cancer is underscored by a variety of aberrant genetic alterations during its development. Although loss of heterozygosity or allelic loss is frequently identified among prostate cancers, few genes have been identified thus far as critical to the development of invasive prostate cancers. In this report, we used the recently developed technology, the "differential subtraction chain," to perform a genome-wide search for sequences that are deleted in an aggressive prostate cancer. Among the deleted sequences, we found that one sequence was deleted in >50% of prostate cancers we tested. We mapped this sequence to chromosome 4q25 by screening the Genebridge 4 hamster radiation panel with primers specific to this probe, and subsequently identify a 54-kb minimal common deletion region that contains the sequence encoding myopodin. Sequence analysis indicates that myopodin shares significant homology with synaptopodin, a protein closely associated with podocyte and neuron differentiation. Further study shows that frequent complete or partial deletions of the myopodin gene occurred among invasive prostate cancer cases (25 of 31 cases, or 80%). Statistical analysis indicates that deletion of myopodin is highly correlated with the invasiveness of prostate cancers, and thus may hold promise as an important prognostic marker for prostate cancers. PMID:11696420

  1. Chromosome band 16q24 is frequently deleted in human gastric cancer.

    PubMed

    Mori, Y; Matsunaga, M; Abe, T; Fukushige, S; Miura, K; Sunamura, M; Shiiba, K; Sato, M; Nukiwa, T; Horii, A

    1999-05-01

    We have analysed the loss of heterozygosity (LOH) on chromosome bands 16q22-q24 in 24 primary gastric cancer tissues and found three regions of frequent allelic loss (16q22, 16q24.1-q24.3 and 16q24.3). The region for the most frequent allelic loss (63%) was in 16q24.1-q24.3. LOH of this region had no relationship with histological subtype, but a significant association between LOH and microscopic lymphangial invasion was observed. Although not significant, vascular and gastric wall invasions are also associated with LOH. The region includes the locus for the H-cadherin gene. Therefore we examined the genetic and epigenetic alterations of this gene. Markedly reduced expression was observed in gastric cancer cell lines compared with that of normal gastric mucosa. However, no mutation was found in this gene in any of the gastric cancer tissues or the gastric cancer cell lines. Furthermore, we analysed the methylation status of the 5'-flanking region of the gene, but no significant association was found. We suggest that some other tumour suppressor gene(s) in 16q24.1-q24.3 may be responsible for gastric carcinogenesis. PMID:10408866

  2. Collagen and calcium-binding EGF domains 1 is frequently inactivated in ovarian cancer by aberrant promoter hypermethylation and modulates cell migration and survival

    PubMed Central

    Barton, C A; Gloss, B S; Qu, W; Statham, A L; Hacker, N F; Sutherland, R L; Clark, S J; O'Brien, P M

    2009-01-01

    Background: Collagen and calcium-binding EGF domains 1 (CCBE1) is an uncharacterised gene that has down-regulated expression in breast cancer. As CCBE1 maps to 18q21.32, a region frequently exhibiting loss of heterozygosity in ovarian cancer, the aim of this study was to determine the expression and function of CCBE1 in ovarian cancer. Methods: Expression and methylation patterns of CCBE1 were determined in ovarian cancer cell lines and primary tumours. CCBE1 contains collagen repeats and an aspartic acid/asparagine hydroxylation/EGF-like domain, suggesting a function in extracellular matrix remodelling and migration, which was determined using small-interfering RNA (siRNA)-mediated knockdown and over-expression of CCBE1 in cell lines. Results: CCBE1 is expressed in normal ovary, but is reduced in ovarian cancer cell lines and primary carcinomas. Pharmacological demethylation/deacetylation in ovarian cancer cell lines re-induced CCBE1 expression, indicating that epigenetic mechanisms contribute to its silencing in cancer. CCBE1 promoter hypermethylation was detected in 6/11 (55%) ovarian cancer cell lines and 38/81 (41%) ovarian carcinomas. siRNA-mediated knockdown of CCBE1 in ovarian cancer cell lines enhanced their migration; conversely, re-expression of CCBE1 reduced migration and survival. Hence, loss of CCBE1 expression may promote ovarian carcinogenesis by enhancing migration and cell survival. Conclusions: These data suggest that CCBE1 is a new candidate tumour suppressor in ovarian cancer. PMID:19935792

  3. SDPR functions as a metastasis suppressor in breast cancer by promoting apoptosis.

    PubMed

    Ozturk, Sait; Papageorgis, Panagiotis; Wong, Chen Khuan; Lambert, Arthur W; Abdolmaleky, Hamid M; Thiagalingam, Arunthathi; Cohen, Herbert T; Thiagalingam, Sam

    2016-01-19

    Metastatic dissemination of breast cancer cells represents a significant clinical obstacle to curative therapy. The loss of function of metastasis suppressor genes is a major rate-limiting step in breast cancer progression that prevents the formation of new colonies at distal sites. However, the discovery of new metastasis suppressor genes in breast cancer using genomic efforts has been slow, potentially due to their primary regulation by epigenetic mechanisms. Here, we report the use of model cell lines with the same genetic lineage for the identification of a novel metastasis suppressor gene, serum deprivation response (SDPR), localized to 2q32-33, a region reported to be associated with significant loss of heterozygosity in breast cancer. In silico metaanalysis of publicly available gene expression datasets suggests that the loss of expression of SDPR correlates with significantly reduced distant-metastasis-free and relapse-free survival of breast cancer patients who underwent therapy. Furthermore, we found that stable SDPR overexpression in highly metastatic breast cancer model cell lines inhibited prosurvival pathways, shifted the balance of Bcl-2 family proteins in favor of apoptosis, and decreased migration and intravasation/extravasation potential, with a corresponding drastic suppression of metastatic nodule formation in the lungs of NOD/SCID mice. Moreover, SDPR expression is silenced by promoter DNA methylation, and as such it exemplifies epigenetic regulation of metastatic breast cancer progression. These observations highlight SDPR as a potential prognostic biomarker and a target for future therapeutic applications. PMID:26739564

  4. A widely expressed transcription factor with multiple DNA sequence specificity, CTCF, is localized at chromosome segment 16q22.1 within one of the smallest regions of overlap for common deletions in breast and prostate cancers.

    PubMed

    Filippova, G N; Lindblom, A; Meincke, L J; Klenova, E M; Neiman, P E; Collins, S J; Doggett, N A; Lobanenkov, V V

    1998-05-01

    The cellular protooncogene MYC encodes a nuclear transcription factor that is involved in regulating important cellular functions, including cell cycle progression, differentiation, and apoptosis. Dysregulated MYC expression appears critical to the development of various types of malignancies, and thus factors involved in regulating MYC expression may also play a key role in the pathogenesis of certain cancers. We have cloned one such MYC regulatory factor, termed CTCF, which is a highly evolutionarily conserved-11-zinc finger transcriptional factor possessing multiple DNA sequence specificity. CTCF binds to a number of important regulatory regions within the 5' noncoding sequence of the human MYC oncogene, and it can regulate its transcription in several experimental systems. CTCF mRNA is expressed in cells of multiple different lineages. Enforced ectopic expression of CTCF inhibits cell growth in culture. Southern blot analyses and fluorescence in situ hybridization (FISH) with normal human metaphase chromosomes showed that the human CTCF is a single-copy gene situated at chromosome locus 16q22. Cytogenetic studies have pointed out that chromosome abnormalities (deletions) at this locus frequently occur in many different human malignancies, suggesting the presence of one or more tumor suppressor genes in the region. To narrow down their localization, several loss of heterozygosity (LOH) studies of chromosome arm 16q in sporadic breast and prostate cancers have been carried out to define the most recurrent and smallest region(s) of overlap (SRO) for commonly deleted chromosome arm 16q material. For CTCF to be considered as a candidate tumor suppressor gene associated with tumorigenesis, it should localize within one of the SROs at 16q. Fine-mapping of CTCF has enabled us to assign the CTCF gene to about a 2 centiMorgan (cM) interval of 16q22.1 between the somatic cell hybrid breakpoints CY130(D) and CY4, which is between markers D16S186 (16AC16-101) and D16S496

  5. 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.

  6. 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

  7. 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

  8. Genetic identification of multiple loci that control breast cancer susceptibility in the rat.

    PubMed Central

    Shepel, L A; Lan, H; Haag, J D; Brasic, G M; Gheen, M E; Simon, J S; Hoff, P; Newton, M A; Gould, M N

    1998-01-01

    We have used a rat model of induced mammary carcinomas in an effort to identify breast cancer susceptibility genes. Using genetic crosses between the carcinoma-resistant Copenhagen (COP) and carcinoma-sensitive Wistar-Furth rats, we have confirmed the identification of the Mcs1 locus that modulates tumor number. We have now also identified two additional loci, Mcs2 and Mcs3. These three loci map to chromosomes 2, 7, and 1, respectively, and interact additively to suppress mammary carcinoma development in the COP strain. They are responsible for a major portion of the tumor-resistant phenotype of the COP rat. No loss of heterozygosity was observed surrounding the three loci. A fourth COP locus, Mcs4, has also been identified on chromosome 8 and acts in contrast to increase the number of carcinomas. These results show that mammary carcinoma susceptibility in the COP rat is a polygenic trait. Interestingly, a polymorphism in the human genomic region homologous to the rat Mcs4 region is associated with an increased breast cancer risk in African-American women. The isolation of the Mcs genes may help elucidate novel mechanisms of carcinogenesis, provide information important for human breast cancer risk estimation, and also provide unique drug discovery targets for breast cancer prevention. PMID:9584103

  9. Microsatellite instability in squamous cell carcinomas of the head and neck related to field cancerization phenomena.

    PubMed Central

    Piccinin, S.; Gasparotto, D.; Vukosavljevic, T.; Barzan, L.; Sulfaro, S.; Maestro, R.; Boiocchi, M.

    1998-01-01

    Patients affected by squamous cell carcinoma of the head and neck (HNSCC) show frequent occurrence of multiple cancers and widespread precancerous lesions in the mucosa of the upper respiratory tract, a phenomenon known as field cancerization. In this study, we investigated the role of genetic instability in the development of HNSCC and in particular in tumour multiplicity phenomena of the upper respiratory tract. For this purpose, we analysed microsatellite instability (MI) and loss of heterozygosity (LOH) at 20 loci mapping on five chromosomal arms in 67 HNSCC patients, 45 of whom had a single cancer and 22 had multiple primary tumours. The possible involvement of the hMLH1 gene in genetic instability and as a potential target of 3p21 deletion phenomena in head and neck cancers was also investigated. Our data indicate that mismatch repair-related genetic instability plays a minor role in the carcinogenesis of HNSCC and in tumour multiplicity of the head and neck region. Moreover, our results exclude a role for the hMLH1 gene as a determinant of MI and as a specific gene target of deletion at 3p21 in HNSCC. We conclude that presumably other genetic mechanisms, such as those hypothesized for MI-negative hereditary non-polyposis colorectal cancer patients, may play a major role in the carcinogenesis of the mucosa of the upper respiratory tract. Images Figure 1 Figure 2 PMID:9820170

  10. Dysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer

    PubMed Central

    Singh, Anju; Misra, Vikas; Thimmulappa, Rajesh K; Lee, Hannah; Ames, Stephen; Hoque, Mohammad O; Herman, James G; Baylin, Stephen B; Sidransky, David; Gabrielson, Edward; Brock, Malcolm V; Biswal, Shyam

    2006-01-01

    Background Nuclear factor erythroid-2 related factor 2 (NRF2) is a redox-sensitive transcription factor that positively regulates the expression of genes encoding antioxidants, xenobiotic detoxification enzymes, and drug efflux pumps, and confers cytoprotection against oxidative stress and xenobiotics in normal cells. Kelch-like ECH-associated protein 1 (KEAP1) negatively regulates NRF2 activity by targeting it to proteasomal degradation. Increased expression of cellular antioxidants and xenobiotic detoxification enzymes has been implicated in resistance of tumor cells against chemotherapeutic drugs. Methods and Findings Here we report a systematic analysis of the KEAP1 genomic locus in lung cancer patients and cell lines that revealed deletion, insertion, and missense mutations in functionally important domains of KEAP1 and a very high percentage of loss of heterozygosity at 19p13.2, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event. Sequencing of KEAP1 in 12 cell lines and 54 non-small-cell lung cancer (NSCLC) samples revealed somatic mutations in KEAP1 in a total of six cell lines and ten tumors at a frequency of 50% and 19%, respectively. All the mutations were within highly conserved amino acid residues located in the Kelch or intervening region domain of the KEAP1 protein, suggesting that these mutations would likely abolish KEAP1 repressor activity. Evaluation of loss of heterozygosity at 19p13.2 revealed allelic losses in 61% of the NSCLC cell lines and 41% of the tumor samples. Decreased KEAP1 activity in cancer cells induced greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps. Conclusions This is the first study to our knowledge to demonstrate that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC. Loss of KEAP1 function leading to constitutive activation of NRF2-mediated gene expression in cancer

  11. Transcribed ultraconserved region in human cancers

    PubMed Central

    Peng, Jiang Chen; Shen, Jun; Ran, Zhi Hua

    2013-01-01

    Long non-coding RNAs (lncRNAs) are transcripts longer than ~200 nucleotides with little or no protein-coding capacity. Growing evidence shows that lncRNAs present important function in development and are associated with many human diseases such as cancers, Alzheimer disease, and heart diseases. Transcribed ultraconserved region (T-UCR) transcripts are a novel class of lncRNAs transcribed from ultraconserved regions (UCRs). UCRs are absolutely conserved (100%) between the orthologous regions of the human, rat, and mouse genomes. The UCRs are frequently located at fragile sites and at genomic regions involved in cancers. Recent data suggest that T-UCRs are altered at the transcriptional level in human tumorigenesis and the aberrant T-UCRs expression profiles can be used to differentiate human cancer types. The profound understanding of T-UCRs can throw new light on the pathogenesis of human cancers. PMID:24384562

  12. 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

  13. Deletion mapping on chromosome 1p in well-differentiated gastric cancer.

    PubMed Central

    Ezaki, T.; Yanagisawa, A.; Ohta, K.; Aiso, S.; Watanabe, M.; Hibi, T.; Kato, Y.; Nakajima, T.; Ariyama, T.; Inazawa, J.; Nakamura, Y.; Horii, A.

    1996-01-01

    To define the region on the short arm of chromosome 1 that is thought to include one or more tumour-suppressor genes for gastric cancers, we carried out loss of heterozygosity (LOH) studies in 26 gastric adenocarcinomas, using three restriction fragment length polymorphism (RFLP) markers and nine microsatellite markers. All tumours were informative with at least one locus; three revealed replication errors (RERs) at multiple microsatellite loci, and interstitial or telomeric allelic deletions were observed in 12 cases. Deletion mapping of these tumours defined a commonly deleted region between two loci, D1S201 and D1S197, that are 13 cM apart. As two loci within the commonly deleted region, D1S57 (pYNZ2) and D1S62 (pTHI54), were mapped respectively to 1p35 and 1p34.3 by fluorescence in situ hybridisation, we conclude that a locus likely to contain a tumour-suppressor gene for gastric cancer is located within a 13 cM region encompassing two chromosomal bands. Images Figure 1 Figure 3 Figure 4 PMID:8595154

  14. Location of several putative genes possibly involved in human breast cancer progression.

    PubMed

    Driouch, K; Briffod, M; Bièche, I; Champème, M H; Lidereau, R

    1998-05-15

    Cancer is a genetic disease resulting from an accumulation of genetic abnormalities in various regulatory genes. Most studies on genetic alterations in human breast cancer have involved primary tumors. The possible involvement of specific tumor suppressor genes in the later stages of cancer progression is poorly documented. We investigated allelic losses associated with breast cancer progression by analyzing 55 polymorphic markers on 11 autosomal chromosomes in a series of 49 relapses (23 local recurrences and 26 distant metastases). All of the loss of heterozygosity (LOH) regions reported in primary breast tumors were frequent in both series of relapses. These results suggest that the allelic losses that are common to the different series of samples occur very early during tumor progression. This study points to candidate metastasis-related genes targeted by LOH on chromosome arms 3p21.3, 16q22.2-23.2, and, possibly, 7q31 but provides no clear evidence of LOH affecting previously described metastasis-related genes such as NME1, MTS1, and TSG101. PMID:9605747

  15. A distinct region of chromosome 19p13.3 associated with the sporadic form of adenoma malignum of the uterine cervix.

    PubMed

    Lee, J Y; Dong, S M; Kim, H S; Kim, S Y; Na, E Y; Shin, M S; Lee, S H; Park, W S; Kim, K M; Lee, Y S; Jang, J J; Yoo, N J

    1998-03-15

    Adenoma malignum (AM) is known to be one of the malignant tumors that is commonly associated with Peutz-Jeghers syndrome. Recently, the genetic locus of Peutz-Jeghers syndrome was mapped to the telomeric region of chromosome 19p. We analyzed nine sporadic cases of AM with high-density loss of heterozygosity to study the region of chromosome 19p13.2-13.3 using eight microsatellite markers. Our deletion mapping data revealed a distinct region with 100% loss of heterozygosity frequency at marker D19S216. This result indicates that a putative tumor suppressor gene for AM is located at D19S216 on chromosomal band 19p13.3 and plays an important role in AM tumorigenesis. PMID:9515797

  16. Breast cancer screening in regional Hispanic populations.

    PubMed

    Ramirez, A G; Talavera, G A; Villarreal, R; Suarez, L; McAlister, A; Trapido, E; Pérez-Stable, E; Marti, J

    2000-10-01

    Although Hispanics' use of breast cancer screening services has been investigated, to date there have been no published studies of distinct Hispanic populations in different areas of the country. Using the diverse populations and sites involved in the National Hispanic Leadership Initiative on Cancer 'En Acción', this study examines ethno-regional differences in breast cancer screening rates among these groups and explores the correlates of screening participation. Data collected through telephone surveys were analyzed for women 40 years of age and older (n = 2082). After controlling for demographic variables traditionally related to breast cancer screening rates, it was found that ethno-regional differences in breast cancer screening practices clearly persisted. In addition to traditional demographic factors, other variables evidently underlie differences in Hispanics' utilization of breast cancer screening services. These variables may be cultural and should be investigated in future research. Meanwhile, researchers should not refer to the 'Hispanic' population at large without identifying, addressing and clarifying the ethno-regional characteristics of their samples. PMID:11184215

  17. Aberrant expression of the candidate tumor suppressor gene DAL-1 due to hypermethylation in gastric cancer

    PubMed Central

    Wang, Hao; Xu, Man; Cui, Xiaobo; Liu, Yixin; Zhang, Yi; Sui, Yu; Wang, Dong; Peng, Lei; Wang, Dexu; Yu, Jingcui

    2016-01-01

    By allelotyping for loss of heterozygosity (LOH), we previously identified a deletion region that harbors the candidate tumor suppressor gene DAL-1 at 18p11.3 in sporadic gastric cancers (GCs). The expression and function of DAL-1 in GCs remained unclear. Here, we demonstrated that the absence of or notable decreases in the expression of DAL-1 mRNA and protein was highly correlated with CpG hypermethylation of the DAL-1 promoter in primary GC tissues and in GC cell lines. Furthermore, abnormal DAL-1 subcellular localization was also observed in GC cells. Exogenous DAL-1 effectively inhibited cancer cell proliferation, migration, invasion and epithelial to mesenchymal transition (EMT); exogenous DAL-1 also promoted apoptosis in GC AGS cells. When endogenous DAL-1 was knocked down in GC HGC-27 cells, the cells appeared highly aggressive. Taken together, these findings provide solid evidence that aberrant expression of DAL-1 by hypermethylation in the promoter region results in tumor suppressor gene behavior that plays important roles in the malignancy of GCs. Understanding the role of it played in the molecular pathogenesis of GC, DAL-1 might be a potential biomarker for molecular diagnosis and evaluation of the GC. PMID:26923709

  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. PMID:25919136

  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. 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.

  2. 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.

  3. Deletions linked to TP53 loss drive cancer through p53-independent mechanisms.

    PubMed

    Liu, Yu; Chen, Chong; Xu, Zhengmin; Scuoppo, Claudio; Rillahan, Cory D; Gao, Jianjiong; Spitzer, Barbara; Bosbach, Benedikt; Kastenhuber, Edward R; Baslan, Timour; Ackermann, Sarah; Cheng, Lihua; Wang, Qingguo; Niu, Ting; Schultz, Nikolaus; Levine, Ross L; Mills, Alea A; Lowe, Scott W

    2016-03-24

    Mutations disabling the TP53 tumour suppressor gene represent the most frequent events in human cancer and typically occur through a two-hit mechanism involving a missense mutation in one allele and a 'loss of heterozygosity' deletion encompassing the other. While TP53 missense mutations can also contribute gain-of-function activities that impact tumour progression, it remains unclear whether the deletion event, which frequently includes many genes, impacts tumorigenesis beyond TP53 loss alone. Here we show that somatic heterozygous deletion of mouse chromosome 11B3, a 4-megabase region syntenic to human 17p13.1, produces a greater effect on lymphoma and leukaemia development than Trp53 deletion. Mechanistically, the effect of 11B3 loss on tumorigenesis involves co-deleted genes such as Eif5a and Alox15b (also known as Alox8), the suppression of which cooperates with Trp53 loss to produce more aggressive disease. Our results imply that the selective advantage produced by human chromosome 17p deletion reflects the combined impact of TP53 loss and the reduced dosage of linked tumour suppressor genes. PMID:26982726

  4. 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

  5. Chromosomal deletions and tumor suppressor genes in prostate cancer.

    PubMed

    Dong, J T

    2001-01-01

    Chromosomal deletion appears to be the earliest as well as the most frequent somatic genetic alteration during carcinogenesis. It inactivates a tumor suppressor gene in three ways, that is, revealing a gene mutation through loss of heterozygosity as proposed in the two-hit theory, inducing haploinsufficiency through quantitative hemizygous deletion and associated loss of expression, and truncating a genome by homozygous deletion. Whereas the two-hit theory has guided the isolation of many tumor suppressor genes, the haploinsufficiency hypothesis seems to be also useful in identifying target genes of chromosomal deletions, especially for the deletions detected by comparative genomic hybridization (CGH). At present, a number of chromosomal regions have been identified for their frequent deletions in prostate cancer, including 2q13-q33, 5q14-q23, 6q16-q22, 7q22-q32, 8p21-p22, 9p21-p22, 10q23-q24, 12p12-13, 13q14-q21, 16q22-24, and 18q21-q24. Strong candidate genes have been identified for some of these regions, including NKX3.1 from 8p21, PTEN from 10q23, p27/Kip1 from 12p13, and KLF5 from 13q21. In addition to their location in a region with frequent deletion, there are functional and/or genetic evidence supporting the candidacy of these genes. Thus far PTEN is the most frequently mutated gene in prostate cancer, and KLF5 showed the most frequent hemizygous deletion and loss of expression. A tumor suppressor role has been demonstrated for NKX3.1, PTEN, and p27/Kip1 in knockout mice models. Such genes are important targets of investigation for the development of biomarkers and therapeutic regimens. PMID:12085961

  6. Allelic loss at chromosome 13q12-q13 is associated with poor prognosis in familial and sporadic breast cancer.

    PubMed Central

    van den Berg, J.; Johannsson, O.; Håkansson, S.; Olsson, H.; Borg, A.

    1996-01-01

    Loss of heterozygosity (LOH) was analysed in 84 primary tumours from sporadic, familial and hereditary breast cancer using five microsatellite markers spanning the chromosomal region 13q12-q13 which harbours the BRCA2 breast cancer susceptibility gene, and using one other marker located within the RBI tumour-suppressor gene at 13q14. LOH at the BRCA2 region was found in 34% and at RBI in 27% of the tumours. Selective LOH at BRCA2 occurred in 7% of the tumours, whereas selective LOH at RBI was observed in another 7%. Moreover, a few tumours demonstrated a restricted deletion pattern, suggesting the presence of additional tumour-suppressor genes both proximal and distal of BRCA2. LOH at BRCA2 was significantly correlated to high S-phase values, low oestrogen and progesterone receptor content and DNA non-diploidy. LOH at BRCA2 was also associated, albeit non-significantly, with large tumour size and the ductal and medullar histological types. No correlation was found with lymph node status, patient age or a family history of breast cancer. A highly significant and independent correlation existed between LOH at BRCA2 and early recurrence and death. LOH at RBI was not associated with the above mentioned factors or prognosis. The present study does not provide conclusive evidence that BRCA2 is the sole target for deletions at 13q12-q13 in breast tumours. However, the results suggest that inactivation of one or several tumour-suppressor genes in the 13q12-q13 region confer a strong tumour growth potential and poor prognosis in both familial and sporadic breast cancer. Images Figure 1 PMID:8932343

  7. A Genome-Wide Study of Cytogenetic Changes in Colorectal Cancer Using SNP Microarrays: Opportunities for Future Personalized Treatment

    PubMed Central

    Jasmine, Farzana; Rahaman, Ronald; Dodsworth, Charlotte; Roy, Shantanu; Paul, Rupash; Raza, Maruf; Paul-Brutus, Rachelle; Kamal, Mohammed; Ahsan, Habibul; Kibriya, Muhammad G.

    2012-01-01

    In colorectal cancer (CRC), chromosomal instability (CIN) is typically studied using comparative-genomic hybridization (CGH) arrays. We studied paired (tumor and surrounding healthy) fresh frozen tissue from 86 CRC patients using Illumina's Infinium-based SNP array. This method allowed us to study CIN in CRC, with simultaneous analysis of copy number (CN) and B-allele frequency (BAF) - a representation of allelic composition. These data helped us to detect mono-allelic and bi-allelic amplifications/deletion, copy neutral loss of heterozygosity, and levels of mosaicism for mixed cell populations, some of which can not be assessed with other methods that do not measure BAF. We identified associations between CN abnormalities and different CRC phenotypes (histological diagnosis, location, tumor grade, stage, MSI and presence of lymph node metastasis). We showed commonalities between regions of CN change observed in CRC and the regions reported in previous studies of other solid cancers (e.g. amplifications of 20q, 13q, 8q, 5p and deletions of 18q, 17p and 8p). From Therapeutic Target Database, we identified relevant drugs, targeted to the genes located in these regions with CN changes, approved or in trials for other cancers and common diseases. These drugs may be considered for future therapeutic trials in CRC, based on personalized cytogenetic diagnosis. We also found many regions, harboring genes, which are not currently targeted by any relevant drugs that may be considered for future drug discovery studies. Our study shows the application of high density SNP arrays for cytogenetic study in CRC and its potential utility for personalized treatment. PMID:22363777

  8. 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

  9. 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. PMID:26243311

  10. The Motor Protein KIF14 Inhibits Tumor Growth and Cancer Metastasis in Lung Adenocarcinoma

    PubMed Central

    Hung, Pei-Fang; Hong, Tse-Ming; Hsu, Yi-Chiung; Chen, Hsuan-Yu; Chang, Yih-Leong; Wu, Chen-Tu; Chang, Gee-Chen; Jou, Yuh-Shan

    2013-01-01

    The motor protein kinesin superfamily proteins (KIFs) are involved in cancer progression. The depletion of one of the KIFs, KIF14, might delay the metaphase-to-anaphase transition, resulting in a binucleated status, which enhances tumor progression; however, the exact correlation between KIF14 and cancer progression remains ambiguous. In this study, using loss of heterozygosity and array comparative genomic hybridization analyses, we observed a 30% loss in the regions surrounding KIF14 on chromosome 1q in lung adenocarcinomas. In addition, the protein expression levels of KIF14 in 122 lung adenocarcinomas also indicated that approximately 30% of adenocarcinomas showed KIF14 down-regulation compared with the expression in the bronchial epithelial cells of adjacent normal counterparts. In addition, the reduced expression of KIF14 mRNA or proteins was correlated with poor overall survival (P = 0.0158 and <0.0001, respectively), and the protein levels were also inversely correlated with metastasis (P<0.0001). The overexpression of KIF14 in lung adenocarcinoma cells inhibited anchorage-independent growth in vitro and xenograft tumor growth in vivo. The overexpression and silencing of KIF14 also inhibited or enhanced cancer cell migration, invasion and adhesion to the extracellular matrix proteins laminin and collagen IV. Furthermore, we detected the adhesion molecules cadherin 11 (CDH11) and melanoma cell adhesion molecule (MCAM) as cargo on KIF14. The overexpression and silencing of KIF14 enhanced or reduced the recruitment of CDH11 in the membrane fraction, suggesting that KIF14 might act through recruiting adhesion molecules to the cell membrane and modulating cell adhesive, migratory and invasive properties. Thus, KIF14 might inhibit tumor growth and cancer metastasis in lung adenocarcinomas. PMID:23626713

  11. The motor protein KIF14 inhibits tumor growth and cancer metastasis in lung adenocarcinoma.

    PubMed

    Hung, Pei-Fang; Hong, Tse-Ming; Hsu, Yi-Chiung; Chen, Hsuan-Yu; Chang, Yih-Leong; Wu, Chen-Tu; Chang, Gee-Chen; Jou, Yuh-Shan; Pan, Szu-Hua; Yang, Pan-Chyr

    2013-01-01

    The motor protein kinesin superfamily proteins (KIFs) are involved in cancer progression. The depletion of one of the KIFs, KIF14, might delay the metaphase-to-anaphase transition, resulting in a binucleated status, which enhances tumor progression; however, the exact correlation between KIF14 and cancer progression remains ambiguous. In this study, using loss of heterozygosity and array comparative genomic hybridization analyses, we observed a 30% loss in the regions surrounding KIF14 on chromosome 1q in lung adenocarcinomas. In addition, the protein expression levels of KIF14 in 122 lung adenocarcinomas also indicated that approximately 30% of adenocarcinomas showed KIF14 down-regulation compared with the expression in the bronchial epithelial cells of adjacent normal counterparts. In addition, the reduced expression of KIF14 mRNA or proteins was correlated with poor overall survival (P = 0.0158 and <0.0001, respectively), and the protein levels were also inversely correlated with metastasis (P<0.0001). The overexpression of KIF14 in lung adenocarcinoma cells inhibited anchorage-independent growth in vitro and xenograft tumor growth in vivo. The overexpression and silencing of KIF14 also inhibited or enhanced cancer cell migration, invasion and adhesion to the extracellular matrix proteins laminin and collagen IV. Furthermore, we detected the adhesion molecules cadherin 11 (CDH11) and melanoma cell adhesion molecule (MCAM) as cargo on KIF14. The overexpression and silencing of KIF14 enhanced or reduced the recruitment of CDH11 in the membrane fraction, suggesting that KIF14 might act through recruiting adhesion molecules to the cell membrane and modulating cell adhesive, migratory and invasive properties. Thus, KIF14 might inhibit tumor growth and cancer metastasis in lung adenocarcinomas. PMID:23626713

  12. 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. PMID:19176640

  13. 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.

  14. Prostate cancer region prediction using MALDI mass spectra

    NASA Astrophysics Data System (ADS)

    Vadlamudi, Ayyappa; Chuang, Shao-Hui; Sun, Xiaoyan; Cazares, Lisa; Nyalwidhe, Julius; Troyer, Dean; Semmes, O. John; Li, Jiang; McKenzie, Frederic D.

    2010-03-01

    For the early detection of prostate cancer, the analysis of the Prostate-specific antigen (PSA) in serum is currently the most popular approach. However, previous studies show that 15% of men have prostate cancer even their PSA concentrations are low. MALDI Mass Spectrometry (MS) proves to be a better technology to discover molecular tools for early cancer detection. The molecular tools or peptides are termed as biomarkers. Using MALDI MS data from prostate tissue samples, prostate cancer biomarkers can be identified by searching for molecular or molecular combination that can differentiate cancer tissue regions from normal ones. Cancer tissue regions are usually identified by pathologists after examining H&E stained histological microscopy images. Unfortunately, histopathological examination is currently done on an adjacent slice because the H&E staining process will change tissue's protein structure and it will derogate MALDI analysis if the same tissue is used, while the MALDI imaging process will destroy the tissue slice so that it is no longer available for histopathological exam. For this reason, only the most confident cancer region resulting from the histopathological examination on an adjacent slice will be used to guide the biomarker identification. It is obvious that a better cancer boundary delimitation on the MALDI imaging slice would be beneficial. In this paper, we proposed methods to predict the true cancer boundary, using the MALDI MS data, from the most confident cancer region given by pathologists on an adjacent slice.

  15. Paternal uniparental disomy 11p15.5 in the pancreatic nodule of an infant with Costello syndrome: Shared mechanism for hyperinsulinemic hypoglycemia in neonates with Costello and Beckwith-Wiedemann syndrome and somatic loss of heterozygosity in Costello syndrome driving clonal expansion.

    PubMed

    Gripp, Karen W; Robbins, Katherine M; Sheffield, Brandon S; Lee, Anna F; Patel, Millan S; Yip, Stephen; Doyle, Daniel; Stabley, Deborah; Sol-Church, Katia

    2016-03-01

    Costello syndrome (CS) entails a cancer predisposition and is caused by activating HRAS mutations, typically arising de novo in the paternal germline. Hypoglycemia is common in CS neonates. A previously reported individual with the rare HRAS p.Gln22Lys had hyperinsulinemic hypoglycemia. Autopsy showed a discrete pancreatic nodule. The morphologic and immunohistochemistry findings, including loss of p57(Kip2) protein, were identical to a focal lesion of congenital hyperinsulinism, however, no KCNJ11 or ABCC8 mutation was identified and germline derived DNA showed no alternation of the maternal or paternal 11p15 alleles. Here we report paternal uniparental disomy (pUPD) within the lesion, similar to the pUPD11p15.5 in Beckwith-Wiedemann syndrome (BWS). The similar extent of the pUPD suggests a similar mechanism driving hyperinsulinemia in both conditions. After coincidental somatic LOH and pUPD, the growth promoting effects of the paternally derived HRAS mutation, in combination with the increased function of the adjacent paternally expressed IGF2, may together result in clonal expansion. Although this somatic LOH within pancreatic tissue resulted in hyperinsulinism, similar LOH in mesenchymal cells may drive embryonal rhabdomyosarcoma (ERMS). Interestingly, biallelic IGF2 expression has been linked to rhabdomyosarcoma tumorigenesis and pUPD11 occurred in all 8 ERMS samples from CS individuals. Somatic KRAS and HRAS mutations occur with comparable frequency in isolated malignancies. Yet, the malignancy risk in CS is notably higher than in Noonan syndrome with a KRAS mutation. It is conceivable that HRAS co-localization with IGF2 and the combined effect of pUPD 11p15.5 on both genes contributes to the oncogenic potential. PMID:26572961

  16. Paternal Uniparental Disomy 11p15.5 in the Pancreatic Nodule of an Infant With Costello Syndrome: Shared Mechanism for Hyperinsulinemic Hypoglycemia in Neonates With Costello and Beckwith–Wiedemann Syndrome and Somatic Loss of Heterozygosity in Costello Syndrome Driving Clonal Expansion

    PubMed Central

    Gripp, Karen W.; Robbins, Katherine M.; Sheffield, Brandon S.; Lee, Anna F.; Patel, Millan S.; Yip, Stephen; Doyle, Daniel; Stabley, Deborah; Sol-Church, Katia

    2016-01-01

    Costello syndrome (CS) entails a cancer predisposition and is caused by activating HRAS mutations, typically arising de novo in the paternal germline. Hypoglycemia is common in CS neonates. A previously reported individual with the rare HRAS p.Gln22Lys had hyperinsulinemic hypoglycemia. Autopsy showed a discrete pancreatic nodule. The morphologic and immunohistochemistry findings, including loss of p57Kip2 protein, were identical to a focal lesion of congenital hyperinsulinism, however, no KCNJ11 or ABCC8 mutation was identified and germline derived DNA showed no alternation of the maternal or paternal 11p15 alleles. Here we report paternal uniparental disomy (pUPD) within the lesion, similar to the pUPD11p15.5 in Beckwith–Wiedemann syndrome (BWS). The similar extent of the pUPD suggests a similar mechanism driving hyperinsulinemia in both conditions. After coincidental somatic LOH and pUPD, the growth promoting effects of the paternally derived HRAS mutation, in combination with the increased function of the adjacent paternally expressed IGF2, may together result in clonal expansion. Although this somatic LOH within pancreatic tissue resulted in hyperinsulinism, similar LOH in mesenchymal cells may drive embryonal rhabdomyosarcoma (ERMS). Interestingly, biallelic IGF2 expression has been linked to rhabdomyosarcoma tumorigenesis and pUPD11 occurred in all 8 ERMS samples from CS individuals. Somatic KRAS and HRAS mutations occur with comparable frequency in isolated malignancies. Yet, the malignancy risk in CS is notably higher than in Noonan syndrome with a KRAS mutation. It is conceivable that HRAS co-localization with IGF2 and the combined effect of pUPD 11p15.5 on both genes contributes to the oncogenic potential. PMID:26572961

  17. Global and regional estimates of cancer mortality and incidence by site: I. Application of regional cancer survival model to estimate cancer mortality distribution by site

    PubMed Central

    Mathers, Colin D; Shibuya, Kenji; Boschi-Pinto, Cynthia; Lopez, Alan D; Murray, Christopher JL

    2002-01-01

    Background The Global Burden of Disease 2000 (GBD 2000) study starts from an analysis of the overall mortality envelope in order to ensure that the cause-specific estimates add to the total all cause mortality by age and sex. For regions where information on the distribution of cancer deaths is not available, a site-specific survival model was developed to estimate the distribution of cancer deaths by site. Methods An age-period-cohort model of cancer survival was developed based on data from the Surveillance, Epidemiology, and End Results (SEER). The model was further adjusted for the level of economic development in each region. Combined with the available incidence data, cancer death distributions were estimated and the model estimates were validated against vital registration data from regions other than the United States. Results Comparison with cancer mortality distribution from vital registration confirmed the validity of this approach. The model also yielded the cancer mortality distribution which is consistent with the estimates based on regional cancer registries. There was a significant variation in relative interval survival across regions, in particular for cancers of bladder, breast, melanoma of the skin, prostate and haematological malignancies. Moderate variations were observed among cancers of colon, rectum, and uterus. Cancers with very poor prognosis such as liver, lung, and pancreas cancers showed very small variations across the regions. Conclusions The survival model presented here offers a new approach to the calculation of the distribution of deaths for areas where mortality data are either scarce or unavailable. PMID:12502433

  18. Allelic loss of chromosome 16q in endometrial cancer: correlation with poor prognosis of patients and less differentiated histology.

    PubMed

    Kihana, T; Yano, N; Murao, S; Iketani, H; Hamada, K; Yano, J; Murao, S; Iketani, H; Hamada, K; Yano, J; Matsuura, S

    1996-11-01

    Deletion of certain chromosomal regions can be demonstrated in malignant cells. Chromosome 16q is one of the regions where allelic loss is frequently detected in carcinoma of the breast and many other tumors, suggesting that gene(s) which retard tumor growth may exist here. To elucidate the clinicopathological significance of chromosome 16q, loss of heterozygosity (LOH) was investigated using microsatellite polymorphism analysis in 58 patients with endometrial lesions (50 with endometrial carcinoma and 8 who had hyperplasia with or without atypia). When 11 regions of chromosome 16q were examined, LOH was found in 20 patients with carcinoma (40%) and none of the patients with hyperplasia. The tumors of 9 of the 20 patients (45%) showed total loss of 16q, while the others (55%) showed partial deletion. Tumors with LOH were histologically less differentiated than those without LOH (P = 0.038, chi2 test). Patients with tumors showing LOH of 16q had a worse prognosis than those without LOH according to Kaplan-Meier survival analysis (P=0.0158, log-rank test). In addition, LOH of 16q showed a significant relationship to prognosis by Cox regression analysis. Deletion mapping of 16q demonstrated that two regions (16q22.1 and 16q22.2-23.1) were frequently involved. Patients with 16q22.1 LOH had a poorer prognosis than those with intact 16q22.1 (P=0.0003, log-rank test). These findings suggest that gene(s) of which defect is possibly related to the aggressiveness of endometrial cancer are localized on a limited region of 16q that includes 16q22.1. PMID:9045949

  19. The application of microarray technology to the analysis of the cancer genome.

    PubMed

    Cowell, John K; Hawthorn, Lesleyann

    2007-02-01

    The identification of genetic events that are involved in the development of human cancer has been facilitated through the development and application of a diverse series of high resolution, high throughput microarray platforms. Essentially there are two types of array; those that carry PCR products from cloned nucleic acids (e.g. cDNA, BACs, cosmids) and those that use oligonucleotides. Each has advantages and disadvantages but it is now possible to survey genome wide DNA copy number abnormalities and expression levels to allow correlations between losses, gains and amplifications in tumor cells with genes that are over- and under-expressed in the same samples. The gene expression arrays that provide estimates of mRNA levels in tumors have given rise to exon-specific arrays that can identify both gene expression levels, alternative splicing events and mRNA processing alterations. Oligonucleotide arrays are also being used to interrogate single nucleotide polymorphisms (SNPs) throughout the genome for linkage and association studies and these have been adapted to quantify copy number abnormalities and loss of heterozygosity events. To identify as yet unknown transcripts tiling arrays across the genome have been developed which can also identify DNA methylation changes and be used to identify DNA-protein interactions using ChIP on Chip protocols. Ultimately DNA sequencing arrays will allow resequencing of chromosome regions and whole genomes. With all of these capabilities becoming routine in genomics laboratories, the idea of a systematic characterization of the sum genetic events that give rise to a cancer cell is rapidly becoming a reality. PMID:17311536

  20. 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

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

    PubMed Central

    Obel, J; McKenzie, J; Buenconsejo-Lum, LE; Durand, AM; Ekeroma, A; Souares, Y; Hoy, D; Baravilala, W; Garland, SM; Kjaer, SK; Roth, A

    2015-01-01

    Objective 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. Materials and Methods A cross-sectional questionnaire-based survey among ministry of health officials from 21 Pacific Island countries and territories (n=21). Results 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. Conclusion 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. PMID:25921158

  2. Colorectal cancer carcinogenesis: a review of mechanisms

    PubMed Central

    Tariq, Kanwal; Ghias, Kulsoom

    2016-01-01

    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. PMID:27144067

  3. Genomic copy number changes affecting the thymidylate synthase (TYMS) gene in cancer: a model for patient classification to aid fluoropyrimidine therapy.

    PubMed

    Brody, Jonathan R; Hucl, Tomas; Gallmeier, Eike; Winter, Jordan M; Kern, Scott E; Murphy, Kathleen M

    2006-10-01

    Thymidylate synthase (TS) is an important target for 5-fluorouracil (5FU)-based therapy. The TS polymorphic 5'-untranslated region tandem repeat sequence is under investigation to guide 5FU treatment, yet current protocols omit consideration of copy number changes at the TS locus. We surveyed the TS tandem repeat sequence and found copy number changes in gastrointestinal cancers. Ten of 12 informative cases had loss of heterozygosity (LOH), whereas two others and an additional cell line had a novel TS genotype, allelic imbalance at the TS locus due to polysomy. Experimentally, we studied a diploid colorectal cancer line heterozygous at TS to mimic three common TS genotypes of cancers. Using genetic engineering, we deleted the short tandem repeat (two repeats) allele and retained the long (three repeats) allele to produce artificial LOH at the TS gene; the TS(+/-) line had a reduced TS protein expression and was hypersensitive to 5FU and 5-fluoro-2'-deoxyuridine in vitro as compared with syngeneic control lines. We linked this sensitivity directly to the reduced TS expression by introducing exogenous TS cDNA expression into the TS(+/-) line (i.e., increased TS copies). Our model predicts that the 5FU sensitivity of a tumor is modified by aneuploidy producing copy number changes of TS alleles by one or more of the following: LOH, amplification, and, as presented here, copy number changes due to polysomy. The data suggest that TS copy number in a patient's tumor may be a dominating variable affecting 5FU responsiveness. PMID:17018589

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

    PubMed

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

    2015-10-01

    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

  5. 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

  6. Animal Models of Cancer in the Head and Neck Region

    PubMed Central

    2009-01-01

    Animal models that resemble the cancers of the head and neck region are of paramount importance in studying the carcinogenesis of these diseases. Although several methods for modeling cancer in the head and neck are available, none are fully satisfactory. Subcutaneous xenograft models of cancer in nude mice are often used in preclinical studies. However, these models are problematic in several aspects as they lack the specific interactions that exist between the tumor cells and their native environment. Establishment of tumors at the orthotopic sites restore these distinct patterns of interactions between the tumor and the host organs that are lost or altered when the tumors are established in ectopic sites. With regard to the transgenic model of cancer in the head and neck region, it should be kept in mind that the transgene used to drive the malignant transformation may not be representative of the carcinogenic process found in human tumors. Low penetrance of tumor formation also translates into high cost and time commitment in performing studies with transgenic models. In this review, we will discuss some of the commonly used methods for modeling cancer in the head and neck region including squamous cell carcinoma of the head and neck as well as thyroid carcinoma. PMID:19565028

  7. Animal models of cancer in the head and neck region.

    PubMed

    Kim, Seungwon

    2009-06-01

    Animal models that resemble the cancers of the head and neck region are of paramount importance in studying the carcinogenesis of these diseases. Although several methods for modeling cancer in the head and neck are available, none are fully satisfactory. Subcutaneous xenograft models of cancer in nude mice are often used in preclinical studies. However, these models are problematic in several aspects as they lack the specific interactions that exist between the tumor cells and their native environment. Establishment of tumors at the orthotopic sites restore these distinct patterns of interactions between the tumor and the host organs that are lost or altered when the tumors are established in ectopic sites. With regard to the transgenic model of cancer in the head and neck region, it should be kept in mind that the transgene used to drive the malignant transformation may not be representative of the carcinogenic process found in human tumors. Low penetrance of tumor formation also translates into high cost and time commitment in performing studies with transgenic models. In this review, we will discuss some of the commonly used methods for modeling cancer in the head and neck region including squamous cell carcinoma of the head and neck as well as thyroid carcinoma. PMID:19565028

  8. Comparing Trends in Cancer Rates Across Overlapping Regions

    PubMed Central

    Li, Yi; Tiwari, Ram C.

    2008-01-01

    Monitoring and comparing trends in cancer rates across geographic regions or over different time periods has been one main task of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program as it profiles health care quality as well as decides health care resource allocations within a spatial-temporal framework. A fundamental difficulty, however, arises when such comparisons have to be made for regions or time intervals that overlap, e.g. comparing the change in trends of mortality rates in a local area (e.g. the mortality rate of Breast Cancer in California) with a more global level (i.e. the national mortality rate of Breast Cancer). In view of sparsity of available methodologies, this paper develops a simple corrected Z-test that accounts for such overlapping. The performance of the proposed test over the two-sample “pooled” t-test that assumes independence across comparison groups is assessed via the Pitman asymptotic relative efficiency as well as Monte Carlo simulations and applications to the SEER cancer data. The proposed test will be important for the SEER*STAT software, maintained by the NCI, for the analysis of the SEER data. PMID:18371122

  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. 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

  11. 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.

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

    PubMed

    Putcha, Balananda-Dhurjati Kumar; Jia, Xu; Katkoori, Venkat Rao; 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

  13. 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

  14. Mutation analysis of PALB2 in BRCA1 and BRCA2-negative breast and/or ovarian cancer families from Eastern Ontario, Canada

    PubMed Central

    2014-01-01

    Background PALB2 has emerged as a breast cancer susceptibility gene. Mutations in PALB2 have been identified in almost all breast cancer populations studied to date, but the rarity of these mutations and lack of information regarding their penetrance makes genetic counseling for these families challenging. We studied BRCA1/2 -negative breast and/or ovarian cancer families to a) assess the contribution of PALB2 mutations in this series and b) identify clinical, pathological and family history characteristics that might make PALB2 screening more efficient. Methods The coding region of the PALB2 gene was analyzed in 175 probands with family histories of breast and/or ovarian cancer ascertained from a single Canadian institution in Eastern Ontario. Results We identified 2 probands with PALB2 mutations that are known or strongly considered to be pathogenic and 3 probands with missense mutations that are possibly pathogenic. One of the identified truncating mutations [c.3113G > A (p.Gly1000_Trp1038del – major product)], has been previously described while the other four mutations [c.3507_3508delTC (p.H1170Ffs*19), c.1846G > C (p.D616H), c.3418 T > G (p.W1140G), c.3287A > G (p.N1096S)] have not been previously reported. Loss of heterozygosity was detected in two breast tumors from one c.3507_3508delTC mutation carrier but not in other available tumors from that family or in tumors from carriers of other mutations. Conclusions PALB2 mutation screening identifies a small, but significant number of mutations in BRCA1/2 -negative breast and/or ovarian cancer families. We show that mutations are more likely to be found in families with three or more breast cancers as well as other BRCA2-related cancers. In our cohort, both clearly pathogenic mutations were identified in premenopausal breast cancer cases (2/77, 2.6%). Testing should be preferentially offered to affected women from such families. PMID:25225577

  15. 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

  16. A Common Region of Deletion on Chromosome 17q in Both Sporadic and Familial Epithelial Ovarian Tumors Distal to BRCA1

    PubMed Central

    Godwin, Andrew K.; Vanderveer, Lisa; Schultz, David C.; Lynch, Henry T.; Altomare, Deborah A.; Buetow, Kenneth H.; Daly, Mary; Getts, Lori A.; Masny, Agnes; Rosenblum, Norman; Hogan, Michael; Ozols, Robert F.; Hamilton, Thomas C.

    1994-01-01

    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 17pl3.1 and 17pl3.3 markers. When six polymorphic markers flanking the familial breast/ovarian cancer susceptibility locus on 17ql2-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 −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. ImagesFigure 1Figure 3 PMID:7942844

  17. 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

  18. Association of allelic losses on human chromosomal arms 11Q and 16Q in sporadic breast cancer.

    PubMed

    Schmutzler, R K; Fimmers, R; Bierhoff, E; Lohmar, B; Homann, A; Speiser, P; Kubista, E; Jaeger, K; Krebs, D; Zeillinger, R; Wiestler, O D; Von Deimling, A

    1996-08-22

    Breast-carcinoma development presumably results from multiple mutational events in tumor-associated genes. Certain results indicate that some tumor-suppressor genes may combine their pathogenetic potential to synergistically promote tumor growth. In an effort to identify such mechanisms in breast tumors, a series of 77 (group I) paired blood tumor samples from patients with sporadic mammary carcinomas was analyzed for loss of heterozygosity with 15 polymorphic markers on the chromosomal arms 7q, 11q, 13q, 16q, 17p and 17q. A significant association was observed for the combination of allelic losses on chromosomes 11q and 16q. In order to confirm these findings, we studied a second independent series of 189 breast-tumor patients (group 2) with comparable histopathological tumor stages. Group 2 was examined for the same genetic alterations using the identical set of polymorphic markers. The data from this group confirmed the detected association of loss of heterozygosity on chromosomes 11q and 16q and indicate the cooperation of putative tumor-suppressor genes on the chromosomal arms 11q and 16q in a sub-set of breast carcinomas. The regions involved harbor the candidate genes ATM (mutated in ataxiatelangiectasia) on chromosome 11q23 and UVO (uvomorulin, cadherin E) and BBCI (breast basic conserved I) on chromosome 16q22-q24. PMID:8797873

  19. Endometrial and cervical cancer: incidence and mortality among women in the Lodz region

    PubMed Central

    Leśniczak, Beata; Krasomski, Grzegorz; Oszukowski, Przemysław; Woźniak, Piotr

    2015-01-01

    Introduction By the early 21st century the most common cancer of female genitals in Poland was cervical cancer. Now endometrial cancer ranks first. The aim of this study was to analyse the incidence and mortality of endometrial and cervical cancer among women in the Lodz region. Material and methods Data on the incidence and mortality of endometrial and cervical cancer among inhabitants of the Lodz region were obtained from the National Cancer Registry and Bulletin of Cancer Cases in the Lodz region. The analysis covered ten consecutive years beginning in 2001. Results The number of new cases reported in 2010 exceeded that observed in 2001 by 181. The standardized incidence rate of endometrial cancer increased by 6.3, while the standardized incidence rate of cervical cancer decreased by 1.4. Conclusions In the years 2001-2010, the incidence of endometrial cancer increased by 88.3% and that of cervical cancer decreased by 6.5% among inhabitants of the Lodz region. In the years 2001-2010, mortality of endometrial cancer increased by 24.5% and that of cervical cancer decreased by 12.6%. In 2010, the highest crude incidence rates in the Lodz region of both endometrial and cervical cancer at 39.1 were recorded in the district town of Piotrków. PMID:26528109

  20. Specific gene hypomethylation and cancer: New insights into coding region feature trends

    PubMed Central

    Daura-Oller, Elias; Cabre, Maria; Montero, Miguel A; Paternain, Jose L; Romeu, Antoni

    2009-01-01

    Giving coding region structural features a role in the hypomethylation of specific genes, the occurrence of G+C content, CpG islands, repeat and retrotransposable elements in demethylated genes related to cancer has been evaluated. A comparative analysis among different cancer types has also been performed. In this work, the inter-cancer coding region features comparative analysis carried out, show insights into what structural trends/patterns are present in the studied cancers. PMID:19707296

  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. Specific TP53 Mutants Overrepresented in Ovarian Cancer Impact CNV, TP53 Activity, Responses to Nutlin-3a, and Cell Survival1

    PubMed Central

    Mullany, Lisa K.; Wong, Kwong-Kwok; Marciano, David C.; Katsonis, Panagiotis; King-Crane, Erin R.; Ren, Yi Athena; Lichtarge, Olivier; Richards, JoAnne S.

    2015-01-01

    Evolutionary Action analyses of The Cancer Gene Atlas data sets show that many specific p53 missense and gain-of-function mutations are selectively overrepresented and functional in high-grade serous ovarian cancer (HGSC). As homozygous alleles, p53 mutants are differentially associated with specific loss of heterozygosity (R273; chromosome 17); copy number variation (R175H; chromosome 9); and up-stream, cancer-related regulatory pathways. The expression of immune-related cytokines was selectively related to p53 status, showing for the first time that specific p53 mutants impact, and are related to, the immune subtype of ovarian cancer. Although the majority (31%) of HGSCs exhibit loss of heterozygosity, a significant number (24%) maintain a wild-type (WT) allele and represent another HGSC subtype that is not well defined. Using human and mouse cell lines, we show that specific p53 mutants differentially alter endogenous WT p53 activity; target gene expression; and responses to nutlin-3a, a small molecular that activates WT p53 leading to apoptosis, providing “proof of principle” that ovarian cancer cells expressing WT and mutant alleles represent a distinct ovarian cancer subtype. We also show that siRNA knock down of endogenous p53 in cells expressing homozygous mutant alleles causes apoptosis, whereas cells expressing WT p53 (or are heterozygous for WT and mutant p53 alleles) are highly resistant. Therefore, despite different gene regulatory pathways associated with specific p53 mutants, silencing mutant p53 might be a suitable, powerful, global strategy for blocking ovarian cancer growth in those tumors that rely on mutant p53 functions for survival. Knowing p53 mutational status in HGSC should permit new strategies tailored to control this disease. PMID:26585234

  3. Population-Based Regional Cancer Incidence in Korea: Comparison between Urban and Rural Areas

    PubMed Central

    Song, Haa-Na; Go, Se-Il; Lee, Won Sup; Kim, Yire; Choi, Hye Jung; Lee, Un Seok; Kang, Myoung Hee; Lee, Gyeong-Won; Kim, Hoon-Gu; Kang, Jung Hun; Kang, Yune Sik; Lee, Jeong-Hee; Jung, Jin-Myung; Hong, Soon Chan

    2016-01-01

    Purpose The purpose of this study is to investigate differences in organ-specific cancer incidence according to the region and population size in Korea. Materials and Methods We reviewed the data of the cancer registration program of Gyeongnam Regional Cancer Center between 2008 and 2011. Age-standardized rates of cancer incidence were analyzed according to population size of the region and administrative zone. Results Incidence of thyroid cancer has been increasing rapidly in both urban and rural areas. However, the thyroid cancer incidence was much lower in rural areas than in urban areas and megalopolis such as Seoul. Gastric cancer was relatively more common in rural areas, in megalopolis near the sea (Ulsan, Busan, and Incheon), and other southern provinces (Chungcheongnam-do, Gyeongsangbuk-do, and Gyeongsangnam-do). A detailed analysis in Gyeongsangnam-do revealed that rural areas have relatively low incidence of thyroid and colorectal cancer, and relatively high incidence of gastric and lung cancer compared to urban areas. Conclusion This study suggests that there are some differences in cancer incidence by population size. Thyroid and colorectal cancer incidence was increasing, and gastric and lung cancer was slightly decreasing in urban areas, whereas gastric and lung cancer incidence still remains high in rural areas. PMID:26194369

  4. 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

  5. Geographical spread of gastrointestinal tract cancer incidence in the Caspian Sea region of Iran: Spatial analysis of cancer registry data

    PubMed Central

    Mohebbi, Mohammadreza; Mahmoodi, Mahmood; Wolfe, Rory; Nourijelyani, Keramat; Mohammad, Kazem; Zeraati, Hojjat; Fotouhi, Akbar

    2008-01-01

    Background High incidence rates of gastrointestinal tract cancers have been reported in the Caspian region of Iran. This study aimed to: 1) describe the geographical spatial patterns of gastrointestinal tract cancer incidence based on cancer registry data and, 2) determine whether geographical clusters of statistical significance exist. Methods The Babol Cancer Registry, which covers the two major northern Iranian provinces of Mazandaran and Golestan (total population = 4,484,622) was used to identify new gastrointestinal tract cancer cases during 2001 to 2005. Age-specific cancer incidence rates were calculated for 7 gastrointestinal tract cancer sites in 26 wards of the Mazandaran and Golestan provinces. Spatial autocorrelation indices, hierarchical Bayesian Poisson models, and spatial scan statistics were used in measuring the geographic pattern and clusters. Results There were non-random spatial patterns in esophageal and stomach cancers that were similar for both sexes. Clusters of high incidence were identified in esophageal, stomach, colorectal and liver cancer for both sexes, as well as a possible cluster of pancreas cancer in males. Conclusion Gastrointestinal tract cancers exhibit significant spatial clustering of risk in northern Iran. Further work is needed to relate these geographical patterns to information on potential life-style and environmental factors. PMID:18479519

  6. 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

  7. 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.

  8. 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.

  9. Clinical significance of promoter region hypermethylation of microRNA-148a in gastrointestinal cancers

    PubMed Central

    Sun, Jingxu; Song, Yongxi; Wang, Zhenning; Wang, Guoli; Gao, Peng; Chen, Xiaowan; Gao, Zhaohua; Xu, Huimian

    2014-01-01

    Background MicroRNAs are associated with tumor genesis and progression in various carcinomas. MicroRNA-148a (miR-148a) was reported to have low expression in gastrointestinal cancers, and might be regulated by promoter region DNA methylation. Methods Bisulfite-modified sequencing was used to determine the promoter region DNA methylation status of human gastrointestinal cancer cell lines. Expression levels of miR-148a in cell lines treated with 5-aza-2′-deoxycytidine were determined by quantitative real-time polymerase chain reaction. Total DNA was extracted from the tissues of 64 patients with gastric cancer and 51 patients with colorectal cancer. Methylation status was determined by methylation-specific polymerase chain reaction. All statistical analyses were performed with SPSS 17.0 software. Results The promoter regions of genes in human gastrointestinal cancer cell lines were all hypermethylated, except for HT-29, and the expression of miR-148a tended to be higher than in controls after treatment with 5-aza-2′-deoxycytidine. The methylation-specific polymerase chain reaction results showed that 56.25% of gastric cancer tissues and 19.61% of colorectal cancer tissues were hypermethylated. A strong correlation was found between the expression of miR-148a and the methylation status of promoter regions (P<0.001, chi-square test and Pearson’s correlation). Furthermore, promoter region CpG site hypermethylation of miR-148a was correlated with increased tumor size (P=0.01) in gastric cancer after analyzing the correlation between methylation status and clinicopathologic characteristics. Conclusion The promoter region CpG sites were hypermethylated in gastrointestinal cancers. Promoter region hypermethylation status was associated with the expression of miR-148a and tumor invasiveness in gastric cancer, and may prove to be a new biomarker and method for treating gastric cancer. PMID:24920927

  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. 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

  12. Patterns and functional implications of rare germline variants across 12 cancer types.

    PubMed

    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

  13. Lung cancers unrelated to smoking: characterized by single oncogene addiction?

    PubMed

    Suda, Kenichi; Tomizawa, Kenji; Yatabe, Yasushi; Mitsudomi, Tetsuya

    2011-08-01

    Lung cancer is a major cause of cancer-related mortality worldwide. Currently, adenocarcinoma is its most common histological subtype in many countries. In contrast with small cell lung cancer or squamous cell carcinoma, lung adenocarcinoma often arises in never-smokers, especially in East Asian countries, as well as in smokers. Adenocarcinoma in never-smokers is associated with a lower incidence of genetic alterations (i.e., somatic mutations, loss of heterozygosity, and methylation) than in smokers. In addition, most adenocarcinomas in never-smokers harbor one of the proto-oncogene aberrations that occur in a mutually exclusive manner (EGFR mutation, KRAS mutation, HER2 mutations, or ALK translocation). It is of note that the proliferation and survival of lung cancer cells that harbor one of these oncogenic aberrations depend on the signaling from each aberrantly activated oncoprotein (oncogene addiction). Therefore, most adenocarcinomas in never-smokers can be effectively treated by molecularly targeted drugs that inhibit each oncoprotein. Moreover, from a pathological aspect, lung adenocarcinoma in never-smokers is characterized by terminal respiratory unit-type adenocarcinoma and a particular gene expression profile. Finally, epidemiological analyses have identified many candidate causes of lung cancer in never-smokers (genetic, environmental, and hormonal factors). The elucidation of the particular features of lung cancer unrelated to smoking and the development of new therapeutic modalities may reduce the mortality from lung cancers in the future. PMID:21655907

  14. The Role of Sialyl-Tn in Cancer

    PubMed Central

    Munkley, Jennifer

    2016-01-01

    Activation of an aberrant glycosylation pathway in cancer cells can lead to expression of the onco-foetal sialyl-Tn (sTn) antigen. STn is a truncated O-glycan containing a sialic acid α-2,6 linked to GalNAc α-O-Ser/Thr and is associated with an adverse outcome and poor prognosis in cancer patients. The biosynthesis of the sTn antigen has been linked to the expression of the sialytransferase ST6GalNAc1, and also to mutations in and loss of heterozygosity of the COSMC gene. sTn neo- or over-expression occurs in many types of epithelial cancer including gastric, colon, breast, lung, oesophageal, prostate and endometrial cancer. sTn is believed to be carried by a variety of glycoproteins and may influence protein function and be involved in tumour development. This review discusses how the role of sTn in cancer development and tumour cell invasiveness might be organ specific and occur through different mechanisms depending on each cancer type or subtype. As the sTn-antigen is expressed early in carcinogenesis targeting sTn in cancer may enable the targeting of tumours from the earliest stage. PMID:26927062

  15. 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

  16. 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

  17. Mutations of the E-cadherin gene in human gynecologic cancers.

    PubMed

    Risinger, J I; Berchuck, A; Kohler, M F; Boyd, J

    1994-05-01

    Expression of the E-cadherin cell adhesion molecule is reduced in several types of human carcinomas, and the protein serves as an invasion suppressor in vitro. To determine if mutations of the E-cadherin gene (on chromosome 16q22) contribute to epithelial tumorigenesis, 135 carcinomas of the endometrium and ovary were examined for alterations in the E-cadherin coding region. Four mutations were identified: one somatic nonsense and one somatic missense mutation, both with retention of the wild-type alleles, and two missense mutations with somatic loss of heterozygosity in the tumour tissue. These data support the classification of E-cadherin as a human tumour suppressor gene. PMID:8075649

  18. Environmental effect and genetic influence: a regional cancer predisposition survey in the Zonguldak region of Northwest Turkey

    NASA Astrophysics Data System (ADS)

    Kadir, Selahattin; Önen-Hall, A. Piril; Aydin, S. Nihal; Yakicier, Cengiz; Akarsu, Nurten; Tuncer, Murat

    2008-03-01

    The Cretaceous-Eocene volcano-sedimentary units of the Zonguldak region of the western Black Sea consist of subalkaline andesite and tuff, and sandstone dominated by smectite, kaolinite, accessory chlorite, illite, mordenite, and analcime associated with feldspar, quartz, opal-CT, amphibole, and calcite. Kaolinization, chloritization, sericitization, albitization, Fe-Ti-oxidation, and the presence of zeolite, epidote, and illite in andesitic rocks and tuffaceous materials developed as a result of the degradation of a glass shards matrix, enclosed feldspar, and clinopyroxene-type phenocrysts, due to alteration processes. The association of feldspar and glass with smectite and kaolinite, and the suborientation of feldspar-edged, subparallel kaolinite plates to fracture axes may exhibit an authigenic smectite or kaolinite. Increased alteration degree upward in which Al, Fe, and Ti are gained, and Si, Na, K, and Ca are depleted, is due to the alteration following possible diagenesis and hydrothermal activities. Micromorphologically, fibrous mordenite in the altered units and the presence of needle-type chrysotile in the residential buildings in which cancer cases lived were detected. In addition, the segregation pattern of cancer susceptibility in the region strongly suggested an environmental effect and a genetic influence on the increased cancer incidence in the region. The most likely diagnosis was Li-Fraumeni syndrome, which is one of the hereditary cancer predisposition syndromes; however, no mutations were observed in the p53 gene, which is the major cause of Li-Fraumeni syndrome. The micromorphology observed in the altered units in which cancer cases were detected may have a role in the expression of an unidentified gene, but does not explain alone the occurrence of cancer as a primary cause in the region.

  19. 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

  20. Myeloperoxidase promoter region polymorphism and lung cancer risk.

    PubMed

    Wu, Xifeng; Schabath, Matthew B; Spitz, Margaret R

    2003-01-01

    Historically, myeloperoxidase activity and subsequent production of hypochlorous acid has been associated with the killing of host-invading microorganisms (bacteria, viruses, and fungi). Currently, there is a wealth of evidence that the MPO polymorphism and enzyme activity is associated with a wide range of pathological and biological processes, including lung cancer carcinogenesis. Although the molecular epidemiology reports reviewed in this chapter are not in complete agreement on all aspects of their findings, it is evident that the MPO polymorphism contributes to the modulation of overall lung cancer risk. Four of the five molecular epidemiologic studies reviewed in this chapter utilized similar case-control study designs with quite different sources of populations. These studies all demonstrate that the MPO variant genotype modulates overall lung cancer risk. However, these studies are not in agreement regarding age and gender effects, and gene-environmental interactions. The nested case control study designed utilized by Misra et al. (35) is a valid and sound approach, but their results found no evidence of an association. Certainly, heterogeneity in study populations can contribute to the variability between these studies. Additionally, epidemiologic issues such as case-control matching and sources of control populations may contribute to the conflicting findings. Thus, the publication of inconsistent or null studies as well as other positive findings is certainly encouraged to elucidate the range of effects associated with the MPO polymorphism and lung cancer risk. PMID:12407737

  1. 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

  2. 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

  3. Variants on the promoter region of PTEN affect breast cancer progression and patient survival

    PubMed Central

    2011-01-01

    Introduction The PTEN gene, a regulator of the phosphatidylinositol-3-kinase (PI3K)/Akt oncogenic pathway, is mutated in various cancers and its expression has been associated with tumor progression in a dose-dependent fashion. We investigated the effect of germline variation in the promoter region of the PTEN gene on clinical characteristics and survival in breast cancer. Methods We screened the promoter region of the PTEN gene for germline variation in 330 familial breast cancer cases and further determined the genotypes of three detected PTEN promoter polymorphisms -903GA, -975GC, and -1026CA in a total of 2,412 breast cancer patients to evaluate the effects of the variants on tumor characteristics and disease outcome. We compared the gene expression profiles in breast cancers of 10 variant carriers and 10 matched non-carriers and performed further survival analyses based on the differentially expressed genes. Results All three promoter variants associated with worse prognosis. The Cox's regression hazard ratio for 10-year breast cancer specific survival in multivariate analysis was 2.01 (95% CI 1.17 to 3.46) P = 0.0119, and for 5-year breast cancer death or distant metastasis free survival 1.79 (95% CI 1.03 to 3.11) P = 0.0381 for the variant carriers, indicating PTEN promoter variants as an independent prognostic factor. The breast tumors from the promoter variant carriers exhibited a similar gene expression signature of 160 differentially expressed genes compared to matched non-carrier tumors. The signature further stratified patients into two groups with different recurrence free survival in independent breast cancer gene expression data sets. Conclusions Inherited variation in the PTEN promoter region affects the tumor progression and gene expression profile in breast cancer. Further studies are warranted to establish PTEN promoter variants as clinical markers for prognosis in breast cancer. PMID:22171747

  4. Regional variations in cancer survival: Impact of tumour stage, socioeconomic status, comorbidity and type of treatment in Norway.

    PubMed

    Skyrud, Katrine Damgaard; Bray, Freddie; Eriksen, Morten Tandberg; Nilssen, Yngvar; Møller, Bjørn

    2016-05-01

    Cancer survival varies by place of residence, but it remains uncertain whether this reflects differences in tumour, patient and treatment characteristics (including tumour stage, indicators of socioeconomic status (SES), comorbidity and information on received surgery and radiotherapy) or possibly regional differences in the quality of delivered health care. National population-based data from the Cancer Registry of Norway were used to identify cancer patients diagnosed in 2002-2011 (n = 258,675). We investigated survival from any type of cancer (all cancer sites combined), as well as for the six most common cancers. The effect of adjusting for prognostic factors on regional variations in cancer survival was examined by calculating the mean deviation, defined by the mean absolute deviation of the relative excess risks across health services regions. For prostate cancer, the mean deviation across regions was 1.78 when adjusting for age and sex only, but decreased to 1.27 after further adjustment for tumour stage. For breast cancer, the corresponding mean deviations were 1.34 and 1.27. Additional adjustment for other prognostic factors did not materially change the regional variation in any of the other sites. Adjustment for tumour stage explained most of the regional variations in prostate cancer survival, but had little impact for other sites. Unexplained regional variations after adjusting for tumour stage, SES indicators, comorbidity and type of treatment in Norway may be related to regional inequalities in the quality of cancer care. PMID:26679150

  5. Genetic polymorphisms in the 9p21 region associated with risk of multiple cancers.

    PubMed

    Li, Wen-Qing; Pfeiffer, Ruth M; Hyland, Paula L; Shi, Jianxin; Gu, Fangyi; Wang, Zhaoming; Bhattacharjee, Samsiddhi; Luo, Jun; Xiong, Xiaoqin; Yeager, Meredith; Deng, Xiang; Hu, Nan; Taylor, Philip R; Albanes, Demetrius; Caporaso, Neil E; Gapstur, Susan M; Amundadottir, Laufey; Chanock, Stephen J; Chatterjee, Nilanjan; Landi, Maria Teresa; Tucker, Margaret A; Goldstein, Alisa M; Yang, Xiaohong R

    2014-12-01

    The chromosome 9p21 region has been implicated in the pathogenesis of multiple cancers. We analyzed 9p21 single nucleotide polymorphisms (SNPs) from eight genome-wide association studies (GWAS) with data deposited in dbGaP, including studies of esophageal squamous cell carcinoma (ESCC), gastric cancer (GC), pancreatic cancer, renal cell carcinoma (RCC), lung cancer (LC), breast cancer (BrC), bladder cancer (BC) and prostate cancer (PrC). The number of subjects ranged from 2252 (PrC) to 7619 (LC). SNP-level analyses for each cancer were conducted by logistic regression or random-effects meta-analysis. A subset-based statistical approach (ASSET) was performed to combine SNP-level P values across multiple cancers. We calculated gene-level P values using the adaptive rank truncated product method. We identified that rs1063192 and rs2157719 in the CDKN2A/2B region were significantly associated with ESCC and rs2764736 (3' of TUSC1) was associated with BC (P ≤ 2.59 × 10(-6)). ASSET analyses identified four SNPs significantly associated with multiple cancers: rs3731239 (CDKN2A intronic) with ESCC, GC and BC (P = 3.96 × 10(-) (4)); rs10811474 (3' of IFNW1) with RCC and BrC (P = 0.001); rs12683422 (LINGO2 intronic) with RCC and BC (P = 5.93 × 10(-) (4)) and rs10511729 (3' of ELAVL2) with LC and BrC (P = 8.63 × 10(-) (4)). At gene level, CDKN2B, CDKN2A and CDKN2B-AS1 were significantly associated with ESCC (P ≤ 4.70 × 10(-) (5)). Rs10511729 and rs10811474 were associated with cis-expression of 9p21 genes in corresponding cancer tissues in the expression quantitative trait loci analysis. In conclusion, we identified several genetic variants in the 9p21 region associated with the risk of multiple cancers, suggesting that this region may contribute to a shared susceptibility across different cancer types. PMID:25239644

  6. Differentiated thyroid cancer: feasibility of loboisthmectomy in an endemic region

    PubMed Central

    CALÒ, P.G.; ERDAS, E.; MEDAS, F.; GORDINI, L.; LONGHEU, A.; PISANO, G.; NICOLOSI, A.

    2015-01-01

    Aim The aim of the present retrospective study was to assess the feasibility of loboisthmectomy for the treatment of differentiated thyroid cancer in a endemic area, evaluating the histopathological features and the results of a case series of 1154 patients. Patients and Methods The clinical records of 1154 patients submitted to total thyroidectomy in our Department were retrospectively reviewed to analyze the histopathological characters and the results. Results In 1044 cases (90.5%) a papillary cancer was observed, in 110 (9.5%) a follicular carcinoma; microcarcinomas were 399 (34.5%). Multifocality was present in 323 cases (28%), in 142 unilateral (12.3%) and in 181 bilateral (15.7%). Thyroiditis coexisted in 472 patients (40.9%), multinodular goiter in 404 (35%), Graves’ disease in 48 (4.1%), and multinodular toxic goiter in 38 (3.3%). Complications were: postoperative bleeding in 20 patients (1.7%), transient unilateral vocal cord paralysis in 20 (1.7%) definitive in 10 (0.86%), a transient bilateral paralysis in 1 (0.08%), a transient hypoparathyroidism in 351 (30.4%), and a definitive in 24 (2.07%). Nodal recurrence occurred in 25 patients (2.16%). Conclusions Total thyroidectomy remains the safest treatment in differentiated thyroid cancer, especially if performed in high volume centers in which complications can be minimized. Loboisthmectomy can be a viable and safe alternative in small (< 1 cm) unifocal tumors in patients at low risk. Loboisthmectomy is limited in endemic areas by the association with other thyroid diseases. A correct and detailed information of the patient is essential before planning surgery. PMID:26888701

  7. 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. PMID:27013474

  8. The Relationship between Eating and Lifestyle Habits and Cancer in Van Lake Region: Another Endemic Region for Esophageal and Gastric Cancers

    PubMed Central

    Celik, Sebahattin; Yılmaz, E. Murat; Özden, Ferhat; Kotan, Cetin

    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. PMID:25648523

  9. The state of regional therapy in the management of metastatic colorectal cancer to the liver.

    PubMed

    Cho, May; Gong, Jun; Fakih, Marwan

    2016-01-01

    Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality in the United States. Most colorectal cancer patients die from advanced disease, and two-thirds of CRC deaths are due to liver metastases. Liver resection provides the best curative option for patients with colorectal liver metastases (CRLM), yet only 20% of those patients are eligible for liver metastases resection for curative intent. Loco-regional treatment of CRLM may provide additional benefits in terms of down-staging for resection and prolonged hepatic disease control. This review focusses on hepatic arterial infusion, radioembolization and chemoembolization. PMID:26652741

  10. Roles of cancer registries in enhancing oncology drug access in the Asia-Pacific region.

    PubMed

    Soon, Swee-Sung; Lim, Hwee-Yong; Lopes, Gilberto; Ahn, Jeonghoon; Hu, Min; Ibrahim, Hishamshah Mohd; Jha, Anand; Ko, Bor-Sheng; Lee, Pak Wai; Macdonell, Diana; Sirachainan, Ekaphop; Wee, Hwee-Lin

    2013-01-01

    Cancer registries help to establish and maintain cancer incidence reporting systems, serve as a resource for investigation of cancer and its causes, and provide information for planning and evaluation of preventive and control programs. However, their wider role in directly enhancing oncology drug access has not been fully explored. We examined the value of cancer registries in oncology drug access in the Asia-Pacific region on three levels: (1) specific registry variable types; (2) macroscopic strategies on the national level; and (3) a regional cancer registry network. Using literature search and proceedings from an expert forum, this paper covers recent cancer registry developments in eight economies in the Asia-Pacific region - Australia, China, Hong Kong, Malaysia, Singapore, South Korea, Taiwan, and Thailand - and the ways they can contribute to oncology drug access. Specific registry variables relating to demographics, tumor characteristics, initial treatment plans, prognostic markers, risk factors, and mortality help to anticipate drug needs, identify high-priority research area and design access programs. On a national level, linking registry data with clinical, drug safety, financial, or drug utilization databases allows analyses of associations between utilization and outcomes. Concurrent efforts should also be channeled into developing and implementing data integrity and stewardship policies, and providing clear avenues to make data available. Less mature registry systems can employ modeling techniques and ad-hoc surveys while increasing coverage. Beyond local settings, a cancer registry network for the Asia-Pacific region would offer cross-learning and research opportunities that can exert leverage through the experiences and capabilities of a highly diverse region. PMID:23725106

  11. 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. PMID:26563255

  12. 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. PMID:26047366

  13. Global and regional estimates of cancer mortality and incidence by site: II. results for the global burden of disease 2000

    PubMed Central

    Shibuya, Kenji; Mathers, Colin D; Boschi-Pinto, Cynthia; Lopez, Alan D; Murray, Christopher JL

    2002-01-01

    Background Mortality estimates alone are not sufficient to understand the true magnitude of cancer burden. We present the detailed estimates of mortality and incidence by site as the basis for the future estimation of cancer burden for the Global Burden of Disease 2000 study. Methods Age- and sex- specific mortality envelope for all malignancies by region was derived from the analysis of country life-tables and cause of death. We estimated the site-specific cancer mortality distributions from vital records and cancer survival model. The regional cancer mortality by site is estimated by disaggregating the regional cancer mortality envelope based on the mortality distribution. Estimated incidence-to-mortality rate ratios were used to back calculate the final cancer incidence estimates by site. Results In 2000, cancer accounted for over 7 million deaths (13% of total mortality) and there were more than 10 million new cancer cases world wide in 2000. More than 60% of cancer deaths and approximately half of new cases occurred in developing regions. Lung cancer was the most common cancers in the world, followed by cancers of stomach, liver, colon and rectum, and breast. There was a significant variations in the distribution of site-specific cancer mortality and incidence by region. Conclusions Despite a regional variation, the most common cancers are potentially preventable. Cancer burden estimation by taking into account both mortality and morbidity is an essential step to set research priorities and policy formulation. Also it can used for setting priorities when combined with data on costs of interventions against cancers. PMID:12502432

  14. 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

  15. 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. PMID:24486917

  16. 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

  17. Effect of Tumor Deposits on Overall Survival in Colorectal Cancer Patients with Regional Lymph Node Metastases

    PubMed Central

    Yabata, Eiichi; Udagawa, Masaru; Okamoto, Hiroyuki

    2014-01-01

    Objectives: The staging system of the International Union Against Cancer considers tumor deposits to be N1c in patients with no regional lymph node metastasis, but the significance of tumor deposits in patients with regional lymph node metastases is unclear. We investigated the effect of tumor deposits on overall survival in colorectal cancer patients with regional lymph node metastases. Patients and Methods: From 2000 to 2008, 551 patients underwent resections for colorectal cancer at our medical center. We excluded 87 patients who had distant metastases or had received neoadjuvant chemotherapy or radiotherapy from our study and statistically analyzed the remaining 464 patients. Results: Stepwise multivariate Cox proportional hazards analysis in patients with regional lymph node metastases showed only tumor deposits to be significant for overall survival (hazard ratio: 2.813; P = 0.0002). Recurrence was seen in 49.2% of patients with tumor deposits (30/61) compared with 14.4% of patients without them (58/403; P < 0.0001). Tumor deposits did not show the same effect on overall survival as lymph node metastases. Conclusions: Tumor deposits were significantly associated with poorer overall survival in colorectal cancer patients with regional lymph node metastases. The effect of tumor deposits on overall survival was between that of lymph node metastasis and distant metastasis. PMID:25648159

  18. 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

  19. 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

  20. 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

  1. 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

  2. Updates on HIPK2: a resourceful oncosuppressor for clearing cancer

    PubMed Central

    2012-01-01

    Homeodomain-interacting protein kinase 2 (HIPK2) is a multitalented protein that exploits its kinase activity to modulate key molecular pathways in cancer to restrain tumor growth and induce response to therapies. HIPK2 phosphorylates oncosuppressor p53 for apoptotic activation. In addition, also p53-independent apoptotic pathways are regulated by HIPK2 and can be exploited for anticancer purpose too. Therefore, HIPK2 activity is considered a central switch in targeting tumor cells toward apoptosis upon genotoxic damage and the preservation and/or restoration of HIPK2 function is crucial for an efficient tumor response to therapies. As a proof of principle, HIPK2 knockdown impairs p53 function, induces chemoresistance, angiogenesis, and tumor growth in vivo, on the contrary, HIPK2 overexpression activates apoptotic pathways, counteracts hypoxia, inhibits angiogenesis, and induces chemosensitivity both in p53-dependent and -independent ways. The role of HIPK2 in restraining tumor development was also confirmed by studies with HIPK2 knockout mice. Recent findings demonstrated that HIPK2 inhibitions do exist in tumors and depend by several mechanisms including HIPK2 cytoplasmic localization, protein degradation, and loss of heterozygosity (LOH), recapitulating the biological outcome obtained by RNA interference studies in tumor cells, such as p53 inactivation, resistance to therapies, apoptosis inhibition, and tumor progression. These findings may lead to new diagnostic and therapeutic approaches for treating cancer patients. This review will focus on the last updates about HIPK2 contribution in tumorigenesis and cancer treatment. PMID:22889244

  3. Evaluation of FHIT gene alterations in ovarian cancer.

    PubMed Central

    Buttitta, F.; Marchetti, A.; Radi, O.; Bertacca, G.; Pellegrini, S.; Gadducci, A.; Genazzani, A. R.; Bevilacqua, G.

    1998-01-01

    The FHIT gene, recently cloned and mapped on chromosome 3p14.2, has frequently been found to be abnormal in several established cancer cell lines and primary tumours. As alterations of chromosome 3p are common events in ovarian cancers with breakpoint sites at 3p14.2, we decided to investigate the role of FHIT in human ovarian tumorigenesis. Fifty-four primary ovarian carcinomas were studied by reverse transcription of FHIT mRNA followed by polymerase chain reaction (PCR) amplification and sequencing of products. The same tumours and matched normal tissues were also investigated for loss of heterozygosity using three microsatellite markers located inside the gene. We found an abnormal transcript of the FHIT gene in two cases (4%) and allelic losses in eight cases (15%). Twelve (22%) of the 54 tumours investigated belonged to young patients with a family history of breast/ovarian cancer. In none of these cases was the FHITgene found to be altered. Our results indicate that FHITplays a role in a small proportion of ovarian carcinomas. Images Figure 1 Figure 2 PMID:9569038

  4. Regional brain activation during verbal declarative memory in metastatic breast cancer

    PubMed Central

    Kesler, Shelli R.; Bennett, F. Chris; Mahaffey, Misty L.; Spiegel, David

    2010-01-01

    Purpose To determine the neurofunctional basis of verbal memory dysfunction in women with metastatic breast cancer. This objective was based on previous research suggesting memory and other cognitive deficits in this population. We attempted to determine if verbal memory impairments were related to the most commonly studied disease parameters including adjuvant chemotherapy and chronic stress-related disruption of limbic system structures. Experimental Design We utilized functional magnetic resonance imaging (fMRI) to test our hypothesis that women with breast cancer would demonstrate significantly lower brain activation during a verbal declarative memory tasks compared to age and education-matched healthy female controls. We also assessed several stress-related variables including diurnal cortisol levels to test our hypothesis that women with breast cancer would demonstrate higher stress and this would contribute to brain activation deficits during memory tasks. Results Women with breast cancer had significantly lower prefrontal cortex activation during the memory encoding condition compared to controls. However, the breast cancer group demonstrated significantly greater activation than controls during the recall condition in multiple, diffuse brain regions. There were no significant differences between the groups in stress-related variables. Women who were treated with CMF chemotherapy demonstrated lower prefrontal cortex activation during memory encoding. Conclusions These results suggest that women with metastatic breast cancer may be at risk for verbal memory impairments as a result of altered functional brain activation profiles. These findings may be associated with chemotherapy type and/or other aspects of the breast cancer disease process. PMID:19843664

  5. Aspergillus spp. colonization in exhaled breath condensate of lung cancer patients from Puglia Region of Italy

    PubMed Central

    2014-01-01

    Background Airways of lung cancer patients are often colonized by fungi. Some of these colonizing fungi, under particular conditions, produce cancerogenic mycotoxins. Given the recent interest in the infective origin of lung cancer, with this preliminary study we aim to give our small contribution to this field of research by analysing the fungal microbiome of the exhaled breath condensate of lung cancer patients from Puglia, a region of Italy. Methods We enrolled 43 lung cancer patients and 21 healthy subjects that underwent exhaled breath condensate and bronchial brushing collection. The fungal incidence and nature of sample collected were analysed by using a selected media for Aspergillus species. Results For the first time we were able to analyse the fungal microbioma of the exhaled breath condensate. 27.9% of lung cancer patients showed a presence of Aspergillus niger, or A. ochraceus or Penicillium ssp. while none of the healthy subjects did so. Conclusion The results confirmed the high percentage of fungal colonization of the airways of lung cancer patients from Puglia, suggesting the need to conduct further analyses in this field in order to evaluate the exact pathogenetic role of these fungi in lung cancer as well as to propose efficient, empirical therapy. PMID:24548615

  6. 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. PMID:26317688

  7. Evidence for two tumor suppressor loci associated with proximal chromosome 9p to q and distal chromosome 9q in bladder cancer and the initial screening for GAS1 and PTC mutations.

    PubMed

    Simoneau, A R; Spruck, C H; Gonzalez-Zulueta, M; Gonzalgo, M L; Chan, M F; Tsai, Y C; Dean, M; Steven, K; Horn, T; Jones, P A

    1996-11-01

    The most common genetic alteration identified to date in bladder cancer is loss of heterozygosity (LOH) of chromosome 9, suggesting the presence of possible tumor suppressor genes on this chromosome. We attempted to map the location of these genes by analyzing 69 primary transitional cell carcinomas of the bladder with a panel of microsatellite markers for LOH on chromosome 9. Monosomy 9 (defined by LOH of all informative markers analyzed on 9p and 9q) was detected in 26 of 69 (38%) tumors, and 22 of 69 (32%) tumors showed subchromosomal deletions. Twelve tumors (17%) demonstrated partial LOH of chromosome 9 and indicated two distinct regions of LOH. Eight tumors showed distal allelic loss of 9q with a minimal region of common deletion flanked proximally by marker GSN on 9q33. Six tumors showed proximal allelic loss of 9p and 9q with a minimal area of common deletion flanked by markers D9S970 on 9p12 and D9S283 on 9q21. Two tumors showed loss of both the distal region of 9q and the proximal region of 9p and 9q, which were separated by a possible 6-44 cM of retained genetic material. The proximal minimal area of common deletion excluded 9q22.3-q31 to where two putative tumor suppressor genes, the nevoid basal cell carcinoma syndrome and multiple self-healing squamous epithelioma (ESS1) genes, have been mapped. The growth arrest-specific gene (GAS1), a candidate tumor suppressor gene, was included within the proximal minimal region. We evaluated the GAS1 gene for its potential role in bladder cancer using single-strand conformational polymorphism to screen for mutations in GAS1 in 10 bladder cancer cell lines and 14 primary bladder tumors. A polymorphism at codon 88 was noted in one primary bladder tumor, but no other abnormalities were found, suggesting that another potential tumor suppressor gene important to bladder cancer resides in these minimally deleted regions. Because the nevoid basal cell carcinoma syndrome gene has long been speculated to be a putative

  8. Analysis of regional bone scan index measurements for the survival of patients with prostate cancer

    PubMed Central

    2014-01-01

    Background 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. Methods 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. Results 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. Conclusion 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. PMID:25012268

  9. Local and Regional Staging of Invasive Breast Cancer With Sonography: 25 Years of Practice at MD Anderson Cancer Center

    PubMed Central

    2014-01-01

    At The University of Texas MD Anderson Cancer Center, we have used sonography (US) extensively for more than 2 decades to refine the local and regional staging of invasive breast cancer. Although magnetic resonance imaging is superior to all other imaging modalities in the measurement of the primary tumor and detection of additional foci of malignancy, in our experience US has shown sufficient accuracy in clinical practice to stage most invasive breast cancers. The exceptions are ill-defined tumors such as invasive lobular cancers and tumors in breasts containing extensive diffuse benign disease. An advantage of US is that multifocality or multicentricity can be confirmed via US-guided fine-needle aspiration within 15 minutes and the information shared immediately with the patient and the breast surgeon or medical oncologist. US has also proved indispensable in the evaluation of lymphatic spread because it can evaluate more nodal basins (e.g., the supraclavicular fossa and low neck) than magnetic resonance imaging can and because it can guide needle biopsy to confirm the status of any indeterminate node (including internal mammary nodes) within minutes. PMID:24309983

  10. Identification of Oncogenic Point Mutations and Hyperphosphorylation of Anaplastic Lymphoma Kinase in Lung Cancer12

    PubMed Central

    Wang, Yi-Wei; Tu, Pang-Hsien; Lin, Kuen-Tyng; Lin, Shu-Chen; Ko, Jenq-Yuh; Jou, Yuh-Shan

    2011-01-01

    The oncogenic property of anaplastic lymphoma kinase (ALK) plays an essential role in the pathogenesis of various cancers and serves as an important therapeutic target. In this study, we identified frequent intragenic loss of heterozygosity and six novel driver mutations within ALK in lung adenocarcinomas. Overexpression of H694R or E1384K mutant ALK leads to hyperphosphorylation of ALK, and activation of its downstream mediators STAT3, AKT, and ERK resulted in enhanced cell proliferation, colony formation, cell migration, and tumor growth in xenograft models. Furthermore, the activated phospho-Y1604 ALK was increasingly detected in 13 human lung cancer cell lines and 263 lung cancer specimens regardless of tumor stages and types. Treatment of two different ALK inhibitors, WHI-P154 and NVP-TAE684, resulted in the down-regulation of aberrant ALK signaling, shrinkage of tumor, and suppression of metastasis and significantly improved survival of ALK mutant-bearing mice. Together, we identified that novel ALK point mutations possessed tumorigenic effects mainly through hyperphosphorylation of Y1604 and activation of downstream oncogenic signaling. The upregulated phospho-Y1604 ALK could serve as a diagnostic biomarker for lung cancer. Furthermore, targeting oncogenic mutant ALKs with inhibitors could be a promising strategy to improve the therapeutic efficacy of fatal lung cancers. PMID:21847362

  11. 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

  12. 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. PMID:26330482

  13. 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. PMID:25456125

  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. Temporal representation of care trajectories of cancer patients using data from a regional information system: an application in breast cancer

    PubMed Central

    2014-01-01

    Background Ensuring that all cancer patients have access to the appropriate treatment within an appropriate time is a strategic priority in many countries. There is in particular a need to describe and analyse cancer care trajectories and to produce waiting time indicators. We developed an algorithm for extracting temporally represented care trajectories from coded information collected routinely by the general cancer Registry in Poitou-Charentes region, France. The present work aimed to assess the performance of this algorithm on real-life patient data in the setting of non-metastatic breast cancer, using measures of similarity. Methods Care trajectories were modeled as ordered dated events aggregated into states, the granularity of which was defined from standard care guidelines. The algorithm generates each state from the aggregation over a period of tracer events characterised on the basis of diagnoses and medical procedures. The sequences are presented in simple form showing presence and order of the states, and in an extended form that integrates the duration of the states. The similarity of the sequences, which are represented in the form of chains of characters, was calculated using a generalised Levenshtein distance. Results The evaluation was performed on a sample of 159 female patients whose itineraries were also calculated manually from medical records using the same aggregation rules and dating system as the algorithm. Ninety-eight per cent of the trajectories were correctly reconstructed with respect to the ordering of states. When the duration of states was taken into account, 94% of the trajectories matched reality within three days. Dissimilarities between sequences were mainly due to the absence of certain pathology reports and to coding anomalies in hospitalisation data. Conclusions These results show the ability of an integrated regional information system to formalise care trajectories and automatically produce indicators for time-lapse to care

  16. 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.

  17. Germline EPHB2 Receptor Variants in Familial Colorectal Cancer

    PubMed Central

    Zogopoulos, George; Jorgensen, Claus; Bacani, Julinor; Montpetit, Alexandre; Lepage, Pierre; Ferretti, Vincent; Chad, Lauren; Selvarajah, Subani; Zanke, Brent; Hudson, Thomas J.; Pawson, Tony; Gallinger, Steven

    2008-01-01

    Familial clustering of colorectal cancer occurs in 15–20% of cases, however recognized cancer syndromes explain only a small fraction of this disease. Thus, the genetic basis for the majority of hereditary colorectal cancer remains unknown. EPHB2 has recently been implicated as a candidate tumor suppressor gene in colorectal cancer. The aim of this study was to evaluate the contribution of EPHB2 to hereditary colorectal cancer. We screened for germline EPHB2 sequence variants in 116 population-based familial colorectal cancer cases by DNA sequencing. We then estimated the population frequencies and characterized the biological activities of the EPHB2 variants identified. Three novel nonsynonymous missense alterations were detected. Two of these variants (A438T and G787R) result in significant residue changes, while the third leads to a conservative substitution in the carboxy-terminal SAM domain (V945I). The former two variants were found once in the 116 cases, while the V945I variant was present in 2 cases. Genotyping of additional patients with colorectal cancer and control subjects revealed that A438T and G787R represent rare EPHB2 alleles. In vitro functional studies show that the G787R substitution, located in the kinase domain, causes impaired receptor kinase activity and is therefore pathogenic, whereas the A438T variant retains its receptor function and likely represents a neutral polymorphism. Tumor tissue from the G787R variant case manifested loss of heterozygosity, with loss of the wild-type allele, supporting a tumor suppressor role for EPHB2 in rare colorectal cancer cases. Rare germline EPHB2 variants may contribute to a small fraction of hereditary colorectal cancer. PMID:18682749

  18. Lung cancer: chemoprevention and intermediate effect markers.

    PubMed

    Tockman, M S

    2001-01-01

    Even after smoking cessation, genetic damage in the airways epithelium may lead to focal progression of lung carcinogenesis. Some centres now report as many new lung cancer cases among former smokers as among current smokers. Chemoprevention is a potential approach to diminish the progression of pre-clinical genetic damage. The most intensively studied lung cancer chemoprevention agents are the retinoids, including vitamin A and its synthetic analogues and precursors. While effective in suppressing lung carcinogenesis in animal models, retinoids have failed to inhibit carcinogenesis in human chemoprevention trials with premalignant end-points (sputum atypia, bronchial metaplasia). In trials with lung cancer end-points, administration of retinoids either was ineffective or, in the case of beta-carotene, led to greater lung cancer incidence and mortality. In view of these findings, markers of specific retinoid effect (i.e., levels of RAR-beta) become less relevant. Other markers of genetic instability and proliferation may be useful for both early detection and potentially as intermediate-effect markers for new chemoprevention trials. Cytological atypia, bronchial metaplasia, protein (hnRNP A2/B1) overexpression, ras oncogene activation and tumour-suppressor gene deletion, genomic instability (loss of heterozygosity, microsatellite alterations), abnormal methylation, helical CT detection of atypical adenomatous hyperplasia and fluorescent bronchoscopic detection of angiogenic squamous dysplasia offer great promise for molecular diagnosis of lung cancer far in advance of clinical presentation. These end-points can now be evaluated as monitors of response to chemoprevention as potential intermediate-effect markers. PMID:11220665

  19. Integrated analysis of germline and somatic variants in ovarian cancer.

    PubMed

    Kanchi, Krishna L; Johnson, Kimberly J; Lu, Charles; McLellan, Michael D; Leiserson, Mark D M; Wendl, Michael C; Zhang, Qunyuan; Koboldt, Daniel C; Xie, Mingchao; Kandoth, Cyriac; McMichael, Joshua F; Wyczalkowski, Matthew A; Larson, David E; Schmidt, Heather K; Miller, Christopher A; Fulton, Robert S; Spellman, Paul T; Mardis, Elaine R; Druley, Todd E; Graubert, Timothy A; Goodfellow, Paul J; Raphael, Benjamin J; Wilson, Richard K; Ding, Li

    2014-01-01

    We report the first large-scale exome-wide analysis of the combined germline-somatic landscape in ovarian cancer. Here we analyse germline and somatic alterations in 429 ovarian carcinoma cases and 557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2 and PALB2. In addition, we observe germline truncation variants in genes not previously associated with ovarian cancer susceptibility (NF1, MAP3K4, CDKN2B and MLL3). Evidence for loss of heterozygosity was found in 100 and 76% of cases with germline BRCA1 and BRCA2 truncations, respectively. Germline-somatic interaction analysis combined with extensive bioinformatics annotation identifies 222 candidate functional germline truncation and missense variants, including two pathogenic BRCA1 and 1 TP53 deleterious variants. Finally, integrated analyses of germline and somatic variants identify significantly altered pathways, including the Fanconi, MAPK and MLL pathways. PMID:24448499

  20. Integrated Analysis of Germline and Somatic Variants in Ovarian Cancer

    PubMed Central

    Kanchi, Krishna L.; Johnson, Kimberly J.; Lu, Charles; McLellan, Michael D.; Leiserson, Mark D.M.; Wendl, Michael C.; Zhang, Qunyuan; Koboldt, Daniel C.; Xie, Mingchao; Kandoth, Cyriac; McMichael, Joshua F.; Wyczalkowski, Matthew A.; Larson, David E.; Schmidt, Heather K.; Miller, Christopher A.; Fulton, Robert S.; Spellman, Paul T.; Mardis, Elaine R.; Druley, Todd E.; Graubert, Timothy A.; Goodfellow, Paul J.; Raphael, Benjamin J.; Wilson, Richard K.; Ding, Li

    2014-01-01

    We report the first large-scale exome-wide analysis of the combined germline-somatic landscape in ovarian cancer. Here we analyze germline and somatic alterations in 429 ovarian carcinoma cases and 557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2, and PALB2. Additionally, we observe germline truncation variants in genes not previously associated with ovarian cancer susceptibility (NF1, MAP3K4, CDKN2B, and MLL3). Evidence for loss of heterozygosity was found in 100% and 76% of cases with germline BRCA1 and BRCA2 truncations respectively. Germline-somatic interaction analysis combined with extensive bioinformatics annotation identifies 237 candidate functional germline truncation and missense variants, including 2 pathogenic BRCA1 and 1 TP53 deleterious variants. Finally, integrated analyses of germline and somatic variants identify significantly altered pathways, including the Fanconi, MAPK, and MLL pathways. PMID:24448499

  1. 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

  2. Telomerase activity in human cancer

    SciTech Connect

    Griffith, J.

    2000-10-01

    The overall goal of this collaborative project was to investigate the role in malignant cells of both chromosome telomeres, and telomerase, the enzyme that replicates telomeres. Telomeres are highly conserved nucleoprotein complexes located at the ends of eucaryotic chromosomes. Telomere length in somatic cells is reduced by 40--50 nucleotide pairs with every cell division due to incomplete replication of terminal DNA sequences and the absence of telomerase, the ribonucleoprotein that adds telomere DNA to chromosome ends. Although telomerase is active in cells with extended proliferative capacities, including more than 85% of tumors, work performed under this contract demonstrated that the telomeres of human cancer cells are shorter than those of paired normal cells, and that the length of the telomeres is characteristic of particular types of cancers. The extent of telomere shortening ostensibly is related to the number of cell divisions the tumor has undergone. It is believed that ongoing cell proliferation leads to the accumulation and fixation of new mutations in tumor cell lineages.Therefore, it is not unreasonable to assume that the degree of phenotypic variability is related to the proliferative history of the tumor, and therefore to telomere length, implying a correlation with prognosis. In some human tumors, short telomeres are also correlated with genomic instabilities, including interstitial chromosome translocation, loss of heterozygosity, and aneuoploidy. Moreover, unprotected chromosome ends are highly recombinogenic and telomere shortening in cultured human cells correlates with the formation of dicentric chromosomes, suggesting that critically short telomeres not only identify, but also predispose, cells to genomic instability, again implying a correlation with prognosis. Therefore, telomere length or content could be an important predictor of metastatic potential or responsiveness to various therapeutic modalities.

  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. Regional spectroscopy of paraffin-embedded breast cancer tissue using pulsed terahertz transmission imaging

    NASA Astrophysics Data System (ADS)

    Bowman, Tyler; El-Shenawee, Magda; Campbell, Lucas

    2016-03-01

    This work seeks to obtain the properties of paraffin-embedded breast cancer tumor tissues using transmission imaging and spectroscopy. Formalin-fixed and paraffin-embedded breast tumors are first sectioned into slices of 20 μm and 30 μm and placed between two tsurupica slides. The slides are then scanned in a pulsed terahertz system using transmission imaging. The tissue regions in adjacent pathology section are compared to the transmission imaging scan in order to define a region of points over which to average the electrical properties results from the scan.

  5. Predictors of Regional Lymph Node Recurrence after Initial Thyroidectomy in Patients with Thyroid Cancer

    PubMed Central

    Sharifi, Amirsina; Shojaeifard, Abolfazl; Soroush, Ahmadreza; Jafari, Mehdi; Abdehgah, Ali Ghorbani; Mahmoudzade, Hossein

    2016-01-01

    Background. Regional lymph node recurrence (RLNR) is common in patients with thyroid cancer but clinicopathological predictors are unclear. We aimed to clarify these predictors and identify patients who would benefit from prophylactic lymph node dissection the most. Method. 343 patients with different types of thyroid cancer were analyzed retrospectively. All patients underwent total thyroidectomy between 2007 and 2013. Results. The median ± interquartile range of patients' age was 40 ± 25 years. 245 (71.4%) patients were female. Regarding the risk of regional lymph node recurrence, we found that male gender, age ≥45 years, non-PTC (i.e., medullary, follicular, and anaplastic types) histopathology, T3 (i.e., tumor size >4 cm in the greatest dimension limited to the thyroid or any tumor with minimal extrathyroid extension), stage IVa, and isolated cervical lymphadenopathy as initial manifestation (ICL) are significant risk factors. T3 (p < 0.001; odds ratio = 156.41, 95% CI [55.72–439.1]) and ICL (p < 0.001; odds ratio = 77.79, 95% CI [31.55–191.81]) were the strongest predictors of regional lymph node recurrence. Conclusion. We found easily achievable risk factors for RLNR in thyroid cancers patients. We suggested that patients with specific clinicopathological features like male gender, age ≥45 years, larger tumor size, and extrathyroidal extension be considered as prophylactic lymphadenectomy candidates. PMID:27403370

  6. Automatic glandular and tubule region segmentation in histological grading of breast cancer

    NASA Astrophysics Data System (ADS)

    Nguyen, Kien; Barnes, Michael; Srinivas, Chukka; Chefd'hotel, Christophe

    2015-03-01

    In the popular Nottingham histologic score system for breast cancer grading, the pathologist analyzes the H and E tissue slides and assigns a score, in the range of 1-3, for tubule formation, nuclear pleomorphism and mitotic activity in the tumor regions. The scores from these three factors are added to give a final score, ranging from 3-9 to grade the cancer. Tubule score (TS), which reflects tubular formation, is a value in 1-3 given by manually estimating the percentage of glandular regions in the tumor that form tubules. In this paper, given an H and E tissue image representing a tumor region, we propose an automated algorithm to detect glandular regions and detect the presence of tubules in these regions. The algorithm first detects all nuclei and lumen candidates in the input image, followed by identifying tumor nuclei from the detected nuclei and identifying true lumina from the lumen candidates using a random forest classifier. Finally, it forms the glandular regions by grouping the closely located tumor nuclei and lumina using a graph-cut-based method. The glandular regions containing true lumina are considered as the ones that form tubules (tubule regions). To evaluate the proposed method, we calculate the tubule percentage (TP), i.e., the ratio of the tubule area to the total glandular area for 353 H and E images of the three TSs, and plot the distribution of these TP values. This plot shows the clear separation among these three scores, suggesting that the proposed algorithm is useful in distinguishing images of these TSs.

  7. Cancer

    MedlinePlus

    ... Leukemia Liver cancer Non-Hodgkin lymphoma Ovarian cancer Pancreatic cancer Testicular cancer Thyroid cancer Uterine cancer ... have any symptoms. In certain cancers, such as pancreatic cancer, symptoms often do not start until the disease ...

  8. Battling regional (stage III) lung cancer: bumpy road of a cancer survivor in the immunotherapy age.

    PubMed

    Hao, Zhonglin; Biddinger, Paul; Schroeder, Carsten; Tariq, Khurram

    2016-01-01

    A 58-year-old woman, a heavy smoker, was diagnosed with stage III squamous cell lung cancer. She was treated with concurrent chemotherapy and radiotherapy, with partial response. 2 months later, she had haemoptysis caused by brisk bleeding from the radiated right upper lobe. Fortunately, her bleed was self-limited. 4 months later, a rapidly enlarging renal mass was discovered and turned out to be metastatic from the lung primary. Second-line chemotherapy with docetaxel and ramucirumab did not have effects on the renal mass after 2 cycles. Despite not being eligible for a durvalumab trial because of lack of PD-L1 expression, she had a meaningful response to nivolumab. Once every 2 weeks, infusion of nivolumab resulted in rapid tumour shrinkage in multiple areas. In the next few months, she experienced a variety of side effects, some of which were potentially life-threatening. She had disease progression 9 months into treatment. PMID:27389724

  9. MicroRNA-373 (miR-373) post-transcriptionally regulates large tumor suppressor, homolog 2 (LATS2) and stimulates proliferation in human esophageal cancer

    SciTech Connect

    Lee, Kuen-Haur; Goan, Yih-Gang; Hsiao, Michael; Lee, Chien-Hsing; Jian, Shu-Huei; Lin, Jen-Tai; Chen, Yuh-Ling; Lu, Pei-Jung

    2009-09-10

    LATS2 is a member of the LATS tumor suppressor family. It has been implicated in regulation of the cell cycle and apoptosis. Frequent loss of heterozygosity (LOH) of LATS2 has been reported in human esophageal cancer. But, the LATS2 gene expression and its regulatory mechanism in esophageal cancer remain unclear. The present study has shown that LATS2 protein expression was mediated by miR-373 at the post-transcriptional level and inversely correlated with miR-373 amounts in esophageal cancer cell lines. Furthermore, we demonstrated that the direct inhibition of LATS2 protein was mediated by miR-373 and manipulated the expression of miR-373 to affect esophageal cancer cells growth. Moreover, this correlation was supported by data collected ex vivo, in which esophageal cancer tissues from esophageal squamous cell carcinoma (ESCC) patients were analyzed. Finally, by miRNA microarray analysis, four miRNAs including miR-373 were over-expressed in ESCC samples. Our findings reveal that miR-373 would be a potential oncogene and it participates in the carcinogenesis of human esophageal cancer by suppressing LATS2 expression.

  10. Identification of significantly mutated regions across cancer types highlights a rich landscape of functional molecular alterations

    PubMed Central

    Araya, Carlos L.; Cenik, Can; Reuter, Jason A.; Kiss, Gert; Pande, Vijay S.; Snyder, Michael P.; Greenleaf, William J.

    2015-01-01

    Cancer sequencing studies have primarily identified cancer-driver genes by the accumulation of protein-altering mutations. An improved method would be annotation-independent, sensitive to unknown distributions of functions within proteins, and inclusive of non-coding drivers. We employed density-based clustering methods in 21 tumor types to detect variably-sized significantly mutated regions (SMRs). SMRs reveal recurrent alterations across a spectrum of coding and non-coding elements, including transcription factor binding sites and untranslated regions mutated in up to ∼15% of specific tumor types. SMRs reveal spatial clustering of mutations at molecular domains and interfaces, often with associated changes in signaling. Mutation frequencies in SMRs demonstrate that distinct protein regions are differentially mutated among tumor types, as exemplified by a linker region of PIK3CA in which biophysical simulations suggest mutations affect regulatory interactions. The functional diversity of SMRs underscores both the varied mechanisms of oncogenic misregulation and the advantage of functionally-agnostic driver identification. PMID:26691984

  11. Knowledge assessment of women living in the Wielkopolska region concerning risk factors for cervical cancer

    PubMed Central

    Gawdzik, Dorota; Jurczyk, Mieczysława U.; Sporny, Stanisław; Opala, Tomasz

    2015-01-01

    Introduction Cervical cancer (CC) is a malignant tumor which for many years has been a serious epidemiological problem in Poland. This issue is important because CC is the second most common type of malignant tumor, after breast cancer, and the second most common cause of death among women. The aim of this study was to assess the knowledge and awareness of women living in the Wielkopolska region (Gniezno district) of risk factors for cervical cancer. Material and methods The study used the diagnostic poll method, based on a previously developed survey questionnaire. The study was carried out between March and April 2013. The study group consisted of 100 women, involving schoolgirls from the secondary school in Gniezno (Group I), workers (doctors, nurses and midwives) of two outpatient clinics in the Gniezno district (Group II) and patients of the same clinics (Group III). Results According to the respondents, the main cause of CC is human papillomavirus (Group II – 36%) and genetic predisposition (Group III – 35%). It is alarming that 26% of women did not know the risk factors for CC. Conclusions It is necessary to improve health education, especially concerning the main factors affecting the development of CC, in order to reduce the morbidity and mortality rates related to this cancer. PMID:26327882

  12. Regional variation in colorectal cancer testing and geographic availability of care in a publicly insured population.

    PubMed

    Wheeler, Stephanie B; Kuo, Tzy-Mey; Goyal, Ravi K; Meyer, Anne-Marie; Hassmiller Lich, Kristen; Gillen, Emily M; Tyree, Seth; Lewis, Carmen L; Crutchfield, Trisha M; Martens, Christa E; Tangka, Florence; Richardson, Lisa C; Pignone, Michael P

    2014-09-01

    Despite its demonstrated effectiveness, colorectal cancer (CRC) testing is suboptimal, particularly in vulnerable populations such as those who are publicly insured. Prior studies provide an incomplete picture of the importance of the intersection of multilevel factors affecting CRC testing across heterogeneous geographic regions where vulnerable populations live. We examined CRC testing across regions of North Carolina by using population-based Medicare and Medicaid claims data from disabled individuals who turned 50 years of age during 2003-2008. We estimated multilevel models to examine predictors of CRC testing, including distance to the nearest endoscopy facility, county-level endoscopy procedural rates, and demographic and community contextual factors. Less than 50% of eligible individuals had evidence of CRC testing; men, African-Americans, Medicaid beneficiaries, and those living furthest away from endoscopy facilities had significantly lower odds of CRC testing, with significant regional variation. These results can help prioritize intervention strategies to improve CRC testing among publicly insured, disabled populations. PMID:25063908

  13. Regional Relapse After Intensity-Modulated Radiotherapy for Head-and-Neck Cancer

    SciTech Connect

    Duprez, Frederic; Bonte, Katrien; De Neve, Wilfried; Boterberg, Tom; De Gersem, Werner; Madani, Indira

    2011-02-01

    Purpose: To evaluate the regional relapse rate in the elective neck using intensity-modulated radiotherapy (IMRT) for head-and-neck cancer. Methods and Materials: We retrospectively analyzed the data from 285 patients treated with IMRT between 2000 and 2008. The median dose prescription to the primary tumor and involved lymph nodes was 69 Gy in 32 fractions. The elective neck was treated simultaneously according to Protocol 1 (multiple dose prescription levels of 56-69 Gy; 2-Gy normalized isoeffective dose, 51-70 Gy; 222 patients) or Protocol 2 (one dose prescription level of 56 Gy; 2-Gy normalized isoeffective dose, 51 Gy; 63 patients). Primary surgery or lymph node dissection was performed before IMRT in 72 (25%) and 157 (55%) patients, respectively. Also, 92 patients (32%) received concomitant chemotherapy. The median follow-up of living patients was 27.4 months (range, 0.3-99). Results: Regional, local, and distant relapse were observed in 16 (5.6%), 35 (12.3%), and 47 (16.5%) patients, respectively. The 2- and 5-year rate of regional relapse was 7% and 10%, respectively, with a trend favoring Protocol 2 (p = 0.06). Seven isolated regional relapses were detected at a median follow-up of 7.3 months in patients treated with Protocol 1 and none in those treated with Protocol 2. Percutaneous gastrostomy was required more frequently in patients who received Protocol 1 (p = 0.079). Conclusion: Isolated regional relapse is rare after IMRT for head-and-neck cancer. Elective neck node doses >51 Gy for a 2-Gy normalized isoeffective dose do not seem to improve regional control.

  14. Genomic distance entrained clustering and regression modelling highlights interacting genomic regions contributing to proliferation in breast cancer

    PubMed Central

    2010-01-01

    Background Genomic copy number changes and regional alterations in epigenetic states have been linked to grade in breast cancer. However, the relative contribution of specific alterations to the pathology of different breast cancer subtypes remains unclear. The heterogeneity and interplay of genomic and epigenetic variations means that large datasets and statistical data mining methods are required to uncover recurrent patterns that are likely to be important in cancer progression. Results We employed ridge regression to model the relationship between regional changes in gene expression and proliferation. Regional features were extracted from tumour gene expression data using a novel clustering method, called genomic distance entrained agglomerative (GDEC) clustering. Using gene expression data in this way provides a simple means of integrating the phenotypic effects of both copy number aberrations and alterations in chromatin state. We show that regional metagenes derived from GDEC clustering are representative of recurrent regions of epigenetic regulation or copy number aberrations in breast cancer. Furthermore, detected patterns of genomic alterations are conserved across independent oestrogen receptor positive breast cancer datasets. Sequential competitive metagene selection was used to reveal the relative importance of genomic regions in predicting proliferation rate. The predictive model suggested additive interactions between the most informative regions such as 8p22-12 and 8q13-22. Conclusions Data-mining of large-scale microarray gene expression datasets can reveal regional clusters of co-ordinate gene expression, independent of cause. By correlating these clusters with tumour proliferation we have identified a number of genomic regions that act together to promote proliferation in ER+ breast cancer. Identification of such regions should enable prioritisation of genomic regions for combinatorial functional studies to pinpoint the key genes and interactions

  15. Regional variation in the management of metastatic gastric cancer in Ontario

    PubMed Central

    Mahar, A.L.; Coburn, N.G.; Kagedan, D.J.; Viola, R.; Johnson, A.P.

    2016-01-01

    Background Geographic variation in cancer care is common when clear clinical management guidelines do not exist. In the present study, we sought to describe health care resource consumption by patients with metastatic gastric cancer (gc) and to investigate the possibility of regional variation. Methods In this population-based cohort study of patients with stage iv gastric adenocarcinoma diagnosed between 1 April 2005 and 31 March 2008, chart review and administrative health care data were linked to study resource utilization outcomes (for example, clinical investigations, treatments) in the province of Ontario. The study took a health care system perspective with a 2-year time frame. Chi-square tests were used to compare proportions of resource utilization, and analysis of variance compared mean per-patient resource consumption between geographic regions. Results A cohort of 1433 patients received 4690 endoscopic investigations, 12,033 computed tomography exams, 12,774 radiography exams, and 5059 ultrasonography exams. Nearly all patients were seen by a general practitioner (98%) and a specialist (99%), and were hospitalized (95%) or visited the emergency department (87%). Fewer than half received chemotherapy (43%), gastrectomy (37%), or radiotherapy (28%). The mean number of clinical investigations, physician visits, hospitalizations, and instances of patient accessing the emergency department or receiving radiotherapy or stent placement varied significantly by region. Conclusions Variations in health care resource utilization for metastatic gc patients are observed across the regions of Ontario. Whether those differences reflect differential access to resources, patient preference, or physician preference is not known. The observed variation might reflect a lack of guidelines based on high-quality evidence and could partly be ameliorated with regionalization of gc care to high-volume centres. PMID:27536175

  16. Commonly deleted region on the long arm of chromosome 7 in differentiated adenocarcinoma of the stomach.

    PubMed Central

    Nishizuka, S.; Tamura, G.; Terashima, M.; Satodate, R.

    1997-01-01

    Loss of heterozygosity (LOH) at several chromosomal loci is a common event in human malignancies. Frequent LOH on the long arm of chromosome 7 has been reported in various human malignancies, and investigators have identified the most common site of LOH as 7q31.1. We have identified ten chromosomal loci, including chromosome 7q, that have been shown by previous allelotype study to be sites of frequent LOH in differentiated adenocarcinoma of the stomach. In the present study, we performed a polymerase chain reaction (PCR) microsatellite analysis to define the common deleted region on 7q, using 14 polymorphic microsatellite markers in matched tumour and non-tumour DNAs from 53 patients with primary gastric carcinoma of the differentiated type. LOH at any locus on 7q occurred in 34% (18 out of 53) of the tumours. Although many tumours exhibited total or large interstitial deletions, we determined the smallest common deleted region to be at D7S480 (7q31.1). This is identical to the region identified for other human malignancies. These observations indicate that a putative tumour suppressor gene at 7q31.1 may be involved in the pathogenesis of differentiated adenocarcinoma of the stomach. Images Figure 1 PMID:9413943

  17. Cervical cancer screening and HPV vaccine acceptability among rural and urban women in Kilimanjaro Region, Tanzania

    PubMed Central

    Cunningham, Melissa S; Skrastins, Emily; Fitzpatrick, Ryan; Jindal, Priya; Oneko, Olola; Yeates, Karen; Booth, Christopher M; Carpenter, Jennifer; Aronson, Kristan J

    2015-01-01

    Objective To determine cervical cancer screening coverage and the knowledge, attitudes and barriers toward screening tests among women in rural and urban areas of Tanzania, as well as explore how they view the acceptability of the HPV vaccine and potential barriers to vaccination. Setting A cross-sectional study using interview-administered questionnaires was conducted using multistage random sampling within urban and rural areas in Kilimanjaro Region, Tanzania. Participants Women aged 18–55 were asked to participate in the survey. The overall response rate was 97.5%, with a final sample of 303 rural and 272 urban dwelling women. Primary and secondary outcome measures Descriptive and simple test statistics were used to compare across rural and urban strata. Multivariate logistic regression models were used to estimate ORs and 95% CIs. Results Most women (82%) reported they had heard of cervical cancer, while self-reported cervical cancer screening among women was very low (6%). In urban areas, factors associated with screening were: older age (OR=4.14, 95% CI 1.86 to 9.24 for ages 40–49, and OR=8.38, 95% CI 2.10 to 33.4 for >50 years), having health insurance (OR=4.15, 95% CI 1.52 to 11.4), and having knowledge about cervical cancer (OR=5.81, 95% CI 1.58 to 21.4). In contrast, among women residing in rural areas, only condom use (OR=6.44, 95% CI 1.12 to 37.1) was associated with screening. Women from both rural and urban areas had low vaccine-related knowledge; however, most indicated they would be highly accepting if it were readily available (93%). Conclusions The current proportion of women screened for cervical cancer is very low in Kilimanjaro Region, and our study has identified several modifiable factors that could be addressed to increase screening rates. Although best implemented concurrently, the availability of prophylactic vaccination for girls may provide an effective means of prevention if they are unable to access screening in the future. PMID

  18. A polymorphic minisatellite region of BORIS regulates gene expression and its rare variants correlate with lung cancer susceptibility

    PubMed Central

    Yoon, Se-Lyun; Roh, Yun-Gil; Chu, In-Sun; Heo, Jeonghoon; Kim, Seung Il; Chang, Heekyung; Kang, Tae-Hong; Chung, Jin Woong; Koh, Sang Seok; Larionov, Vladimir; Leem, Sun-Hee

    2016-01-01

    Aberrant expression of BORIS/CTCFL (Brother of the Regulator of Imprinted Sites/CTCF-like protein) is reported in different malignancies. In this study, we characterized the entire promoter region of BORIS/CTCFL, including the CpG islands, to assess the relationship between BORIS expression and lung cancer. To simplify the construction of luciferase reporter cassettes with various-sized portions of the upstream region, genomic copies of BORIS were isolated using TAR cloning technology. We analyzed three promoter blocks: the GATA/CCAAT box, the CpG islands and the minisatellite region BORIS-MS2. Polymorphic minisatellite sequences were isolated from genomic DNA prepared from the blood of controls and cases. Of the three promoter blocks, the GATA/CCAAT box was determined to be a critical element of the core promoter, while the CpG islands and the BORIS-MS2 minisatellite region were found to act as regulators. Interestingly, the polymorphic minisatellite region BORIS-MS2 was identified as a negative regulator that repressed the expression levels of luciferase reporter cassettes less effectively in cancer cells compared with normal cells. We also examined the association between the size of BORIS-MS2 and lung cancer in a case–control study with 590 controls and 206 lung cancer cases. Rare alleles of BORIS-MS2 were associated with a statistically significantly increased risk of lung cancer (odds ratio, 2.04; 95% confidence interval, 1.02–4.08; and P=0.039). To conclude, our data provide information on the organization of the BORIS promoter region and gene regulation in normal and cancer cells. In addition, we propose that specific alleles of the BORIS-MS2 region could be used to identify the risk for lung cancer. PMID:27416782

  19. A polymorphic minisatellite region of BORIS regulates gene expression and its rare variants correlate with lung cancer susceptibility.

    PubMed

    Yoon, Se-Lyun; Roh, Yun-Gil; Chu, In-Sun; Heo, Jeonghoon; Kim, Seung Il; Chang, Heekyung; Kang, Tae-Hong; Chung, Jin Woong; Koh, Sang Seok; Larionov, Vladimir; Leem, Sun-Hee

    2016-01-01

    Aberrant expression of BORIS/CTCFL (Brother of the Regulator of Imprinted Sites/CTCF-like protein) is reported in different malignancies. In this study, we characterized the entire promoter region of BORIS/CTCFL, including the CpG islands, to assess the relationship between BORIS expression and lung cancer. To simplify the construction of luciferase reporter cassettes with various-sized portions of the upstream region, genomic copies of BORIS were isolated using TAR cloning technology. We analyzed three promoter blocks: the GATA/CCAAT box, the CpG islands and the minisatellite region BORIS-MS2. Polymorphic minisatellite sequences were isolated from genomic DNA prepared from the blood of controls and cases. Of the three promoter blocks, the GATA/CCAAT box was determined to be a critical element of the core promoter, while the CpG islands and the BORIS-MS2 minisatellite region were found to act as regulators. Interestingly, the polymorphic minisatellite region BORIS-MS2 was identified as a negative regulator that repressed the expression levels of luciferase reporter cassettes less effectively in cancer cells compared with normal cells. We also examined the association between the size of BORIS-MS2 and lung cancer in a case-control study with 590 controls and 206 lung cancer cases. Rare alleles of BORIS-MS2 were associated with a statistically significantly increased risk of lung cancer (odds ratio, 2.04; 95% confidence interval, 1.02-4.08; and P=0.039). To conclude, our data provide information on the organization of the BORIS promoter region and gene regulation in normal and cancer cells. In addition, we propose that specific alleles of the BORIS-MS2 region could be used to identify the risk for lung cancer. PMID:27416782

  20. Cell migration leads to spatially distinct but clonally related airway cancer precursors

    PubMed Central

    Pipinikas, Christodoulos P; Kiropoulos, Theodoros S; Teixeira, Vitor H; Brown, James M; Varanou, Aikaterini; Falzon, Mary; Capitanio, Arrigo; Bottoms, Steven E; Carroll, Bernadette; Navani, Neal; McCaughan, Frank; George, Jeremy P; Giangreco, Adam; Wright, Nicholas A; McDonald, Stuart A C; Graham, Trevor A; Janes, Sam M

    2014-01-01

    Background Squamous cell carcinoma of the lung is a common cancer with 95% mortality at 5 years. These cancers arise from preinvasive lesions, which have a natural history of development progressing through increasing severity of dysplasia to carcinoma in situ (CIS), and in some cases, ending in transformation to invasive carcinoma. Synchronous preinvasive lesions identified at autopsy have been previously shown to be clonally related. Methods Using autofluorescence bronchoscopy that allows visual observation of preinvasive lesions within the upper airways, together with molecular profiling of biopsies using gene sequencing and loss-of-heterozygosity analysis from both preinvasive lesions and from intervening normal tissue, we have monitored individual lesions longitudinally and documented their visual, histological and molecular relationship. Results We demonstrate that rather than forming a contiguous field of abnormal tissue, clonal CIS lesions can develop at multiple anatomically discrete sites over time. Further, we demonstrate that patients with CIS in the trachea have invariably had previous lesions that have migrated proximally, and in one case, into the other lung over a period of 12 years. Conclusions Molecular information from these unique biopsies provides for the first time evidence that field cancerisation of the upper airways can occur through cell migration rather than via local contiguous cellular expansion as previously thought. Our findings urge a clinical strategy of ablating high-grade premalignant airway lesions with subsequent attentive surveillance for recurrence in the bronchial tree. PMID:24550057

  1. Potential role of a navigator gene NAV3 in colorectal cancer

    PubMed Central

    Carlsson, E; Ranki, A; Sipilä, L; Karenko, L; Abdel-Rahman, W M; Ovaska, K; Siggberg, L; Aapola, U; Ässämäki, R; Häyry, V; Niiranen, K; Helle, M; Knuutila, S; Hautaniemi, S; Peltomäki, P; Krohn, K

    2012-01-01

    Background: The recently described navigator proteins have a multifaceted role in cytoskeletal dynamics. We report here on the relevance of one of them, navigator 3 (NAV3), in colorectal cancer (CRC). Methods: We analysed changes in chromosome 12 and NAV3 copy number in CRC/adenoma samples of 59 patients and in 6 CRC cell lines, using fluorescence in situ hybridisation, loss of heterozygosity, and array-CGH. NAV3 target genes were identified by siRNA depletion, expression arrays, and immunohistochemistry. Results: NAV3 deletion and chromosome 12 polysomy were detected in 30 and 70% of microsatellite stability (MSS) carcinomas, in 23 and 30% of adenomas and in four of six CRC cell lines. NAV3 amplification was found in 25% of MSS samples. NAV3 alterations correlated with lymph node metastasis. In normal colon cells, NAV3 silencing induced upregulation of interleukin 23 receptor (IL23R) and gonadotropin releasing hormone receptor. In MSS and microsatellite instability tumours, IL23R immunoreactivity correlated with Dukes' staging and lymph node metastases, whereas nuclear beta-catenin correlated with lymph node metastases only. Conclusion: NAV3 copy number changes are frequent in CRC and in adenomas, and upregulation of IL23R, following NAV3 silencing, strongly correlates with Dukes' staging and lymph node metastases. This suggests that NAV3 has a role in linking tissue inflammation to cancer development in the colon. PMID:22173670

  2. Amplification of the 9p13.3 chromosomal region in prostate cancer.

    PubMed

    Latonen, Leena; Leinonen, Katri A; Grönlund, Teemu; Vessella, Robert L; Tammela, Teuvo L J; Saramäki, Outi R; Visakorpi, Tapio

    2016-08-01

    Amplification of the 9p13.3 chromosomal region occurs in a subset of prostate cancers (PCs); however, the target gene or genes of this amplification have remained unidentified. The aim of this study was to investigate the 9p13.3 amplification in more detail to identify genes that are potentially advantageous for cancer cells. We narrowed down the minimally amplified area and assessed the frequency of the 9p13.3 amplification. Of the clinical samples from untreated PCs that were examined (n = 134), 9.7% showed high-level amplification, and 32.1% showed low-level amplification. Additionally, in clinical samples from castration-resistant PCs (n = 70), high- and low-level amplification was seen in 14.3% and 44.3% of the samples, respectively. We next analyzed the protein-coding genes in this chromosomal region for both their expression in clinical PC samples as well as their potential as growth regulators in PC cells. We found that the 9p13.3 amplification harbors several genes that are able to affect the growth of PC cells when downregulated using siRNA. Of these, UBAP2 was the most prominently upregulated gene in the clinical prostate tumor samples. © 2016 Wiley Periodicals, Inc. PMID:27074291

  3. Isolated tumor cells and micrometastases in regional lymph nodes in stage I to II endometrial cancer

    PubMed Central

    Minobe, Shinichiro

    2016-01-01

    Objective The aim of this study was to clarify the clinical significance of isolated tumor cells (ITCs) or micrometastasis (MM) in regional lymph nodes in patients with International Federation of Gynecology and Obstetrics (FIGO) stage I to II endometrial cancer. Methods In this study, a series of 63 patients with FIGO stage I to II were included, who had at least one of the following risk factors for recurrence: G3 endometrioid/serous/clear cell adenocarcinomas, deep myometrial invasion, cervical involvement, lympho-vascular space invasion, and positive peritoneal cytology. These cases were classified as intermediate-risk endometrial cancer. Ultrastaging by multiple slicing, staining with hematoxylin and eosin and cytokeratin, and microscopic examination was performed on regional lymph nodes that had been diagnosed as negative for metastases. Results Among 61 patients in whom paraffin-embedded block was available, ITC/MM was identified in nine patients (14.8%). Deep myometrial invasion was significantly associated with ITC/MM (p=0.028). ITC/MM was an independent risk factor for extrapelvic recurrence (hazard ratio, 17.9; 95% confidence interval [CI], 1.4 to 232.2). The 8-year overall survival (OS) and recurrence-free survival (RFS) rates were more than 20% lower in the ITC/MM group than in the node-negative group (OS, 71.4% vs. 91.9%; RFS, 55.6% vs. 84.0%), which were statistically not significant (OS, p=0.074; RFS, p=0.066). Time to recurrence tended to be longer in the ITC/MM group than in the node-negative group (median, 49 months vs. 16.5 months; p=0.080). Conclusions It remains unclear whether ITC/MM have an adverse influence on prognosis of intermediate-risk endometrial cancer. A multicenter cooperative study is needed to clarify the clinical significance of ITC/MM. PMID:25925293

  4. VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research.

    PubMed

    Lai, Zhongwu; Markovets, Aleksandra; Ahdesmaki, Miika; Chapman, Brad; Hofmann, Oliver; McEwen, Robert; Johnson, Justin; Dougherty, Brian; Barrett, J Carl; Dry, Jonathan R

    2016-06-20

    Accurate variant calling in next generation sequencing (NGS) is critical to understand cancer genomes better. Here we present VarDict, a novel and versatile variant caller for both DNA- and RNA-sequencing data. VarDict simultaneously calls SNV, MNV, InDels, complex and structural variants, expanding the detected genetic driver landscape of tumors. It performs local realignments on the fly for more accurate allele frequency estimation. VarDict performance scales linearly to sequencing depth, enabling ultra-deep sequencing used to explore tumor evolution or detect tumor DNA circulating in blood. In addition, VarDict performs amplicon aware variant calling for polymerase chain reaction (PCR)-based targeted sequencing often used in diagnostic settings, and is able to detect PCR artifacts. Finally, VarDict also detects differences in somatic and loss of heterozygosity variants between paired samples. VarDict reprocessing of The Cancer Genome Atlas (TCGA) Lung Adenocarcinoma dataset called known driver mutations in KRAS, EGFR, BRAF, PIK3CA and MET in 16% more patients than previously published variant calls. We believe VarDict will greatly facilitate application of NGS in clinical cancer research. PMID:27060149

  5. VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research

    PubMed Central

    Lai, Zhongwu; Markovets, Aleksandra; Ahdesmaki, Miika; Chapman, Brad; Hofmann, Oliver; McEwen, Robert; Johnson, Justin; Dougherty, Brian; Barrett, J. Carl; Dry, Jonathan R.

    2016-01-01

    Accurate variant calling in next generation sequencing (NGS) is critical to understand cancer genomes better. Here we present VarDict, a novel and versatile variant caller for both DNA- and RNA-sequencing data. VarDict simultaneously calls SNV, MNV, InDels, complex and structural variants, expanding the detected genetic driver landscape of tumors. It performs local realignments on the fly for more accurate allele frequency estimation. VarDict performance scales linearly to sequencing depth, enabling ultra-deep sequencing used to explore tumor evolution or detect tumor DNA circulating in blood. In addition, VarDict performs amplicon aware variant calling for polymerase chain reaction (PCR)-based targeted sequencing often used in diagnostic settings, and is able to detect PCR artifacts. Finally, VarDict also detects differences in somatic and loss of heterozygosity variants between paired samples. VarDict reprocessing of The Cancer Genome Atlas (TCGA) Lung Adenocarcinoma dataset called known driver mutations in KRAS, EGFR, BRAF, PIK3CA and MET in 16% more patients than previously published variant calls. We believe VarDict will greatly facilitate application of NGS in clinical cancer research. PMID:27060149

  6. LINE-1 hypomethylation in normal colon mucosa is associated with poor survival in Chinese patients with sporadic colon cancer.

    PubMed

    Zhuo, Changhua; Li, Qingguo; Wu, Yuchen; Li, Yiwei; Nie, Jia; Li, Dawei; Peng, Junjie; Lian, Peng; Li, Bin; Cai, Guoxiang; Li, Xinxiang; Cai, Sanjun

    2015-09-15

    Genetic and epigenetic pathways are not independent in colorectal cancer (CRC) carcinogenesis. We aimed to determine the influence of various molecular features on Chinese patients' colon cancer-specific survival (CCSS). Various genetic and epigenetic modifications were detected in paired tumor and normal mucosa tissue samples. The prognostic variables regarding patient CCSS were determined. Overall, 127 patients, including 83 males and 44 females, completed a median follow-up of 65 (3-85) months. A mean LINE-1 methylation rate of 64.62% (range, 9.45-86.93) was observed. Hypermethylation at the hMLH1 gene promoter was detected in 26 (20.47%) patients. KRAS was mutated in 52 (40.94%) patients. Sixteen (12.60%) patients were confirmed as microsatellite instability (MSI)-High, and 76 (59.84%) were found to have loss of heterozygosity at 18q. The LINE-1 methylation level, MSI status, perineural invasion and distant metastases were confirmed as independent prognostic factors for patient CCSS. A stratified survival analysis further revealed that certain subgroups of patients with LINE-1 hypomethylation had significantly worse survival (all p < 0.05). Our data revealed that both genetic and epigenetic abnormalities can concurrently exist during colonic tumorigenesis. As a global epigenetic change, LINE-1 hypomethylation in normal colon mucosa might be associated with a worse outcome in certain Chinese patients with colon cancer. PMID:26172297

  7. LINE-1 hypomethylation in normal colon mucosa is associated with poor survival in Chinese patients with sporadic colon cancer

    PubMed Central

    Wu, Yuchen; Li, Yiwei; Nie, Jia; Li, Dawei; Peng, Junjie; Lian, Peng; Li, Bin; Cai, Guoxiang; Li, Xinxiang; Cai, Sanjun

    2015-01-01

    Genetic and epigenetic pathways are not independent in colorectal cancer (CRC) carcinogenesis. We aimed to determine the influence of various molecular features on Chinese patients' colon cancer-specific survival (CCSS). Various genetic and epigenetic modifications were detected in paired tumor and normal mucosa tissue samples. The prognostic variables regarding patient CCSS were determined. Overall, 127 patients, including 83 males and 44 females, completed a median follow-up of 65 (3–85) months. A mean LINE-1 methylation rate of 64.62% (range, 9.45–86.93) was observed. Hypermethylation at the hMLH1 gene promoter was detected in 26 (20.47%) patients. KRAS was mutated in 52 (40.94%) patients. Sixteen (12.60%) patients were confirmed as microsatellite instability (MSI)-High, and 76 (59.84%) were found to have loss of heterozygosity at 18q. The LINE-1 methylation level, MSI status, perineural invasion and distant metastases were confirmed as independent prognostic factors for patient CCSS. A stratified survival analysis further revealed that certain subgroups of patients with LINE-1 hypomethylation had significantly worse survival (all p < 0.05). Our data revealed that both genetic and epigenetic abnormalities can concurrently exist during colonic tumorigenesis. As a global epigenetic change, LINE-1 hypomethylation in normal colon mucosa might be associated with a worse outcome in certain Chinese patients with colon cancer. PMID:26172297

  8. A region of consistent deletion in neuroblastoma maps within human chromosome 1p36.2-36.3

    SciTech Connect

    White, P.S.; Maris, J.M.; Beltinger, C.

    1995-06-06

    Deletion of the short arm of human chromosome 1 is the most common cytogenetic abnormality observed in neuroblastoma. To characterize the region of consistent deletion, we performed loss of heterozygosity (LOH) studies on 122 neuroblastoma tumor samples with 30 distal chromosome 1p polymorphisms. LOH was detected in 32 of the 122 tumors (26%). A single region of LOH, marked distally by D1Z2 and proximally by D1S228, was detected in all tumors demonstrating loss. Also, cells from a patient with a constitutional deletion of 1p36, and from a neuroblastoma cell line with a small 1p36 deletion, were analyzed by fluorescence in situ hybridization. Cells from both sources had interstitial deletions of 1p36.2-36.3 which overlapped the consensus region of LOH defined by the tumors. Interstitial deletion in the constitutional case was confirmed by allelic loss studies using the panel of polymorphic markers. Four proposed candidate genes-DAN, ID3 (heir-1), CDC2L1 (p58), and TNFR2-were shown to lie outside of the consensus region of allelic loss, as defined by the above deletions. These results more precisely define the location of a neuroblastoma suppressor gene within 1p36.2-36.3, eliminating 33 centimorgans of proximal 1p36 from consideration. Furthermore, a consensus region of loss, which excludes the four leading candidate genes, was found in all tumors with 1p36 LOH. 31 refs., 4 figs.

  9. Regional Variation in Identified Cancer Care Needs of Early-Career Oncologists in China, India, and Pakistan

    PubMed Central

    Fawzy, Maria R.; Aziz, Zeba; Nair, Reena; Pramesh, C.S.; Parmar, Vani; Parikh, Purvish M.; Jamal, Rozmin; Irumnaz, Azizunissa; Ren, Jun; Stockler, Martin R.; Abernethy, Amy P.

    2015-01-01

    Background. Cancer incidence and mortality is increasing in the developing world. Inequities between low-, middle-, and high-income countries affect disease burden and the infrastructure needs in response to cancer. We surveyed early-career oncologists attending workshops in clinical research in three countries with emerging economies about their perception of the evolving cancer burden. Methods. A cross-sectional survey questionnaire was distributed at clinical trial concept development workshops held in Beijing, Lahore, Karachi, and Mumbai at major hospitals to acquire information regarding home-country health conditions and needs. Results. A total of 100 respondents participated in the workshops held at major hospitals in the region (India = 29, China = 25, Pakistan = 42, and other = 4). Expected consensus on many issues (e.g., emergence of cancer as a significant health issue) was balanced with significant variation in priorities, opportunities, and challenges. Chinese respondents prioritized improvements in cancer-specific care and palliative care, Indian respondents favored improved cancer detection and advancing research in cancer care, and Pakistani respondents prioritized awareness of cancer and improvements in disease detection and cancer care research. For all, the most frequently cited opportunity was help in improving professional cancer education and training. Conclusion. Predominantly early-career oncologists attending clinical research workshops (in China, India, and Pakistan) identified needs for increasing clinical cancer research, professional education, and public awareness of cancer. Decision makers supporting efforts to reduce the burden of cancer worldwide will need to factor the specific needs and aspirations of health care providers in their country in prioritizing health policies and budgets. PMID:25888267

  10. Gastric cancer incidence and mortality is associated with altitude in the mountainous regions of Pacific Latin America

    PubMed Central

    Torres, Javier; Correa, Pelayo; Ferreccio, Catterina; Hernandez-Suarez, Gustavo; Herrero, Rolando; Cavazza-Porro, Maria; Dominguez, Ricardo; Morgan, Douglas

    2013-01-01

    In Latin America, gastric cancer is a leading cancer, and countries in the region have some of the highest mortality rates worldwide, including Chile, Costa Rica, and Colombia. Geographic variation in mortality rates is observed both between neighboring countries and within nations. We discuss epidemiological observations suggesting an association between altitude and gastric cancer risk in Latin America. In the Americas, the burden of gastric cancer mortality is concentrated in the mountainous areas along the Pacific rim, following the geography of the Andes sierra, from Venezuela to Chile, and the Sierra Madre and Cordillera de Centroamérica, from southern Mexico to Costa Rica. Altitude is probably a surrogate for host genetic, bacterial, dietary, and environmental factors that may cluster in the mountainous regions. For example, H. pylori strains from patients of the Andean Nariño region of Colombia display European ancestral haplotypes, whereas strains from the Pacific coast are predominantly of African origin. The observation of higher gastric cancer rates in the mountainous areas is not universal: the association is absent in Chile, where risk is more strongly associated with the age of H. pylori acquisition and socio-economic determinants. The dramatic global and regional variations in gastric cancer incidence and mortality rates offer the opportunity for scientific discovery and focused prevention programs. PMID:23224271

  11. The analysis of a large Danish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 11q24.

    PubMed

    Rudkjøbing, Laura Aviaja; Eiberg, Hans; Mikkelsen, Hanne Birte; Binderup, Marie Louise Mølgaard; Bisgaard, Marie Luise

    2015-09-01

    Hereditary colorectal cancer accounts for approximately 30% of all colorectal cancers, but currently only 5% of these families can be explained by highly penetrant, inherited mutations. In the remaining 25% it is not possible to perform a gene test to identify the family members who would benefit from prophylactic screening. Consequently, all family members are asked to follow a screening program. The purpose of this study was to localize a new gene which causes colorectal cancer. We performed a linkage analysis using data from a SNP6.0 chip in one large family with 12 affected family members. We extended the linkage analysis with microsatellites (STS) and single nucleotide polymorphisms (SNP's) and looked for the loss of heterozygosity in tumour tissue. Furthermore, we performed the exome sequencing of one family member and we sequenced candidate genes by use of direct sequencing. Major rearrangements were excluded after karyotyping. The linkage analysis with SNP6 data revealed three candidate areas, on chromosome 2, 6 and 11 respectively, with a LOD score close to two and no negative LOD scores. After extended linkage analysis, the area on chromosome 6 was excluded, leaving areas on chromosome 2 and chromosome 11 with the highest possible LOD scores of 2.6. Two other studies have identified 11q24 as a candidate area for colorectal cancer susceptibility and this area is supported by our results. PMID:25724759

  12. Adjuvant radiotherapy of regional lymph nodes in breast cancer - a meta-analysis of randomized trials

    PubMed Central

    2013-01-01

    Background Radiotherapy (RT) improves overall survival (OS) of breast cancer patients after breast conserving surgery and after mastectomy in patients with involved lymph nodes (LN). The contribution of RT to the regional LN to this survival benefit was poorly understood. Recently, the results of three large randomized trials addressing this question have become available. Material and methods The published abstracts (full publication pending) of the MA.20 (n=1832) and the EORTC 22922–10925 (EORTC) (n=4004) trial and the full publication of the French trial (n=1334) were basis of the meta-analysis. Main eligibility criteria were positive axillary LN (all trials), LN negative disease with high risk for recurrence (MA.20), and medial/central tumor location (French, EORTC). The MA.20 and the EORTC trial tested the effect of additional regional RT to the internal mammary (IM) LN and medial supraclavicular (MS) LN, whereas in the French trial all patients received RT to the MS-LN and solely RT to the IM-LN was randomized. Primary endpoint was OS. Secondary endpoints were disease-free survival (DFS) and distant metastasis free survival (DMFS). Results Regional RT of the MS-LN and the IM-LN (MA.20 and EORTC) resulted in a significant improvement of OS (Hazard Ratio (HR) 0.85 (95% CL 0.75 - 0.96)). Adding the results of the French trial and using the random effects model to respect the different design of the French trial, the effect on OS of regional radiotherapy was still significant (HR 0.88 (95% CL 0.80 - 0.97)). The absolute benefits in OS were 1.6% in the MA.20 trial at 5 years, 1.6% in the EORTC trial at 10 years, and 3.3% in the French trial at 10 years (not significant in single trials). Regional radiotherapy of the MS-LN and the IM-LN (MA.20 and EORTC) was associated with a significant improvement of DFS (HR 0.85 (95% CL 0.77 - 0.94)) and DMFS (HR 0.82 (95% CL 0.73 - 0.92)). The effect sizes were not significantly different between trials for any end point

  13. Long non-coding RNA containing ultraconserved genomic region 8 promotes bladder cancer tumorigenesis.

    PubMed

    Olivieri, Michele; Ferro, Matteo; Terreri, Sara; Durso, Montano; Romanelli, Alessandra; Avitabile, Concetta; De Cobelli, Ottavio; Messere, Anna; Bruzzese, Dario; Vannini, Ivan; Marinelli, Luciana; Novellino, Ettore; Zhang, Wei; Incoronato, Mariarosaria; Ilardi, Gennaro; Staibano, Stefania; Marra, Laura; Franco, Renato; Perdonà, Sisto; Terracciano, Daniela; Czerniak, Bogdan; Liguori, Giovanna L; Colonna, Vincenza; Fabbri, Muller; Febbraio, Ferdinando; Calin, George A; Cimmino, Amelia

    2016-04-12

    Ultraconserved regions (UCRs) have been shown to originate non-coding RNA transcripts (T-UCRs) that have different expression profiles and play functional roles in the pathophysiology of multiple cancers. The relevance of these functions to the pathogenesis of bladder cancer (BlCa) is speculative. To elucidate this relevance, we first used genome-wide profiling to evaluate the expression of T-UCRs in BlCa tissues. Analysis of two datasets comprising normal bladder tissues and BlCa specimens with a custom T-UCR microarray identified ultraconserved RNA (uc.) 8+ as the most upregulated T-UCR in BlCa tissues, although its expression was lower than in pericancerous bladder tissues. These results were confirmed on BlCa tissues by real-time PCR and by in situ hybridization. Although uc.8+ is located within intron 1 of CASZ1, a zinc-finger transcription factor, the transcribed non-coding RNA encoding uc.8+ is expressed independently of CASZ1. In vitro experiments evaluating the effects of uc.8+ silencing, showed significantly decreased capacities for cancer cell invasion, migration, and proliferation. From this, we proposed and validated a model of interaction in which uc.8+ shuttles from the nucleus to the cytoplasm of BlCa cells, interacts with microRNA (miR)-596, and cooperates in the promotion and development of BlCa. Using computational analysis, we investigated the miR-binding domain accessibility, as determined by base-pairing interactions within the uc.8+ predicted secondary structure, RNA binding affinity, and RNA species abundance in bladder tissues and showed that uc.8+ is a natural decoy for miR-596. Thus uc.8+ upregulation results in increased expression of MMP9, increasing the invasive potential of BlCa cells. These interactions between evolutionarily conserved regions of DNA suggest that natural selection has preserved this potentially regulatory layer that uses RNA to modulate miR levels, opening up the possibility for development of useful markers for

  14. Long non-coding RNA containing ultraconserved genomic region 8 promotes bladder cancer tumorigenesis

    PubMed Central

    Durso, Montano; Romanelli, Alessandra; Avitabile, Concetta; De Cobelli, Ottavio; Messere, Anna; Bruzzese, Dario; Vannini, Ivan; Marinelli, Luciana; Novellino, Ettore; Zhang, Wei; Incoronato, Mariarosaria; Ilardi, Gennaro; Staibano, Stefania; Marra, Laura; Franco, Renato; Perdonà, Sisto; Terracciano, Daniela; Czerniak, Bogdan; Liguori, Giovanna L.; Colonna, Vincenza; Fabbri, Muller; Febbraio, Ferdinando

    2016-01-01

    Ultraconserved regions (UCRs) have been shown to originate non-coding RNA transcripts (T-UCRs) that have different expression profiles and play functional roles in the pathophysiology of multiple cancers. The relevance of these functions to the pathogenesis of bladder cancer (BlCa) is speculative. To elucidate this relevance, we first used genome-wide profiling to evaluate the expression of T-UCRs in BlCa tissues. Analysis of two datasets comprising normal bladder tissues and BlCa specimens with a custom T-UCR microarray identified ultraconserved RNA (uc.) 8+ as the most upregulated T-UCR in BlCa tissues, although its expression was lower than in pericancerous bladder tissues. These results were confirmed on BlCa tissues by real-time PCR and by in situ hybridization. Although uc.8+ is located within intron 1 of CASZ1, a zinc-finger transcription factor, the transcribed non-coding RNA encoding uc.8+ is expressed independently of CASZ1. In vitro experiments evaluating the effects of uc.8+ silencing, showed significantly decreased capacities for cancer cell invasion, migration, and proliferation. From this, we proposed and validated a model of interaction in which uc.8+ shuttles from the nucleus to the cytoplasm of BlCa cells, interacts with microRNA (miR)-596, and cooperates in the promotion and development of BlCa. Using computational analysis, we investigated the miR-binding domain accessibility, as determined by base-pairing interactions within the uc.8+ predicted secondary structure, RNA binding affinity, and RNA species abundance in bladder tissues and showed that uc.8+ is a natural decoy for miR-596. Thus uc.8+ upregulation results in increased expression of MMP9, increasing the invasive potential of BlCa cells. These interactions between evolutionarily conserved regions of DNA suggest that natural selection has preserved this potentially regulatory layer that uses RNA to modulate miR levels, opening up the possibility for development of useful markers for

  15. A method to determine the mammographic regions that show early changes due to the development of breast cancer

    NASA Astrophysics Data System (ADS)

    Karemore, Gopal; Nielsen, Mads; Karssemeijer, Nico; Brandt, Sami S.

    2014-11-01

    It is well understood nowadays that changes in the mammographic parenchymal pattern are an indicator of a risk of breast cancer and we have developed a statistical method that estimates the mammogram regions where the parenchymal changes, due to breast cancer, occur. This region of interest is computed from a score map by utilising the anatomical breast coordinate system developed in our previous work. The method also makes an automatic scale selection to avoid overfitting while the region estimates are computed by a nested cross-validation scheme. In this way, it is possible to recover those mammogram regions that show a significant difference in classification scores between the cancer and the control group. Our experiments suggested that the most significant mammogram region is the region behind the nipple and that can be justified by previous findings from other research groups. This result was conducted on the basis of the cross-validation experiments on independent training, validation and testing sets from the case-control study of 490 women, of which 245 women were diagnosed with breast cancer within a period of 2-4 years after the baseline mammograms. We additionally generalised the estimated region to another, mini-MIAS study and showed that the transferred region estimate gives at least a similar classification result when compared to the case where the whole breast region is used. In all, by following our method, one most likely improves both preclinical and follow-up breast cancer screening, but a larger study population will be required to test this hypothesis.

  16. Knowledge of Cervical Cancer Screening among Women across Different Socio-Economic Regions of China

    PubMed Central

    Di, Jiangli; Rutherford, Shannon; Wu, Jiuling; Song, Bo; Ma, Lan; Chen, Jingyi; Chu, Cordia

    2015-01-01

    Background and Objective China has a high burden of cervical cancer (CC) and wide disparities in CC burden exist among different socio-economic regions. In order to reduce these disparities, China’s government launched the National Cervical Cancer Screening Program in Rural Areas (NCCSPRA) in 2009. Understanding the factors associated with underutilization of CC screening among target populations is important to improve the screening participation rate, and a high participation rate is key to achieving the goals of a screening program. However, data on the knowledge of CC among target populations in program areas is lacking in China. This study will investigate the knowledge of CC prevention and control among women in specific project counties to develop a better understanding of factors that might influence CC screening participation in order to improve the implementation of the NCCSPRA. Materials and Methods A cross-sectional survey was conducted and face-to-face interview questionnaires were completed by 308 women who received CC screening services in 6 project counties of NCCSPRA across different socio-economic regions of China. ANOVA and Chi-square tests were used to compare the knowledge rates and scores across the different subgroups. Logistic regression was conducted to examine factors associated with knowledge level. Results The overall CC knowledge rate of the target population was only 19.5%. Regional socio-economic level, advice from doctors, age, and educational status were strong predictors of knowledge level of CC screening. Significantly lower knowledge rates and scores were identified in older women (55–64 years old), less educated women (with primary school or illiterate), women in less developed regions and women who did not receive any advice about screening results from doctors. Conclusion The knowledge of CC screening among women in the project counties of NCCSPRA was found to be very poor. Given the importance of knowledge in encouraging

  17. Mapping the chromosome 16 cadherin gene cluster to a minimal deleted region in ductal breast cancer.

    PubMed

    Chalmers, I J; Aubele, M; Hartmann, E; Braungart, E; Werner, M; Höfler, H; Atkinson, M J

    2001-04-01

    The cadherin family of cell adhesion molecules has been implicated in tumor metastasis and progression. Eight family members have been mapped to the long arm of chromosome 16. Using radiation hybrid mapping, we have located six of these genes within a cluster at 16q21-q22.1. In invasive lobular carcinoma of the breast frequent LOH and accompanying mutation affect the CDH1 gene, which is a member of this chromosome 16 gene cluster. CDH1 LOH also occurs in invasive ductal carcinoma, but in the absence of gene mutation. The proximity of other cadherin genes to 16q22.1 suggests that they may be affected by LOH in invasive ductal carcinomas. Using the mapping data, microsatellite markers were selected which span regions of chromosome 16 containing the cadherin genes. In breast cancer tissues, a high rate of allelic loss was found over the gene cluster region, with CDH1 being the most frequently lost marker. In invasive ductal carcinoma a minimal deleted region was identified within part of the chromosome 16 cadherin gene cluster. This provides strong evidence for the existence of a second 16q22 suppressor gene locus within the cadherin cluster. PMID:11343777

  18. Role of 3’-untranslated region translational control in cancer development, diagnostics and treatment

    PubMed Central

    Vislovukh, Andrii; Vargas, Thaiz Rivera; Polesskaya, Anna; Groisman, Irina

    2014-01-01

    The messenger RNA 3’-untranslated region (3’UTR) plays an important role in regulation of gene expression on the posttranscriptional level. The 3’UTR controls gene expression via orchestrated interaction between the structural components of mRNAs (cis-element) and the specific trans-acting factors (RNA binding proteins and non-coding RNAs). The crosstalk of these factors is based on the binding sequences and/or direct protein-protein interaction, or just functional interaction. Much new evidence that has accumulated supports the idea that several RNA binding factors can bind to common mRNA targets: to the non-overlapping binding sites or to common sites in a competitive fashion. Various factors capable of binding to the same RNA can cooperate or be antagonistic in their actions. The outcome of the collective function of all factors bound to the same mRNA 3’UTR depends on many circumstances, such as their expression levels, affinity to the binding sites, and localization in the cell, which can be controlled by various physiological conditions. Moreover, the functional and/or physical interactions of the factors binding to 3’UTR can change the character of their actions. These interactions vary during the cell cycle and in response to changing physiological conditions. Abnormal functioning of the factors can lead to disease. In this review we will discuss how alterations of these factors or their interaction can affect cancer development and promote or enhance the malignant phenotype of cancer cells. Understanding these alterations and their impact on 3’UTR-directed posttranscriptional gene regulation will uncover promising new targets for therapeutic intervention and diagnostics. We will also discuss emerging new tools in cancer diagnostics and therapy based on 3’UTR binding factors and approaches to improve them. PMID:24600513

  19. Targeting glucose metabolism in cancer: new class of agents for loco-regional and systemic therapy of liver cancer and beyond?

    PubMed Central

    Savic, Lynn Jeanette; Chapiro, Julius; Duwe, Gregor; Geschwind, Jean-François

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and the third leading cause of cancer-related deaths worldwide. In patients with unresectable disease, loco-regional catheter-based intra-arterial therapies (IAT) can achieve selective tumor control while minimizing systemic toxicity. As molecular features of tumor growth and microenvironment are better understood, new targets arise for selective anticancer therapy. Particularly, antiglycolytic drugs that exploit the hyperglycolytic cancer cell metabolism – also known as the ‘Warburg effect’ – have emerged as promising therapeutic options. Thus, future developments will combine the selective character of loco-regional drug delivery platforms with highly specific molecular targeted antiglycolytic agents. This review will exemplify literature on antiglycolytic approaches and particularly focus on intra-arterial delivery methods. PMID:26989470

  20. How to identify rectal sub-regions likely involved in rectal bleeding in prostate cancer radiotherapy

    NASA Astrophysics Data System (ADS)

    Dréan, G.; Acosta, O.; Ospina, J. D.; Voisin, C.; Rigaud, B.; Simon, A.; Haigron, P.; de Crevoisier, R.

    2013-11-01

    Nowadays, the de nition of patient-speci c constraints in prostate cancer radiotherapy planning are solely based on dose-volume histogram (DVH) parameters. Nevertheless those DVH models lack of spatial accuracy since they do not use the complete 3D information of the dose distribution. The goal of the study was to propose an automatic work ow to de ne patient-speci c rectal sub-regions (RSR) involved in rectal bleeding (RB) in case of prostate cancer radiotherapy. A multi-atlas database spanning the large rectal shape variability was built from a population of 116 individuals. Non-rigid registration followed by voxel-wise statistical analysis on those templates allowed nding RSR likely correlated with RB (from a learning cohort of 63 patients). To de ne patient-speci c RSR, weighted atlas-based segmentation with a vote was then applied to 30 test patients. Results show the potentiality of the method to be used for patient-speci c planning of intensity modulated radiotherapy (IMRT).

  1. Fluorescence diagnostics of metastatic lesion of regional lymph nodes upon surgical treatment of breast cancer

    NASA Astrophysics Data System (ADS)

    Filonenko, E. V.; Pak, D. D.; Yanikova, A. G.

    2013-06-01

    We have performed intraoperative fluorescence diagnostics of 60 patients for metastases of breast cancer to regional lymph nodes. All the patients were divided into two groups. The first group consisted of 50 patients, which were surgically treated at the first stage. The second group consisted of ten patients, which underwent combined treatment. At the first stage, they received from two to four courses of neoadjuvant chemotherapy, and, at the second stage, the surgical intervention was performed. The intraoperative fluorescence diagnostics was performed using the preparation alasens (precursor of protoporphyrin IX in the human organism). The occurrence of fluorescence of alasens-induced protoporphyrin IX was determined visually and using the local fluorescence spectroscopy method. Altogether, 498 lymph nodes were examined: 408 in the first group and 90 in the second one. For the first group, the sensitivity of the method was found to be 87.2%, and its specificity, 94.8%; in the second group, these parameters were determined to be 77 and 78%, respectively. The first experience of the application of the intraoperative fluorescence diagnostics of metastatic lesion of lymph nodes in patients with breast cancer has shown its high efficiency and application potential.

  2. Cancer

    MedlinePlus

    ... body. Cancerous cells are also called malignant cells. Causes Cancer grows out of cells in the body. Normal ... of many cancers remains unknown. The most common cause of cancer-related death is lung cancer. In the U.S., ...

  3. Isolated local-regional recurrence of breast cancer following mastectomy: Radiotherapeutic management

    SciTech Connect

    Halverson, K.J.; Perez, C.A.; Kuske, R.R.; Garcia, D.M.; Simpson, J.R.; Fineberg, B. )

    1990-10-01

    Two hundred twenty-four patients with their first, isolated local-regional recurrence of breast cancer were irradiated with curative intent. Patients who had previous chest wall or regional lymphatic irradiation were not included in the study. With a median follow-up of 46 months (range 24 to 241 months), the 5- and 10-year survival for the entire group were 43% and 26%, respectively. Overall, 57% of the patients were projected to be loco-regionally controlled at 5 years. The 5-year local-regional tumor control was best for patients with isolated chest wall recurrences (63%), intermediate for nodal recurrences (45%), and poor for concomitant chest wall and nodal recurrences (27%). In patients with solitary chest wall recurrences, large field radiotherapy encompassing the entire chest wall resulted in a 5- and 10-year freedom from chest wall re-recurrence of 75% and 63% in contrast to 36% and 18% with small field irradiation (p = 0.0001). For the group with recurrences completely excised, tumor control was adequate at all doses ranging from 4500 to 7000 cGy. For the recurrences less than 3 cm, 100% were controlled at doses greater than or equal to 6000 cGy versus 76% at lower doses. No dose response could be demonstrated for the larger lesions. The supraclavicular failure rate was 16% without elective radiotherapy versus 6% with elective radiotherapy (p = 0.0489). Prophylactic irradiation of the uninvolved chest wall decreased the subsequent re-recurrence rate (17% versus 27%), but the difference is not statistically significant (p = .32). The incidence of chest wall re-recurrence was 12% with doses greater than or equal to 5000 cGy compared to 27% with no elective radiotherapy, but again was not statistically significant (p = .20). Axillary and internal mammary failures were infrequent, regardless of prophylactic treatment.

  4. A new breast cancer risk analysis approach using features extracted from multiple sub-regions on bilateral mammograms

    NASA Astrophysics Data System (ADS)

    Sun, Wenqing; Tseng, Tzu-Liang B.; Zheng, Bin; Zhang, Jianying; Qian, Wei

    2015-03-01

    A novel breast cancer risk analysis approach is proposed for enhancing performance of computerized breast cancer risk analysis using bilateral mammograms. Based on the intensity of breast area, five different sub-regions were acquired from one mammogram, and bilateral features were extracted from every sub-region. Our dataset includes 180 bilateral mammograms from 180 women who underwent routine screening examinations, all interpreted as negative and not recalled by the radiologists during the original screening procedures. A computerized breast cancer risk analysis scheme using four image processing modules, including sub-region segmentation, bilateral feature extraction, feature selection, and classification was designed to detect and compute image feature asymmetry between the left and right breasts imaged on the mammograms. The highest computed area under the curve (AUC) is 0.763 ± 0.021 when applying the multiple sub-region features to our testing dataset. The positive predictive value and the negative predictive value were 0.60 and 0.73, respectively. The study demonstrates that (1) features extracted from multiple sub-regions can improve the performance of our scheme compared to using features from whole breast area only; (2) a classifier using asymmetry bilateral features can effectively predict breast cancer risk; (3) incorporating texture and morphological features with density features can boost the classification accuracy.

  5. Impact of NGS in the medical sciences: Genetic syndromes with an increased risk of developing cancer as an example of the use of new technologies.

    PubMed

    Lapunzina, Pablo; López, Rocío Ortiz; Rodríguez-Laguna, Lara; García-Miguel, Purificación; Martínez, Augusto Rojas; Martínez-Glez, Víctor

    2014-03-01

    The increased speed and decreasing cost of sequencing, along with an understanding of the clinical relevance of emerging information for patient management, has led to an explosion of potential applications in healthcare. Currently, SNP arrays and Next-Generation Sequencing (NGS) technologies are relatively new techniques used to scan genomes for gains and losses, losses of heterozygosity (LOH), SNPs, and indel variants as well as to perform complete sequencing of a panel of candidate genes, the entire exome (whole exome sequencing) or even the whole genome. As a result, these new high-throughput technologies have facilitated progress in the understanding and diagnosis of genetic syndromes and cancers, two disorders traditionally considered to be separate diseases but that can share causal genetic alterations in a group of developmental disorders associated with congenital malformations and cancer risk. The purpose of this work is to review these syndromes as an example of a group of disorders that has been included in a panel of genes for NGS analysis. We also highlight the relationship between development and cancer and underline the connections between these syndromes. PMID:24764758

  6. Impact of NGS in the medical sciences: Genetic syndromes with an increased risk of developing cancer as an example of the use of new technologies

    PubMed Central

    Lapunzina, Pablo; López, Rocío Ortiz; Rodríguez-Laguna, Lara; García-Miguel, Purificación; Martínez, Augusto Rojas; Martínez-Glez, Víctor

    2014-01-01

    The increased speed and decreasing cost of sequencing, along with an understanding of the clinical relevance of emerging information for patient management, has led to an explosion of potential applications in healthcare. Currently, SNP arrays and Next-Generation Sequencing (NGS) technologies are relatively new techniques used to scan genomes for gains and losses, losses of heterozygosity (LOH), SNPs, and indel variants as well as to perform complete sequencing of a panel of candidate genes, the entire exome (whole exome sequencing) or even the whole genome. As a result, these new high-throughput technologies have facilitated progress in the understanding and diagnosis of genetic syndromes and cancers, two disorders traditionally considered to be separate diseases but that can share causal genetic alterations in a group of developmental disorders associated with congenital malformations and cancer risk. The purpose of this work is to review these syndromes as an example of a group of disorders that has been included in a panel of genes for NGS analysis. We also highlight the relationship between development and cancer and underline the connections between these syndromes. PMID:24764758

  7. Cables enhances cdk2 tyrosine 15 phosphorylation by Wee1, inhibits cell growth, and is lost in many human colon and squamous cancers.

    PubMed

    Wu, C L; Kirley, S D; Xiao, H; Chuang, Y; Chung, D C; Zukerberg, L R

    2001-10-01

    Cyclin-dependent kinase 2 (cdk2) is a small serine/threonine kinase that regulates cell cycle progression. Cdk2 activity is tightly controlled by several mechanisms, including phosphorylation and dephosphorylation events. Cables is a recently described novel cdk-interacting protein. In proliferating cells, Cables was predominantly localized in the nucleus by cell fractionation and immunostaining. Expression of Cables in HeLa cells inhibited cell growth and colony formation. Cables enhanced cdk2 tyrosine 15 phosphorylation by the Wee1 protein kinase, an inhibitory phosphorylation, which led to decreased cdk2 kinase activity. The gene encoding Cables is located on human chromosome 18q11-12, a site that is frequently lost in squamous, colon, and pancreas cancers. We found that Cables was strongly expressed in normal human epithelial cells including squamous and glandular mucosa. Breast and pancreatic cancers show strong Cables expression; however, loss of Cables expression was found in approximately 50-60% of primary colon and head and neck cancer specimens. Lack of Cables expression was associated with loss of heterozygosity on chromosome 18q11. The data provide evidence for a Cables-mediated interplay between cdk2 and Wee1 that leads to inhibition of cell growth. Conversely, loss of Cables may cause uncontrolled cell growth and enhance tumor formation. PMID:11585773

  8. Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy.

    PubMed

    Jenner, Zachary B; Sood, Anil K; Coleman, Robert L

    2016-06-01

    Rucaparib camsylate (CO-338; 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid salt) is a PARP1, 2 and 3 inhibitor. Phase I studies identified a recommended Phase II dose of 600 mg orally twice daily. ARIEL2 Part 1 established a tumor genomic profiling test for homologous recombination loss of heterozygosity quantification using a next-generation sequencing companion diagnostic (CDx). Rucaparib received US FDA Breakthrough Therapy designation for treatment of platinum-sensitive BRCA-mutated advanced ovarian cancer patients who received greater than two lines of platinum-based therapy. Comparable to rucaparib development, other PARP inhibitors, such as olaparib, niraparib, veliparib and talazoparib, are developing CDx tests for targeted therapy. PARP inhibitor clinical trials and CDx assays are discussed in this review, as are potential PARP inhibitor combination therapies and likely resistance mechanisms. PMID:27087632

  9. Cadherins in cancer.

    PubMed

    Strumane, K; Berx, G; Van Roy, F

    2004-01-01

    The presence of a functional E-cadherin/catenin cell-cell adhesion complex is a prerequisite for normal development and maintenance of epithelial structures in the mammalian body. This implies that the acquisition of molecular abnormalities that disturb the expression or function of this complex is related to the development and progression of most, if not all, epithelial cell-derived tumors, i.e. carcinomas. E-cadherin downregulation is indeed correlated with malignancy parameters such as tumor progression, loss of differentiation, invasion and metastasis, and hence poor prognosis. Moreover, E-cadherin has been shown to be a potent invasion suppressor as well as a tumor suppressor. Disturbed expression profiles of the E-cadherin/catenin complex have been demonstrated in histological sections of many human tumor types. In different kinds of carcinomas, biallelic downregulation of the E-cadherin gene, resulting in tumor-restricted decrease or even complete loss of E-cadherin expression, appears to be caused by a variety of inactivation mechanisms. Gene deletion due to loss of heterozygosity of the CDH1 locus on 16q22.1 frequently occurs in many carcinoma types. However, somatic inactivating mutations resulting in aberrant E-cadherin expression by loss of both wild-type alleles is rare and restricted to only a few cancer types. A majority of carcinomas thus seems to show deregulated E-cadherin expression by other mechanisms. The present evidence proposes transcriptional repression as a powerful and recurrent molecular mechanism for silencing E-cadherin expression. The predominant mechanisms emerging in most carcinomas are hypermethylation of the E-cadherin promoter and expression of transrepressor molecules such as SIP1, Snail, and Slug that bind sequence elements in the proximal E-cadherin promoter. Interestingly, complex differential expression of other cadherins seems to be associated with loss of E-cadherin and to reinforce effects of this loss on tumor

  10. Oesophageal cancer treatment in North East Thames region, 1981: medical audit using Hospital Activity Analysis data.

    PubMed Central

    Earlam, R

    1984-01-01

    Figures from the Hospital Activity Analysis in the North East Thames region in 1981 were used to perform a medical audit on oesophageal cancer treatment. Four hundred and forty four patients were admitted with this diagnosis; 80 had been intubated without a thoracotomy or laparotomy, and 73 had had surgery (two thirds radical and one third palliative) with an overall operative mortality of 33%. Fifty five patients had had radiotherapy and 179 patients had no recorded operation or investigation. One hundred and seventy seven different consultants had looked after all these inpatients, most being general surgeons. Only five consultants had looked after 10 or more patients each year. From a calculated estimate of a total 286 patients in the region, 28% had palliative intubation and 25% had surgery; 20% of all the patients had radiotherapy either as a radical or palliative treatment, the remainder having no recorded therapeutic procedure. One hundred and eighty seven patients (66% of the calculated total) died in hospital. Investigation and treatment do not seem to be limited by lack of money, but money is being wasted by admitting patients for terminal care into acute hospital beds. It would be more humane for these patients to die at home or in a hospice if they wished. PMID:6203599