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Sample records for 17p deletion tp53

  1. The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases.

    PubMed

    Stengel, A; Kern, W; Haferlach, T; Meggendorfer, M; Fasan, A; Haferlach, C

    2017-03-01

    Alterations in TP53 have been described in many cancer types including hematological neoplasms. We aimed at comparing TP53 mutations (mut) and deletions (del) in a large cohort of patients with hematological malignancies (n=3307), including AML (n=858), MDS (n=943), ALL (n=358), CLL (n=1148). Overall, alterations in TP53 were detected in 332/3307 cases (10%). The highest frequency was observed in ALL (total: 19%; mut+del: 6%; mut only: 8%; del only: 5%) and AML (total: 13%; mut+del: 5%; mut only: 7%; del only: 1%), whereas TP53 alterations occurred less frequently in CLL (total: 8%) and MDS (total: 7%). TP53 mutations were significantly more frequent in patients ⩾60 vs <60 years in AML (9% vs 2%, P<0.001) and ALL (12% vs 6%, P<0.001). TP53mut+del had a significant negative impact on overall survival in all entities, whereas differences were observed regarding TP53mut only or TP53del only: TP53mut only impacted survival in AML (36 vs 9 months, P<0.001) and MDS (65 vs 19 months, P<0.001), TP53del only in CLL (not reached vs 64 months, P=0.008) and MDS (65 vs 24 months, P=0.011). As substantial differences between the entities are observed regarding correlation to age and survival, we suggest evaluation of both TP53 deletion and mutation status.

  2. Outcomes in patients with multiple myeloma with TP53 deletion after autologous hematopoietic stem cell transplant.

    PubMed

    Gaballa, Sameh; Saliba, Rima M; Srour, Samer; Lu, Gary; Brammer, Jonathan E; Shah, Nina; Bashir, Qaiser; Patel, Krina; Bock, Fabian; Parmar, Simrit; Hosing, Chitra; Popat, Uday; Delgado, Ruby; Rondon, Gabriela; Shah, Jatin J; Manasanch, Elisabet E; Orlowski, Robert Z; Champlin, Richard; Qazilbash, Muzaffar H

    2016-10-01

    TP53 gene deletion is associated with poor outcomes in multiple myeloma (MM). We report the outcomes of patients with MM with and without TP53 deletion who underwent immunomodulatory drug (IMiD) and/or proteasome inhibitor (PI) induction followed by autologous hematopoietic stem cell transplant (auto-HCT). We identified 34 patients with MM and TP53 deletion who underwent IMiD and/or PI induction followed by auto-HCT at our institution during 2008-2014. We compared their outcomes with those of control patients (n = 111) with MM without TP53 deletion. Median age at auto-HCT was 59 years in the TP53-deletion group and 58 years in the control group (P = 0.4). Twenty-one patients (62%) with TP53 deletion and 69 controls (62%) achieved at least partial remission before auto-HCT (P = 0.97). Twenty-three patients (68%) with TP53 deletion and 47 controls (42%) had relapsed disease at auto-HCT (P = 0.01). Median progression-free survival was 8 months for patients with TP53 deletion and 28 months for controls (P < 0.001). Median overall survival was 21 months for patients with TP53 deletion and 56 months for controls (P < 0.001). On multivariate analysis of both groups, TP53 deletion (hazard ratio 3.4, 95% confidence interval 1.9-5.8, P < 0.001) and relapsed disease at auto-HCT (hazard ratio 2.0, 95% confidence interval 1.2-3.4, P = 0.008) were associated with a higher risk of earlier progression. In MM patients treated with PI and/or IMiD drugs, and auto-HCT, TP53 deletion and relapsed disease at the time of auto-HCT are independent predictors of progression. Novel approaches should be evaluated in this high-risk population. Am. J. Hematol. 91:E442-E447, 2016. © 2016 Wiley Periodicals, Inc.

  3. TP53 dysfunction in CLL: Implications for prognosis and treatment.

    PubMed

    Te Raa, Gera D; Kater, Arnon P

    2016-03-01

    Despite the availability of novel targeted agents, TP53 defects remain the most important adverse prognostic factor in chronic lymphocytic leukemia (CLL). Detection of deletion of TP53 locus (17p deletion) by fluorescent in situ hybridization (FISH) has become standard and performed prior to every line of treatment as the incidence dramatically increases as relapses occur. As monoallelic mutations of TP53 equally affect outcome, novel methods are being developed to improve detection of TP53 defects and include next-generation sequencing (NGS) and functional assays. TP53 defects highly affect outcome of immunochemotherapy but also alter response durations of tyrosine kinase inhibitors. Although BCR-targeting agents and Bcl-2-inhibitos have achieved durable responses in some patients with TP53 defects, long-term follow-up is currently lacking. In this review biological and clinical consequences of TP53 dysfunction as well as applicability of currently available methods to detect TP53 defects are described. In addition, proposed novel therapeutic strategies specifically for patients with TP53 dysfunction are discussed. In summary, the only curative treatment option for TP53-defective CLL is still allogeneic hematopoietic stem cell transplantation. Other treatment strategies such as rationale combinations of agents with different (TP53 independent) targets, including kinase inhibitors and inhibitors of anti-apoptotic molecules but also immunomodulatory agents need to be further explored.

  4. Whole-arm translocation of der(5;17)(p10;q10) with concurrent TP53 mutations in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS): A unique molecular-cytogenetic subgroup.

    PubMed

    Hong, Ming; Hao, Suyang; Patel, Keyur P; Kantarjian, Hagop M; Garcia-Manero, Guillermo; Yin, C Cameron; Medeiros, L Jeffrey; Lin, Pei; Lu, Xinyan

    2016-05-01

    Der(5;17)(p10;q10) is a recurrent but rare aberration reported in myeloid neoplasms (MNs). We report 48 such patients including 19 acute myeloid leukemia (AML) and 29 myelodysplastic syndrome (MDS), to characterize their clinicopathological features. There were 29 men and 19 women, with a median age of 61 years (range, 18-80). 62.5% patients had therapy-related diseases (t-MNs), 70.8% had multilineage dysplasia and 83.3% showed complex karyotypes. In 39 patients tested, FLT3, NPM1, CEBPA, KIT were all wild type and NRAS, KRAS, IDH1, APC, TET2 mutations were detected in single case(s) respectively. TP53 mutations were identified in 8 of 10 cases (80%) tested. Median disease-free survival (DFS) and overall survival (OS) were 3 and 10 months, respectively and did not differ between AML or MDS cases, or between de novo versus therapy-related cases, or between the groups with or without complex karyotypes. In 19 patients who achieved complete remission after chemotherapy, and in 9 patients who underwent stem cell transplantation, the OS was better (14 and 17.5 months, P = 0.0128 and P = 0.0086, respectively). The der(5;17)(p10;q10) represents a unique molecular-cytogenetic subgroup in t-MNs and, associated with complex karyotypes. TP53 inactivation, resulting from 17p deletion coupled with TP53 mutation, likely contributes to the poor clinical outcome of these patients.

  5. Deletion/duplication mutation screening of TP53 gene in patients with transitional cell carcinoma of urinary bladder using multiplex ligation-dependent probe amplification.

    PubMed

    Bazrafshani, Mohammad Reza R; Nowshadi, Pouriaali A; Shirian, Sadegh; Daneshbod, Yahya; Nabipour, Fatemeh; Mokhtari, Maral; Hosseini, Fatemehsadat; Dehghan, Somayeh; Saeedzadeh, Abolfazl; Mosayebi, Ziba

    2016-02-01

    Bladder cancer is a molecular disease driven by the accumulation of genetic, epigenetic, and environmental factors. The aim of this study was to detect the deletions/duplication mutations in TP53 gene exons using multiplex ligation-dependent probe amplification (MLPA) method in the patients with transitional cell carcinoma (TCC). The achieved formalin-fixed paraffin-embedded tissues from 60 patients with TCC of bladder were screened for exonal deletions or duplications of every 12 TP53 gene exons using MLPA. The pathological sections were examined by three pathologists and categorized according to the WHO scoring guideline as 18 (30%) grade I, 22 (37%) grade II, 13 (22%) grade III, and 7 (11%) grade IV cases of TCC. None mutation changes of TP53 gene were detected in 24 (40%) of the patients. Furthermore, mutation changes including, 15 (25%) deletion, 17 (28%) duplication, and 4 (7%) both deletion and duplication cases were observed among 60 samples. From 12 exons of TP53 gene, exon 1 was more subjected to exonal deletion. Deletion of exon 1 of TP53 gene has occurred in 11 (35.4%) patients with TCC. In general, most mutations of TP53, either deletion or duplication, were found in exon 1, which was statistically significant. In addition, no relation between the TCC tumor grade and any type of mutation were observed in this research. MLPA is a simple and efficient method to analyze genomic deletions and duplications of all 12 exons of TP53 gene. The finding of this report that most of the mutations of TP53 occur in exon 1 is in contrast to that of the other reports suggesting that exons 5-8 are the most (frequently) mutated exons of TP53 gene. The mutations of exon 1 of TP53 gene may play an important role in the tumorogenesis of TCC.

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

    PubMed

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

    2016-03-01

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

  7. Treatment of Chronic Lymphocytic Leukemia With del(17p)/TP53 Mutation: Allogeneic Hematopoietic Stem Cell Transplantation or BCR-Signaling Inhibitors?

    PubMed

    Montserrat, Emili; Dreger, Peter

    2016-08-01

    The treatment of patients with chronic lymphocytic leukemia (CLL) whose tumor presents the del(17p)/TP53 mutation is a major challenge. Treatment with chemo(immuno)therapy, immunomodulators, or the anti-CD52 monoclonal antibody alemtuzumab produces transient, unsatisfactory responses. Reduced-intensity-conditioning allotransplantation produces sustained progression-free survival and overall survival (40%-60% at 5 years), equivalent to the cure of the disease, even in cases with adverse biomarkers. Unfortunately, despite improvements in this procedure, the non-relapse mortality continues to be high (15%-30%), and only highly selected patients (young, physically fit, with treatment-sensitive disease, not heavily pretreated, and with a fully matched donor) may benefit from the intervention without incurring unacceptable treatment-related risks. The advent of non-cytotoxic agents, such as the inhibitors of the B-cell-antigen receptor signaling (BCRi; ibrutinib, idelasilib) and anti-BCL2 proteins (venetoclax), is rapidly changing the treatment landscape in CLL, including its high-risk forms. These agents are satisfactorily safe. Moreover, they are effective across all genetic subgroups, albeit results in del(17p)/TP53 mutated cases are inferior to those with no adverse genetics. Importantly, progression-free and overall survival decline over time. These agents are tolerated much better and are more effective than conventional therapies used in high-risk CLL, and treatment results are close to those obtained with allotransplantation. As there is no proof as to which treatment (BCRi vs. allotransplantation) is preferable, treatment recommendations should be individualized, weighing the pros and cons of each of these interventions. In most patients, however, initial therapy with BCRi (ideally in combination with monoclonal antibodies and/or other small molecules) is a reasonable approach, and allotransplantation should be considered in selected patients refractory to BCRi

  8. TP53 mutations are early events in chronic lymphocytic leukemia disease progression and precede evolution to complex karyotypes.

    PubMed

    Lazarian, Gregory; Tausch, Eugen; Eclache, Virginie; Sebaa, Amel; Bianchi, Vincent; Letestu, Remi; Collon, Jean-Francois; Lefebvre, Valerie; Gardano, Laura; Varin-Blank, Nadine; Soussi, Thierry; Stilgenbauer, Stephen; Cymbalista, Florence; Baran-Marszak, Fanny

    2016-10-15

    TP53 abnormalities lead to resistance to purine analogues and are found in over 40% of patients with refractory chronic lymphocytic leukemia (CLL). At diagnosis, no more than 5% of patients carry the 17p deletion, most cases harbour mutations within the other TP53 allele. The incidence of a TP53 mutation as the only alteration is approximately 5%, but this depends on the sensitivity of the technique. Recently, having a complex karyotype has been considered a strong adverse prognostic factor. However, there are no longitudinal studies simultaneously examining the presence of the 17p deletion, TP53 mutations and karyotype abnormalities. We conducted a retrospective longitudinal study of 31 relapsed/refractory CLL patients. Two to six blood samples per patient were analyzed, with a median follow-up of 8 years. In this report, we assessed the sequence of events of TP53 clonal evolution and correlated the presence of TP53 abnormalities to genetic instability during progression and treatment. Next-generation sequencing allowed the early detection of TP53 mutated clones and was able to be performed on a routine basis, demonstrating an excellent correlation between the Illumina and Ion Torrent technologies. We concluded that TP53 mutations are early events and precede clonal evolution to complex karyotypes. We strongly recommend the early and iterated detection of TP53 mutations in progressive cases.

  9. Progressive leukemic non-nodal mantle cell lymphoma associated with deletions of TP53, ATM, and/or 13q14.

    PubMed

    Chapman-Fredricks, Jennifer; Sandoval-Sus, Jose; Vega, Francisco; Lossos, Izidore S

    2014-08-01

    Leukemic, non-nodal mantle cell lymphoma (MCL) is a relatively indolent disease characterized by asymptomatic leukemic presentation, non-nodal disease distribution, and slow disease progression, particularly in comparison to that of classic nodal MCL. We studied 3 cases of leukemic, non-nodal MCL in which TP53, ATM, and/or 13q14 deletions were identified. All three patients had disease progression leading to treatment requirements in two of the patients at 5 and 18 months after initial diagnosis. The third patient also clinically progressed 25 months after initial diagnosis but was lost to follow up despite recommendation for initiation of therapy. We present these cases as potential evidence that while leukemic non-nodal MCL is typically an indolent disease compared to classically defined mantle cell lymphoma, cytogenetic heterogeneity exists and cases with TP53, ATM, and/or 13q14 deletions may have a relatively aggressive clinical course.

  10. Ancestry of the Brazilian TP53 c.1010G>A (p.Arg337His, R337H) Founder Mutation: Clues from Haplotyping of Short Tandem Repeats on Chromosome 17p

    PubMed Central

    Paskulin, Diego Davila; Giacomazzi, Juliana; Achatz, Maria Isabel; Costa, Sandra; Reis, Rui Manoel; Hainaut, Pierre; dos Santos, Sidney Emanuel Batista; Ashton-Prolla, Patricia

    2015-01-01

    Rare germline mutations in TP53 (17p13.1) cause a highly penetrant predisposition to a specific spectrum of early cancers, defining the Li-Fraumeni Syndrome (LFS). A germline mutation at codon 337 (p.Arg337His, c1010G>A) is found in about 0.3% of the population of Southern Brazil. This mutation is associated with partially penetrant LFS traits and is found in the germline of patients with early cancers of the LFS spectrum unselected for familial history. To characterize the extended haplotypes carrying the mutation, we have genotyped 9 short tandem repeats on chromosome 17p in 12 trios of Brazilian p.Arg337His carriers. Results confirm that all share a common ancestor haplotype of Caucasian/Portuguese-Iberic origin, distant in about 72–84 generations (2000 years assuming a 25 years intergenerational distance) and thus pre-dating European migration to Brazil. So far, the founder p.Arg337His haplotype has not been detected outside Brazil, with the exception of two residents of Portugal, one of them of Brazilian origin. On the other hand, increased meiotic recombination in p.Arg337His carriers may account for higher than expected haplotype diversity. Further studies comparing haplotypes in populations of Brazil and of other areas of Portuguese migration are needed to understand the historical context of this mutation in Brazil. PMID:26618902

  11. Ancestry of the Brazilian TP53 c.1010G>A (p.Arg337His, R337H) Founder Mutation: Clues from Haplotyping of Short Tandem Repeats on Chromosome 17p.

    PubMed

    Paskulin, Diego Davila; Giacomazzi, Juliana; Achatz, Maria Isabel; Costa, Sandra; Reis, Rui Manoel; Hainaut, Pierre; dos Santos, Sidney Emanuel Batista; Ashton-Prolla, Patricia

    2015-01-01

    Rare germline mutations in TP53 (17p13.1) cause a highly penetrant predisposition to a specific spectrum of early cancers, defining the Li-Fraumeni Syndrome (LFS). A germline mutation at codon 337 (p.Arg337His, c1010G>A) is found in about 0.3% of the population of Southern Brazil. This mutation is associated with partially penetrant LFS traits and is found in the germline of patients with early cancers of the LFS spectrum unselected for familial history. To characterize the extended haplotypes carrying the mutation, we have genotyped 9 short tandem repeats on chromosome 17p in 12 trios of Brazilian p.Arg337His carriers. Results confirm that all share a common ancestor haplotype of Caucasian/Portuguese-Iberic origin, distant in about 72-84 generations (2000 years assuming a 25 years intergenerational distance) and thus pre-dating European migration to Brazil. So far, the founder p.Arg337His haplotype has not been detected outside Brazil, with the exception of two residents of Portugal, one of them of Brazilian origin. On the other hand, increased meiotic recombination in p.Arg337His carriers may account for higher than expected haplotype diversity. Further studies comparing haplotypes in populations of Brazil and of other areas of Portuguese migration are needed to understand the historical context of this mutation in Brazil.

  12. Telomere status in chronic lymphocytic leukemia with TP53 disruption.

    PubMed

    Guièze, Romain; Pages, Mélanie; Véronèse, Lauren; Combes, Patricia; Lemal, Richard; Gay-Bellile, Mathilde; Chauvet, Martine; Callanan, Mary; Kwiatkowski, Fabrice; Pereira, Bruno; Vago, Philippe; Bay, Jacques-Olivier; Tournilhac, Olivier; Tchirkov, Andreï

    2016-08-30

    In chronic lymphocytic leukemia (CLL), telomere dysfunction is associated with poor outcomes. TP53 is involved in cellular responses to dysfunctional telomeres, and its inactivation is the strongest adverse prognostic factor for CLL. Given the biological relationship between TP53 and telomeres, and their prognostic value, it is important to improve our understanding of the impact of TP53 alterations on telomeres. We performed a comprehensive study of the deletions and mutations of the TP53 gene and telomere parameters, including hTERT and the shelterin complex, in 115 CLL patients. We found that any type of TP53 alteration was associated with very short telomeres and high hTERT expression, independently of other biological CLL features. Patients with disrupted TP53 showed telomere deletions and chromosomal end-to-end fusions in cells with complex karyotypes. TP53 disruption was characterized by downregulation of shelterin genes. Interestingly, low expression of POT1, TPP1 and TIN2 was also found in some patients with wild-type TP53 and had an adverse impact on progression-free survival after standard genotoxic therapy. In conclusion, we have demonstrated that patients with disrupted TP53 have severe telomere dysfunction and high genomic instability. Thus, the telomeric profile could be tested as a biomarker in CLL patients treated with new therapeutic agents.

  13. Telomere status in chronic lymphocytic leukemia with TP53 disruption

    PubMed Central

    Guièze, Romain; Pages, Mélanie; Véronèse, Lauren; Combes, Patricia; Lemal, Richard; Gay-bellile, Mathilde; Chauvet, Martine; Callanan, Mary; Kwiatkowski, Fabrice; Pereira, Bruno; Vago, Philippe; Bay, Jacques-Olivier; Tournilhac, Olivier; Tchirkov, Andreï

    2016-01-01

    In chronic lymphocytic leukemia (CLL), telomere dysfunction is associated with poor outcomes. TP53 is involved in cellular responses to dysfunctional telomeres, and its inactivation is the strongest adverse prognostic factor for CLL. Given the biological relationship between TP53 and telomeres, and their prognostic value, it is important to improve our understanding of the impact of TP53 alterations on telomeres. We performed a comprehensive study of the deletions and mutations of the TP53 gene and telomere parameters, including hTERT and the shelterin complex, in 115 CLL patients. We found that any type of TP53 alteration was associated with very short telomeres and high hTERT expression, independently of other biological CLL features. Patients with disrupted TP53 showed telomere deletions and chromosomal end-to-end fusions in cells with complex karyotypes. TP53 disruption was characterized by downregulation of shelterin genes. Interestingly, low expression of POT1, TPP1 and TIN2 was also found in some patients with wild-type TP53 and had an adverse impact on progression-free survival after standard genotoxic therapy. In conclusion, we have demonstrated that patients with disrupted TP53 have severe telomere dysfunction and high genomic instability. Thus, the telomeric profile could be tested as a biomarker in CLL patients treated with new therapeutic agents. PMID:27486974

  14. Karyotypic complexity rather than chromosome 8 abnormalities aggravates the outcome of chronic lymphocytic leukemia patients with TP53 aberrations.

    PubMed

    Blanco, Gonzalo; Puiggros, Anna; Baliakas, Panagiotis; Athanasiadou, Anastasia; García-Malo, MªDolores; Collado, Rosa; Xochelli, Aliki; Rodríguez-Rivera, María; Ortega, Margarita; Calasanz, Mª José; Luño, Elisa; Vargas, MªTeresa; Grau, Javier; Martínez-Laperche, Carolina; Valiente, Alberto; Cervera, José; Anagnostopoulos, Achilles; Gimeno, Eva; Abella, Eugènia; Stalika, Evangelia; Hernández-Rivas, Jesús Mª; Ortuño, Francisco José; Robles, Diego; Ferrer, Ana; Ivars, David; González, Marcos; Bosch, Francesc; Abrisqueta, Pau; Stamatopoulos, Kostas; Espinet, Blanca

    2016-12-06

    Patients with chronic lymphocytic leukemia (CLL) harboring TP53 aberrations (TP53abs; chromosome 17p deletion and/or TP53 mutation) exhibit an unfavorable clinical outcome. Chromosome 8 abnormalities, namely losses of 8p (8p-) and gains of 8q (8q+) have been suggested to aggravate the outcome of patients with TP53abs. However, the reported series were small, thus hindering definitive conclusions. To gain insight into this issue, we assessed a series of 101 CLL patients harboring TP53 disruption. The frequency of 8p- and 8q+ was 14.7% and 17.8% respectively. Both were associated with a significantly (P < 0.05) higher incidence of a complex karyotype (CK, ≥3 abnormalities) detected by chromosome banding analysis (CBA) compared to cases with normal 8p (N-8p) and 8q (N-8q), respectively. In univariate analysis for 10-year overall survival (OS), 8p- (P = 0.002), 8q+ (P = 0.012) and CK (P = 0.009) were associated with shorter OS. However, in multivariate analysis only CK (HR = 2.47, P = 0.027) maintained independent significance, being associated with a dismal outcome regardless of chromosome 8 abnormalities. In conclusion, our results highlight the association of chromosome 8 abnormalities with CK amongst CLL patients with TP53abs, while also revealing that CK can further aggravate the prognosis of this aggressive subgroup.

  15. Karyotypic complexity rather than chromosome 8 abnormalities aggravates the outcome of chronic lymphocytic leukemia patients with TP53 aberrations

    PubMed Central

    Blanco, Gonzalo; Puiggros, Anna; Baliakas, Panagiotis; Athanasiadou, Anastasia; García-Malo, MªDolores; Collado, Rosa; Xochelli, Aliki; Rodríguez-Rivera, María; Ortega, Margarita; Calasanz, Mª José; Luño, Elisa; Vargas, MªTeresa; Grau, Javier; Martínez-Laperche, Carolina; Valiente, Alberto; Cervera, José; Anagnostopoulos, Achilles; Gimeno, Eva; Abella, Eugènia; Stalika, Evangelia; Hernández-Rivas, Jesús Mª; Ortuño, Francisco José; Robles, Diego; Ferrer, Ana; Ivars, David; González, Marcos; Bosch, Francesc; Abrisqueta, Pau; Stamatopoulos, Kostas; Espinet, Blanca

    2016-01-01

    Patients with chronic lymphocytic leukemia (CLL) harboring TP53 aberrations (TP53abs; chromosome 17p deletion and/or TP53 mutation) exhibit an unfavorable clinical outcome. Chromosome 8 abnormalities, namely losses of 8p (8p−) and gains of 8q (8q+) have been suggested to aggravate the outcome of patients with TP53abs. However, the reported series were small, thus hindering definitive conclusions. To gain insight into this issue, we assessed a series of 101 CLL patients harboring TP53 disruption. The frequency of 8p− and 8q+ was 14.7% and 17.8% respectively. Both were associated with a significantly (P < 0.05) higher incidence of a complex karyotype (CK, ≥3 abnormalities) detected by chromosome banding analysis (CBA) compared to cases with normal 8p (N-8p) and 8q (N-8q), respectively. In univariate analysis for 10-year overall survival (OS), 8p− (P = 0.002), 8q+ (P = 0.012) and CK (P = 0.009) were associated with shorter OS. However, in multivariate analysis only CK (HR = 2.47, P = 0.027) maintained independent significance, being associated with a dismal outcome regardless of chromosome 8 abnormalities. In conclusion, our results highlight the association of chromosome 8 abnormalities with CK amongst CLL patients with TP53abs, while also revealing that CK can further aggravate the prognosis of this aggressive subgroup. PMID:27821812

  16. Molecular spectrum of TP53 mutations in plasma cell dyscrasias by next generation sequencing: an Italian cohort study and overview of the literature.

    PubMed

    Lionetti, Marta; Barbieri, Marzia; Manzoni, Martina; Fabris, Sonia; Bandini, Cecilia; Todoerti, Katia; Nozza, Filomena; Rossi, Davide; Musto, Pellegrino; Baldini, Luca; Neri, Antonino

    2016-04-19

    The prevalence of TP53 mutations greatly varies between tumor types; in multiple myeloma (MM) they were rarely detected at presentation, while increased frequency was reported with disease progression. Using next-generation sequencing, we analyzed TP53 exons 4-9 in a large representative cohort comprising patients with MM at diagnosis and more aggressive forms of plasma cell (PC) dyscrasia, identifying mutations in 4/129 (3%) MM, 6/24 (25%) primary PC leukemia, and 2/10 (20%) secondary PC leukemia cases. A similar increase in prevalence associated with disease aggressiveness (5%, 29.2% and 44%, respectively) was observed for TP53 deletion. Interestingly, in five patients mutations were not concomitant with TP53 deletion. Furthermore, longitudinal analysis revealed the acquisition of TP53 mutations in three of nineteen cases analyzed at relapse. Identified variants were mostly missense mutations concentrated in the DNA binding domain, only partly reflecting the pattern globally observed in human cancers. Our data confirm that TP53 mutations are rare in MM at presentation and rather represent a marker of progression, similarly to del(17p); however, their occurrence even in absence of deletions supports the importance of their assessment in patients with PC dyscrasia, in terms of both risk stratification and therapeutic implications.

  17. The Genomic Landscape of TP53 and p53 Annotated High Grade Ovarian Serous Carcinomas from a Defined Founder Population Associated with Patient Outcome

    PubMed Central

    Wojnarowicz, Paulina M.; Oros, Kathleen Klein; Quinn, Michael C. J.; Arcand, Suzanna L.; Gambaro, Karen; Madore, Jason; Birch, Ashley H.; de Ladurantaye, Manon; Rahimi, Kurosh; Provencher, Diane M.; Mes-Masson, Anne-Marie; Greenwood, Celia M. T.; Tonin, Patricia N.

    2012-01-01

    High-grade ovarian serous carcinomas (HGSC) are characterized by TP53 mutations and non-random patterns of chromosomal anomalies, where the nature of the TP53 mutation may correlate with clinical outcome. However, the frequency of common somatic genomic events occurring in HGSCs from demographically defined populations has not been explored. Whole genome SNP array, and TP53 mutation, gene and protein expression analyses were assessed in 87 confirmed HGSC samples with clinical correlates from French Canadians, a population exhibiting strong founder effects, and results were compared with independent reports describing similar analyses from unselected populations. TP53 mutations were identified in 91% of HGSCs. Anomalies observed in more than 50% of TP53 mutation-positive HGSCs involved gains of 3q, 8q and 20q, and losses of 4q, 5q, 6q, 8p, 13q, 16q, 17p, 17q, 22q and Xp. Nearly 400 regions of non-overlapping amplification or deletion were identified, where 178 amplifications and 98 deletions involved known genes. The subgroup expressing mutant p53 protein exhibited significantly prolonged overall and disease-free survival as compared with the p53 protein null subgroup. Interestingly, a comparative analysis of genomic landscapes revealed a significant enrichment of gains involving 1q, 8q, and 12p intervals in the subgroup expressing mutant p53 protein as compared with the p53 protein null subgroup. Although the findings show that the frequency of TP53 mutations and the genomic landscapes observed in French Canadian samples were similar to those reported for samples from unselected populations, there were differences in the magnitude of global gains/losses of specific chromosomal arms and in the spectrum of amplifications and deletions involving focal regions in individual samples. The findings from our comparative genomic analyses also support the notion that there may be biological differences between HGSCs that could be related to the nature of the TP53 mutation

  18. [TP53 mutations and molecular epidemiology].

    PubMed

    Otsuka, Kazunori; Ishioka, Chikashi

    2007-05-01

    Tumor suppressor p53 protein is activated by a variety of cellular stresses through several pathways and transactivates its downstream genes, including regulators of cell cycle, apoptosis and DNA repair. The loss of p53 function by TP53 gene mutations therefore fails to activate these genes and is thought to be a critical cause of carcinogenesis and/or tumor progression. TP53 is one of the most frequently mutated genes in human cancer. TP53 mutations are found in about 50% of human cancers, although the frequency of TP53 mutations differs among tumor types. However, the degree of functional disorder of mutant p53 varies according to the type of TP53 mutation. And the effects of p53 on cancer formation and/or progression are influenced by the degree of p53 dysfunction. So it is important to analyze the effects of TP53 mutations carefully according to the oncogenicity of each mutation from the molecular epidemiological point of view. Here, together with some cautions needed for analyzing and interpreting the significance of TP53 gene mutations, we present some examples of the identified specific mutation spectrum and the correlation between the prognosis and TP53 mutation in some cancers.

  19. TP53inp1 Gene Is Implicated in Early Radiation Response in Human Fibroblast Cells.

    PubMed

    Sándor, Nikolett; Schilling-Tóth, Boglárka; Kis, Enikő; Fodor, Lili; Mucsányi, Fruzsina; Sáfrány, Géza; Hegyesi, Hargita

    2015-10-23

    Tumor protein 53-induced nuclear protein-1 (TP53inp1) is expressed by activation via p53 and p73. The purpose of our study was to investigate the role of TP53inp1 in response of fibroblasts to ionizing radiation. γ-Ray radiation dose-dependently induces the expression of TP53inp1 in human immortalized fibroblast (F11hT) cells. Stable silencing of TP53inp1 was done via lentiviral transfection of shRNA in F11hT cells. After irradiation the clonogenic survival of TP53inp1 knockdown (F11hT-shTP) cells was compared to cells transfected with non-targeting (NT) shRNA. Radiation-induced senescence was measured by SA-β-Gal staining and autophagy was detected by Acridine Orange dye and microtubule-associated protein-1 light chain 3 (LC3B) immunostaining. The expression of TP53inp1, GDF-15, and CDKN1A and alterations in radiation induced mitochondrial DNA deletions were evaluated by qPCR. TP53inp1 was required for radiation (IR) induced maximal elevation of CDKN1A and GDF-15 expressions. Mitochondrial DNA deletions were increased and autophagy was deregulated following irradiation in the absence of TP53inp1. Finally, we showed that silencing of TP53inp1 enhances the radiation sensitivity of fibroblast cells. These data suggest functional roles for TP53inp1 in radiation-induced autophagy and survival. Taken together, we suppose that silencing of TP53inp1 leads radiation induced autophagy impairment and induces accumulation of damaged mitochondria in primary human fibroblasts.

  20. Expression signature based on TP53 target genes doesn't predict response to TP53-MDM2 inhibitor in wild type TP53 tumors.

    PubMed

    Sonkin, Dmitriy

    2015-10-22

    A number of TP53-MDM2 inhibitors are currently under investigation as therapeutic agents in a variety of clinical trials in patients with TP53 wild type tumors. Not all wild type TP53 tumors are sensitive to such inhibitors. In an attempt to improve selection of patients with TP53 wild type tumors, an mRNA expression signature based on 13 TP53 transcriptional target genes was recently developed (Jeay et al. 2015). Careful reanalysis of TP53 status in the study validation data set of cancer cell lines considered to be TP53 wild type detected TP53 inactivating alterations in 23% of cell lines. The subsequent reanalysis of the remaining TP53 wild type cell lines clearly demonstrated that unfortunately the 13-gene signature cannot predict response to TP53-MDM2 inhibitor in TP53 wild type tumors.

  1. Chronic lymphocytic leukaemia with 17p deletion: a retrospective analysis of prognostic factors and therapy results.

    PubMed

    Delgado, Julio; Espinet, Blanca; Oliveira, Ana C; Abrisqueta, Pau; de la Serna, Javier; Collado, Rosa; Loscertales, Javier; Lopez, Montserrat; Hernandez-Rivas, Jose A; Ferra, Christelle; Ramirez, Angel; Roncero, Josep M; Lopez, Cristina; Aventin, Anna; Puiggros, Anna; Abella, Eugenia; Carbonell, Felix; Costa, Dolors; Carrio, Anna; Gonzalez, Marcos

    2012-04-01

    Patients with chronic lymphocytic leukaemia (CLL) whose tumour cells harbour a 17p deletion (17p-) are universally considered to have a poor prognosis. The deletion can be detected at diagnosis or during the evolution of the disease, particularly in patients who have received chemotherapy. We sought to evaluate the natural history of patients with 17p- CLL, identify predictive factors within this prognostic subgroup, and evaluate the results of different therapeutic approaches. Data from 294 patients with 17p- CLL followed up at 20 different institutions was retrospectively collected and analysed. Median age was 68 (range 27-98) years at the time of fluorescence in situ hybridization analysis. After 17p- documentation, 52% received treatment, achieving an overall response rate of 50%. Median overall survival was 41 months, and was significantly shorter in patients with elevated beta(2)-microglobulin concentration (P < 0·001), B symptoms (P = 0·016), higher percentage of cells with deletion (P < 0·001), and acquired deletions (P = 0·012). These findings suggest that patients with 17p- CLL have a variable prognosis that can be refined using simple clinical and laboratory features, including 17p- clone size, beta2-microglobulin concentration, presence of B symptoms and type of deletion (de novo versus acquired).

  2. TP53 dysfunction in diffuse large B-cell lymphoma.

    PubMed

    Lu, Ting-Xun; Young, Ken H; Xu, Wei; Li, Jian-Yong

    2016-01-01

    The aberrations of TP53 gene and dysregulation of the TP53 pathway are important in the pathogenesis of many human cancers, including malignant lymphomas, especially for diffuse large B cell lymphoma (DLBCL). By regulating many downstream target genes or molecules, TP53 governs major defenses against tumor growth and promotes cellular DNA repair, apoptosis, autophagy, cell cycle arrest, signaling, transcription, immune or inflammatory responses and metabolism. Dysfunction of TP53, including microRNA regulations, copy number alterations of TP53 pathway and TP53 itself, dysregulation of TP53 regulators, and somatic mutations by abnormal TP53 function modes, play an important role in lymphoma generation, progression and invasion. The role of TP53 in DLBCL has been widely explored recently. In this review, we summarized recent advances on different mechanisms of TP53 in DLBCL and new therapeutic approaches to overcome TP53 inactivation.

  3. TP53 alterations in primary and secondary Sézary syndrome: A diagnostic tool for the assessment of malignancy in patients with erythroderma

    PubMed Central

    Gros, Audrey; Prochazkova-Carlotti, Martina; Pham-Ledard, Anne; Bandres, Thomas; Poglio, Sandrine; Berhouet, Sabine; Vergier, Béatrice; Vial, Jean-Philippe; Chevret, Edith; Beylot-Barry, Marie

    2017-01-01

    Recent massive parallel sequencing data have evidenced the genetic diversity and complexity of Sézary syndrome mutational landscape with TP53 alterations being the most prevalent genetic abnormality. We analyzed a cohort of 35 patients with SS and a control group of 8 patients with chronic inflammatory dermatoses. TP53 status was analyzed at different clinical stages especially in 9 patients with a past-history of mycosis fungoides (MF), coined secondary SS. TP53 mutations were only detected in 10 patients with either primary or secondary SS (29%) corresponding to point mutations, small insertions and deletions which were unique in each case. Interestingly, TP53 mutations were both detected in sequential unselected blood mononuclear cells and in skin specimens. Cytogenetic analysis of blood specimens of 32 patients with SS showed a TP53 deletion in 27 cases (84%). Altogether 29 out of 35 cases exhibited TP53 mutation and/or deletion (83%). No difference in prognosis was observed according to TP53 status while patients with secondary SS had a worse prognosis than patients with primary SS. Interestingly, patients with TP53 alterations displayed a younger age and the presence of TP53 alteration at initial diagnosis stage supports a pivotal oncogenic role for TP53 mutation in SS as well as in erythrodermic MF making TP53 assessment an ancillary method for the diagnosis of patients with erythroderma as patients with inflammatory dermatoses did not display TP53 alteration. PMID:28301507

  4. TP53 alterations in primary and secondary Sézary syndrome: A diagnostic tool for the assessment of malignancy in patients with erythroderma.

    PubMed

    Gros, Audrey; Laharanne, Elodie; Vergier, Marie; Prochazkova-Carlotti, Martina; Pham-Ledard, Anne; Bandres, Thomas; Poglio, Sandrine; Berhouet, Sabine; Vergier, Béatrice; Vial, Jean-Philippe; Chevret, Edith; Beylot-Barry, Marie; Merlio, Jean-Philippe

    2017-01-01

    Recent massive parallel sequencing data have evidenced the genetic diversity and complexity of Sézary syndrome mutational landscape with TP53 alterations being the most prevalent genetic abnormality. We analyzed a cohort of 35 patients with SS and a control group of 8 patients with chronic inflammatory dermatoses. TP53 status was analyzed at different clinical stages especially in 9 patients with a past-history of mycosis fungoides (MF), coined secondary SS. TP53 mutations were only detected in 10 patients with either primary or secondary SS (29%) corresponding to point mutations, small insertions and deletions which were unique in each case. Interestingly, TP53 mutations were both detected in sequential unselected blood mononuclear cells and in skin specimens. Cytogenetic analysis of blood specimens of 32 patients with SS showed a TP53 deletion in 27 cases (84%). Altogether 29 out of 35 cases exhibited TP53 mutation and/or deletion (83%). No difference in prognosis was observed according to TP53 status while patients with secondary SS had a worse prognosis than patients with primary SS. Interestingly, patients with TP53 alterations displayed a younger age and the presence of TP53 alteration at initial diagnosis stage supports a pivotal oncogenic role for TP53 mutation in SS as well as in erythrodermic MF making TP53 assessment an ancillary method for the diagnosis of patients with erythroderma as patients with inflammatory dermatoses did not display TP53 alteration.

  5. TP53 Promoter Methylation in Primary Glioblastoma: Relationship with TP53 mRNA and Protein Expression and Mutation Status

    PubMed Central

    Szybka, Malgorzata; Malachowska, Beata; Fendler, Wojciech; Potemski, Piotr; Piaskowski, Sylwester; Jaskolski, Dariusz; Papierz, Wielislaw; Skowronski, Wieslaw; Och, Waldemar; Kordek, Radzislaw

    2014-01-01

    Reduced expression of TP53 by promoter methylation has been reported in several neoplasms. It remains unclear whether TP53 promoter methylation is associated with reduced transcriptional and protein expression in glioblastoma (GB). The aim of our work was to study the impact of TP53 methylation and mutations on TP53 mRNA level and protein expression in 42 molecularly characterized primary GB tumors. We also evaluate the impact of all molecular alterations on the overall patient survival. The frequency of TP53 promoter methylation was found in 21.4%. To the best of our knowledge, this is the first report showing such high frequency of TP53 promoter methylation in primary GB. There was no relation between TP53 promoter methylation and TP53 mRNA level (p=0.5722) and between TP53 promoter methylation and TP53 protein expression (p=0.2045). No significant associations were found between TP53 mRNA expression and mutation of TP53 gene (p=0.9076). However, significant association between TP53 mutation and TP53 protein expression was found (p=0.0016). Our data suggest that in primary GB TP53 promoter methylation does not play a role in silencing of TP53 transcriptional and protein expression and is probably regulated by other genetic and epigenetic mechanisms associated with genes involved in the TP53 pathway. PMID:24506545

  6. YAF2 promotes TP53-mediated genotoxic stress response via stabilization of PDCD5.

    PubMed

    Park, Soo-Yeon; Choi, Hyo-Kyoung; Jo, Seong-Ho; Seo, JaeSung; Han, Eun-Jeong; Choi, Kyung-Chul; Jeong, Jae-Wook; Choi, Youngsok; Yoon, Ho-Geun

    2015-05-01

    Programmed cell death 5 (PDCD5) plays a crucial role in TP53-mediated apoptosis, but the regulatory mechanism of PDCD5 itself during apoptosis remains obscure. We identified YY1-associated factor 2 (YAF2) as a novel PDCD5-interacting protein in a yeast two-hybrid screen for PDCD5-interacting proteins. We found that YY1-associated factor 2 (YAF2) binds to and increases PDCD5 stability by inhibiting the ubiquitin-dependent proteosomal degradation pathway. However, knocking-down of YAF2 diminishes the levels of PDCD5 protein but not the levels of PDCD5 mRNA. Upon genotoxic stress response, YAF2 promotes TP53 activation via association with PDCD5. Strikingly, YAF2 failed to promote TP53 activation in the deletion of PDCD5, whereas restoration of wild-type PDCD5WT efficiently reversed the ineffectiveness of YAF2 on TP53 activation. Conversely, PDCD5 efficiently overcame the knockdown effect of YAF2 on ET-induced TP53 activation. Finally, impaired apoptosis upon PDCD5 ablation was substantially rescued by restoration of PDCD5WT but not YAF2-interacting defective PDCD5E4D nor TP53-interacting defective PDCD5E16D mutant. Our findings uncovered an apoptotic signaling cascade linking YAF2, PDCD5, and TP53 during genotoxic stress responses.

  7. TP53 and CDKN1A mutation analysis in families with Li-Fraumeni and Li-Fraumeni like syndromes.

    PubMed

    Andrade, Raissa Coelho; Dos Santos, Anna Claudia Evangelista; de Aguirre Neto, Joaquim Caetano; Nevado, Julián; Lapunzina, Pablo; Vargas, Fernando Regla

    2017-04-01

    Li-Fraumeni and Li-Fraumeni like syndromes (LFS/LFL) represent rare cancer-prone conditions associated mostly with sarcomas, breast cancer, brain tumors, and adrenocortical carcinomas. TP53 germline mutations are present in up to 80 % of families with classic Li-Fraumeni syndrome, and in 20-60 % of families with Li-Fraumeni like phenotypes. The frequency of LFS/LFL families with no TP53 mutations detected suggests the involvement of other genes in the syndrome. In this study, we searched for mutations in TP53 in 39 probands from families with criteria for LFS/LFL. We also searched for mutations in the gene encoding the main mediator of p53 in cell cycle arrest, CDKN1A/p21, in all patients with no mutations in TP53. Eight probands carried germline disease-causing mutations in TP53: six missense mutations and two partial gene deletions. No mutations in CDKN1A coding region were detected. TP53 partial deletions in our cohort represented 25 % (2/8) of the mutations found, a much higher frequency than usually reported, emphasizing the need to search for TP53 rearrangements in patients with LFS/LFL phenotypes. Two benign tumors were detected in two TP53 mutation carriers: an adrenocortical adenoma and a neurofibroma, which raises a question about the possible implication of TP53 mutations on the development of such lesions.

  8. TP53 mutations, expression and interaction networks in human cancers

    PubMed Central

    Wang, Xiaosheng; Sun, Qingrong

    2017-01-01

    Although the associations of p53 dysfunction, p53 interaction networks and oncogenesis have been widely explored, a systematic analysis of TP53 mutations and its related interaction networks in various types of human cancers is lacking. Our study explored the associations of TP53 mutations, gene expression, clinical outcomes, and TP53 interaction networks across 33 cancer types using data from The Cancer Genome Atlas (TCGA). We show that TP53 is the most frequently mutated gene in a number of cancers, and its mutations appear to be early events in cancer initiation. We identified genes potentially repressed by p53, and genes whose expression correlates significantly with TP53 expression. These gene products may be especially important nodes in p53 interaction networks in human cancers. This study shows that while TP53-truncating mutations often result in decreased TP53 expression, other non-truncating TP53 mutations result in increased TP53 expression in some cancers. Survival analyses in a number of cancers show that patients with TP53 mutations are more likely to have worse prognoses than TP53-wildtype patients, and that elevated TP53 expression often leads to poor clinical outcomes. We identified a set of candidate synthetic lethal (SL) genes for TP53, and validated some of these SL interactions using data from the Cancer Cell Line Project. These predicted SL genes are promising candidates for experimental validation and the development of personalized therapeutics for patients with TP53-mutated cancers. PMID:27880943

  9. TP53 mutations, expression and interaction networks in human cancers.

    PubMed

    Wang, Xiaosheng; Sun, Qingrong

    2017-01-03

    Although the associations of p53 dysfunction, p53 interaction networks and oncogenesis have been widely explored, a systematic analysis of TP53 mutations and its related interaction networks in various types of human cancers is lacking. Our study explored the associations of TP53 mutations, gene expression, clinical outcomes, and TP53 interaction networks across 33 cancer types using data from The Cancer Genome Atlas (TCGA). We show that TP53 is the most frequently mutated gene in a number of cancers, and its mutations appear to be early events in cancer initiation. We identified genes potentially repressed by p53, and genes whose expression correlates significantly with TP53 expression. These gene products may be especially important nodes in p53 interaction networks in human cancers. This study shows that while TP53-truncating mutations often result in decreased TP53 expression, other non-truncating TP53 mutations result in increased TP53 expression in some cancers. Survival analyses in a number of cancers show that patients with TP53 mutations are more likely to have worse prognoses than TP53-wildtype patients, and that elevated TP53 expression often leads to poor clinical outcomes. We identified a set of candidate synthetic lethal (SL) genes for TP53, and validated some of these SL interactions using data from the Cancer Cell Line Project. These predicted SL genes are promising candidates for experimental validation and the development of personalized therapeutics for patients with TP53-mutated cancers.

  10. Molecular analysis of deletion (17)(p11.2p11.2) in a family segregating a 17p paracentric inversion: implications for carriers of paracentric inversions.

    PubMed Central

    Yang, S P; Bidichandani, S I; Figuera, L E; Juyal, R C; Saxon, P J; Baldini, A; Patel, P I

    1997-01-01

    A male child with multiple congenital anomalies initially was clinically diagnosed as having Smith-Lemli-Opitz syndrome (SLOS). Subsequent cytogenetic studies revealed an interstitial deletion of 17p11.2, which is associated with Smith-Magenis syndrome (SMS). Biochemical studies were not supportive of a diagnosis of SLOS, and the child did not display the typical SMS phenotype. The father's karyotype showed a paracentric inversion of 17p, with breakpoints in p11.2 and p13.3, and the same inversion was also found in two of the father's sisters. FISH analyses of the deleted and inverted 17p chromosomes indicated that the deletion was similar to that typically seen in SMS patients and was found to bracket the proximal inversion breakpoint. Available family members were genotyped at 33 polymorphic DNA loci in 17p. These studies determined that the deletion was of paternal origin and that the inversion was of grandpaternal origin. Haplotype analysis demonstrated that the 17p11.2 deletion arose following a recombination event involving the father's normal and inverted chromosome 17 homologues. A mechanism is proposed to explain the simultaneous deletion and apparent "reinversion" of the recombinant paternal chromosome. These findings have implications for prenatal counseling of carriers of paracentric inversions, who typically are considered to bear minimal reproductive risk. Images Figure 1 Figure 2 Figure 3 PMID:9150166

  11. Nutlin-3a selects for cells harbouring TP53 mutations.

    PubMed

    Kucab, Jill E; Hollstein, Monica; Arlt, Volker M; Phillips, David H

    2017-02-15

    TP53 mutations occur in half of all human tumours. Mutagen-induced or spontaneous TP53 mutagenesis can be studied in vitro using the human TP53 knock-in (Hupki) mouse embryo fibroblast (HUF) immortalisation assay (HIMA). TP53 mutations arise in up to 30% of mutagen-treated, immortalised HUFs; however, mutants are not identified until TP53 sequence analysis following immortalisation (2-5 months) and much effort is expended maintaining TP53-WT cultures. In order to improve the selectivity of the HIMA for HUFs harbouring TP53 mutations, we explored the use of Nutlin-3a, an MDM2 inhibitor that leads to stabilisation and activation of wild-type (WT) p53. First, we treated previously established immortal HUF lines carrying WT or mutated TP53 with Nutlin-3a to examine the effect on cell growth and p53 activation. Nutlin-3a induced the p53 pathway in TP53-WT HUFs and inhibited cell growth, whereas most TP53-mutated HUFs were resistant to Nutlin-3a. We then assessed whether Nutlin-3a treatment could discriminate between TP53-WT and TP53-mutated cells during the HIMA (n = 72 cultures). As immortal clones emerged from senescent cultures, each was treated with 10 µM Nutlin-3a for 5 days and observed for sensitivity or resistance. TP53 was subsequently sequenced from all immortalised clones. We found that all Nutlin-3a-resistant clones harboured TP53 mutations, which were diverse in position and functional impact, while all but one of the Nutlin-3a-sensitive clones were TP53-WT. These data suggest that including a Nutlin-3a counter-screen significantly improves the specificity and efficiency of the HIMA, whereby TP53-mutated clones are selected prior to sequencing and TP53-WT clones can be discarded.

  12. Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients

    SciTech Connect

    Juyal, R.C.; Figuera, L.E.; Hauge, X.

    1996-05-01

    Smith-Magenis syndrome (SMS) is a clinically recognizable, multiple congenital anomalies/mental retardation syndrome caused by an interstitial deletion involving band p11.2 of chromosome 17. Toward the molecular definition of the interval defining this microdeletion syndrome, 62 unrelated SMS patients in conjunction with 70 available unaffected parents were molecularly analyzed with respect to the presence or absence of 14 loci in the proximal region of the short arm of chromosome 17. A multifaceted approach was used to determine deletion status at the various loci that combined (1) FISH analysis, (2) PCR and Southern analysis of somatic cell hybrids retaining the deleted chromosome 17 from selected patients, and (3) genotype determination of patients for whom a parent(s) was available at four microsatellite marker loci and at four loci with associated RFLPs. The relative order of two novel anonymous markers and a new microsatellite marker was determined in 17p11.2. The results confirmed that the proximal deletion breakpoint in the majority of SMS patients is located between markers D17S58 (EW301) and D17S446 (FG1) within the 17p11.1-17p11.2 region. The common distal breakpoint was mapped between markers cCI17-638, which lies distal to D17S71, and cCI17-498, which lies proximal to the Charcot Marie-Tooth disease type 1A locus. The locus D17S258 was found to be deleted in all 62 patients, and probes from this region can be used for diagnosis of the SMS deletion by FISH. Ten patients demonstrated molecularly distinct deletions; of these, two patients had smaller deletions and will enable the definition of the critical interval for SMS. 49 refs.

  13. A Turkish patient with large 17p11.2 deletion presenting with Smith Magenis syndrome.

    PubMed

    Tug, E; Cine, N; Aydin, H

    2011-01-01

    Smith-Magenis syndrome (SMS), which occurs as a result of an interstitial deletion within chromosome 17p11.2-p12, is a disorder that presents itself with minor dysmorphic features, brachydactyly, short stature, hypotonia, delayed speech, cognitive deficits and neurobehavioral problems including sleep disturbances and maladaptive repetitive and self-injurious behavior. We present a girl with full SMS phenotype. G-banding cytogenetic analysis showed normal 46,XX karyotype. Whole-genome array comparative genomic hybridization (CGH) was performed due to the severity of the phenotype and the unusual features present in the patient. An interstitial deletion in 17p11.2-p12, approximately 4.73 Mb in size was determined. Characteristic physical and behavioral phenotype strongly suggested SMS. This, to the best of our knowledge is the first patient with SMS reported in Turkey. We emphasize the need for whole genome analysis in multiple congenital abnormalities/mental retardation disorders with unusual and severe phenotypes.

  14. Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion.

    PubMed

    Strati, Paolo; Keating, Michael J; O'Brien, Susan M; Ferrajoli, Alessandra; Burger, Jan; Faderl, Stefan; Tambaro, Francesco Paolo; Jain, Nitin; Wierda, William G

    2014-08-01

    Although uncommon in treatment-naive patients with chronic lymphocytic leukemia, deletion 17p is a high-risk disease characteristic. We analyzed and reported outcomes for 63 patients with deletion 17p chronic lymphocytic leukemia who received first-line therapy at our institution; at time of first treatment, 81% had unmutated immunoglobulin heavy chain variable gene and 58% had complex karyotype. Forty-nine patients (76%) received first-line fludarabine, cyclophosphamide, rituximab-based therapy, 6 (11%) received rituximab-based and 8 (13%) received lenalidomide-based treatment. Overall, the complete plus nodular partial remission rate was 33%; on multivariable model, higher complete plus nodular partial remission rate was observed in patients with less than 50% cells positive for deletion 17p, and a higher probability of achieving at least a partial remission was observed with fludarabine, cyclophosphamide, rituximab-based treatment. After a median follow up of 33 months (range 1-89 months), the estimated median progression-free survival was 14 months (95% confidence interval 10-18) and estimated median overall survival was 63 months (95% confidence interval 43-83). In multivariable analysis, factors independently associated with longer progression-free survival were response to treatment and absence of complex karyotype. Achievement of complete plus nodular partial remission rate and mutated immunoglobulin heavy chain variable gene were independently associated with longer overall survival in multivariable model. Complex karyotype was associated with increased risk for Richter's transformation. New first-line strategies and agents must aim at both improving response and maintaining remission in patients with deletion 17p, particularly in the presence of complex karyotype.

  15. Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion

    PubMed Central

    Strati, Paolo; Keating, Michael J.; O’Brien, Susan M.; Ferrajoli, Alessandra; Burger, Jan; Faderl, Stefan; Tambaro, Francesco Paolo; Jain, Nitin; Wierda, William G.

    2014-01-01

    Although uncommon in treatment-naive patients with chronic lymphocytic leukemia, deletion 17p is a high-risk disease characteristic. We analyzed and reported outcomes for 63 patients with deletion 17p chronic lymphocytic leukemia who received first-line therapy at our institution; at time of first treatment, 81% had unmutated immunoglobulin heavy chain variable gene and 58% had complex karyotype. Forty-nine patients (76%) received first-line fludarabine, cyclophosphamide, rituximab-based therapy, 6 (11%) received rituximab-based and 8 (13%) received lenalidomide-based treatment. Overall, the complete plus nodular partial remission rate was 33%; on multivariable model, higher complete plus nodular partial remission rate was observed in patients with less than 50% cells positive for deletion 17p, and a higher probability of achieving at least a partial remission was observed with fludarabine, cyclophosphamide, rituximab-based treatment. After a median follow up of 33 months (range 1–89 months), the estimated median progression-free survival was 14 months (95% confidence interval 10–18) and estimated median overall survival was 63 months (95% confidence interval 43–83). In multivariable analysis, factors independently associated with longer progression-free survival were response to treatment and absence of complex karyotype. Achievement of complete plus nodular partial remission rate and mutated immunoglobulin heavy chain variable gene were independently associated with longer overall survival in multivariable model. Complex karyotype was associated with increased risk for Richter’s transformation. New first-line strategies and agents must aim at both improving response and maintaining remission in patients with deletion 17p, particularly in the presence of complex karyotype. PMID:24859876

  16. Baseline characteristics, chromosomal alterations, and treatment affecting prognosis of deletion 17p in newly diagnosed myeloma.

    PubMed

    Merz, Maximilian; Hielscher, Thomas; Seckinger, Anja; Hose, Dirk; Mai, Elias K; Raab, Marc S; Goldschmidt, Hartmut; Jauch, Anna; Hillengass, Jens

    2016-11-01

    Deletion 17p13, del(17p), is associated with poor outcome in myeloma but some patients show long-term survival. With the current study we intended to identify factors impacting outcome of such high risk patients. We analyzed 110 newly diagnosed, symptomatic patients with del(17p) detected by fluorescence in situ hybridization (FISH) in CD138-purified myeloma cells to identify prognostic factors for survival. Age >65 years, ISS III, and elevated LDH negatively impacted survival. Patients with subclonal (10-60% of plasma cells) del(17p) had longer progression-free survival (PFS) than patients with del(17p) in >60% of plasma cells (26 vs. 19 months, P = 0.03). Additional gain of 1q21 was associated with shorter PFS (17 vs. 25 months, P = 0.01). Hyperdiploidy did not ameliorate impact of del(17p), but gain 19q13 predicted longer PFS (30 vs. 18 months, P = 0.01) and overall survival (50 vs. 29 months, P = 0.01). Multivariate analysis in transplant eligible patients (≤65 years) revealed better survival for patients treated with upfront autologous transplantation (hazard ratio, [95% confidence interval]: 0.15 [0.04, 0.58], P = 0.006). Application of maintenance therapy was associated with better survival in transplant-eligible patients (0.30 [0.09, 0.99], P = 0.05). We demonstrate heterogeneous outcome of patients with del(17p) according to baseline characteristics and treatment. 19q13 should be included in routine FISH panel, since gains were associated with better survival. Am. J. Hematol. 91:E473-E477, 2016. © 2016 Wiley Periodicals, Inc.

  17. TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data.

    PubMed

    Bouaoun, Liacine; Sonkin, Dmitriy; Ardin, Maude; Hollstein, Monica; Byrnes, Graham; Zavadil, Jiri; Olivier, Magali

    2016-09-01

    TP53 gene mutations are one of the most frequent somatic events in cancer. The IARC TP53 Database (http://p53.iarc.fr) is a popular resource that compiles occurrence and phenotype data on TP53 germline and somatic variations linked to human cancer. The deluge of data coming from cancer genomic studies generates new data on TP53 variations and attracts a growing number of database users for the interpretation of TP53 variants. Here, we present the current contents and functionalities of the IARC TP53 Database and perform a systematic analysis of TP53 somatic mutation data extracted from this database and from genomic data repositories. This analysis showed that IARC has more TP53 somatic mutation data than genomic repositories (29,000 vs. 4,000). However, the more complete screening achieved by genomic studies highlighted some overlooked facts about TP53 mutations, such as the presence of a significant number of mutations occurring outside the DNA-binding domain in specific cancer types. We also provide an update on TP53 inherited variants including the ones that should be considered as neutral frequent variations. We thus provide an update of current knowledge on TP53 variations in human cancer as well as inform users on the efficient use of the IARC TP53 Database.

  18. Family with inflammatory demyelinating polyneuropathy and the HNPP 17p12 deletion.

    PubMed

    Korn-Lubetzki, Isabelle; Argov, Zohar; Raas-Rothschild, Annick; Wirguin, Itzchak; Steiner, Israel

    2002-12-01

    Hereditary neuropathy with liability to pressure palsies (HNPP), classically presenting as recurrent focal neuropathies precipitated by trauma or compression, is an autosomal dominant neuropathy due to a deletion at chromosomal locus 17p12. Inflammatory demyelinating polyneuropathy (IDP), a putative autoimmune disorder presenting in an acute (AIDP) or a chronic form (CIDP), has been rarely reported as familial. We present a father and two daughters of Jewish Kurdish origin who developed IDP within 10 years. The unusual familial history led us to reevaluate the diagnosis of IDP, and suggested an autosomal dominant pedigree. DNA analysis identified the deletion typical of HNPP on chromosome 17. Screening for the HNPP deletion in patients with atypical, recurrent, or familial IDP might be warranted.

  19. The TP53 tumour suppressor gene in colorectal carcinomas. II. Relation to DNA ploidy pattern and clinicopathological variables.

    PubMed Central

    Meling, G. I.; Lothe, R. A.; Børresen, A. L.; Graue, C.; Hauge, S.; Clausen, O. P.; Rognum, T. O.

    1993-01-01

    Heterozygous loss of the TP53 gene on chromosome arm 17p in colorectal carcinomas was strongly associated with DNA aneuploidy (P < 0.0001). This association was seen only in tumours with loss on both 17p and 17q (P < 0.001), but not for loss on 17p only. DNA near diploid (ND) carcinomas and DNA aneuploid (AN) tumours with DNA index > or = 1.1 and < 1.3 had similar frequencies of TP53 gene loss (49% and 42%, respectively), whereas AN tumours with DNA index > or = 1.3 had a significantly higher frequency of TP53 gene loss (85%) (P < 0.0001 and P < 0.0001, respectively). There was a significant association between loss of the TP53 gene and histological grade (P < 0.01), and there tended to be an association between loss of the TP53 gene and degree of cellular atypia (P < 0.05), with TP53 gene loss being most frequent in moderately differentiated carcinomas, and in carcinomas with severe cellular atypia, respectively. The proportion of tumours with loss of the TP53 gene increased significantly towards the distal part of the large bowel (P < 0.0001). These results indicate that different genetic mechanisms may be involved in the carcinogenesis in colon and rectum carcinomas, and in the two subsets of DNA aneuploid carcinomas. Furthermore, the data may suggest a role for the TP53 gene in the aneuploidisation process, possibly as a 'target' for a whole chromosome loss. PMID:8427784

  20. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism.

    PubMed

    Anderson, Mary Ann; Deng, Jing; Seymour, John F; Tam, Constantine; Kim, Su Young; Fein, Joshua; Yu, Lijian; Brown, Jennifer R; Westerman, David; Si, Eric G; Majewski, Ian J; Segal, David; Heitner Enschede, Sari L; Huang, David C S; Davids, Matthew S; Letai, Anthony; Roberts, Andrew W

    2016-06-23

    BCL2 blunts activation of the mitochondrial pathway to apoptosis, and high-level expression is required for chronic lymphocytic leukemia (CLL) survival. Venetoclax (ABT-199) is a small-molecule selective inhibitor of BCL2 currently in clinical trials for CLL and other malignancies. In conjunction with the phase 1 first-in-human clinical trial of venetoclax in patients with relapsed or refractory CLL (M12-175), we investigated the mechanism of action of venetoclax in vivo, explored whether in vitro sensitivity assays or BH3 profiling correlated with in vivo responses in patients, and determined whether loss of TP53 function affected responses in vitro and in vivo. In all samples tested, venetoclax induced death of CLL cells in vitro at concentrations achievable in vivo, with cell death evident within 4 hours. Apoptotic CLL cells were detected in vivo 6 or 24 hours after a single 20-mg or 50-mg dose in some patients. The extent of mitochondrial depolarization by a BIM BH3 peptide in vitro was correlated with percentage reduction of CLL in the blood and bone marrow in vivo, whereas the half lethal concentration derived from standard cytotoxicity assays was not. CLL cell death in vitro and the depth of clinical responses were independent of deletion of chromosome 17p, TP53 mutation, and TP53 function. These data provide direct evidence that venetoclax kills CLL cells in a TP53-independent fashion by inhibition of BCL2 in patients and support further assessment of BH3 profiling as a predictive biomarker for this drug.

  1. The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism

    PubMed Central

    Anderson, Mary Ann; Deng, Jing; Seymour, John F.; Tam, Constantine; Kim, Su Young; Fein, Joshua; Yu, Lijian; Brown, Jennifer R.; Westerman, David; Si, Eric G.; Majewski, Ian J.; Segal, David; Heitner Enschede, Sari L.; Huang, David C. S.; Davids, Matthew S.; Letai, Anthony

    2016-01-01

    BCL2 blunts activation of the mitochondrial pathway to apoptosis, and high-level expression is required for chronic lymphocytic leukemia (CLL) survival. Venetoclax (ABT-199) is a small-molecule selective inhibitor of BCL2 currently in clinical trials for CLL and other malignancies. In conjunction with the phase 1 first-in-human clinical trial of venetoclax in patients with relapsed or refractory CLL (M12-175), we investigated the mechanism of action of venetoclax in vivo, explored whether in vitro sensitivity assays or BH3 profiling correlated with in vivo responses in patients, and determined whether loss of TP53 function affected responses in vitro and in vivo. In all samples tested, venetoclax induced death of CLL cells in vitro at concentrations achievable in vivo, with cell death evident within 4 hours. Apoptotic CLL cells were detected in vivo 6 or 24 hours after a single 20-mg or 50-mg dose in some patients. The extent of mitochondrial depolarization by a BIM BH3 peptide in vitro was correlated with percentage reduction of CLL in the blood and bone marrow in vivo, whereas the half lethal concentration derived from standard cytotoxicity assays was not. CLL cell death in vitro and the depth of clinical responses were independent of deletion of chromosome 17p, TP53 mutation, and TP53 function. These data provide direct evidence that venetoclax kills CLL cells in a TP53-independent fashion by inhibition of BCL2 in patients and support further assessment of BH3 profiling as a predictive biomarker for this drug. PMID:27069256

  2. Nutlin‐3a selects for cells harbouring TP 53 mutations

    PubMed Central

    Hollstein, Monica; Arlt, Volker M.; Phillips, David H.

    2016-01-01

    TP53 mutations occur in half of all human tumours. Mutagen‐induced or spontaneous TP53 mutagenesis can be studied in vitro using the human TP53 knock‐in (Hupki) mouse embryo fibroblast (HUF) immortalisation assay (HIMA). TP53 mutations arise in up to 30% of mutagen‐treated, immortalised HUFs; however, mutants are not identified until TP53 sequence analysis following immortalisation (2–5 months) and much effort is expended maintaining TP53‐WT cultures. In order to improve the selectivity of the HIMA for HUFs harbouring TP53 mutations, we explored the use of Nutlin‐3a, an MDM2 inhibitor that leads to stabilisation and activation of wild‐type (WT) p53. First, we treated previously established immortal HUF lines carrying WT or mutated TP53 with Nutlin‐3a to examine the effect on cell growth and p53 activation. Nutlin‐3a induced the p53 pathway in TP53‐WT HUFs and inhibited cell growth, whereas most TP53‐mutated HUFs were resistant to Nutlin‐3a. We then assessed whether Nutlin‐3a treatment could discriminate between TP53‐WT and TP53‐mutated cells during the HIMA (n = 72 cultures). As immortal clones emerged from senescent cultures, each was treated with 10 µM Nutlin‐3a for 5 days and observed for sensitivity or resistance. TP53 was subsequently sequenced from all immortalised clones. We found that all Nutlin‐3a‐resistant clones harboured TP53 mutations, which were diverse in position and functional impact, while all but one of the Nutlin‐3a‐sensitive clones were TP53‐WT. These data suggest that including a Nutlin‐3a counter‐screen significantly improves the specificity and efficiency of the HIMA, whereby TP53‐mutated clones are selected prior to sequencing and TP53‐WT clones can be discarded. PMID:27813088

  3. TP53 mutations in astrocytic gliomas: an association with histological grade, TP53 codon 72 polymorphism and p53 expression.

    PubMed

    Faria, Mario H G; Neves Filho, Eduardo H C; Alves, Markenia K S; Burbano, Rommel M R; de Moraes Filho, Manoel O; Rabenhorst, Silvia H B

    2012-11-01

    TP53 mutations and polymorphisms have been widely related to many cancers as long as these alterations may impair its capacity to induce cell cycle arrest, DNA repair mechanisms, and apoptosis. Although TP53 alterations have been studied in astrocytic tumors, there is a lack of analysis considering specific TP53 mutations and their associations with p53 immunostainning, polymorphisms and their significance among the histological grades. Thus, we analyzed TP53 alterations in exons 2-11, including the codon 72 polymorphism, using DNA sequencing in 96 astrocytic gliomas (18 grade I, 20 grade II, 14 grade III, and 44 grade IV). Also, immunohistochemistry was assessed to evaluate the p53 protein expression. In this study, we found that the higher histological grades were statistically associated with TP53 mutations. Some of these mutations, such as TP53 P98T and TP53 G244S, seemed to be a specific marker for the higher grades, and the TP53 E286K mutation appears to be a World Health Organization grade III-IV progression marker. Also, the TP53 P98T mutation, in exon 4, is very likely to be important on the stabilization of the p53 protein, leading to its immunopositivity and it is potentially associated with the TP53 72Pro/Pro genotype.

  4. TP53 Mutational Spectrum in Endometrioid and Serous Endometrial Cancers.

    PubMed

    Schultheis, Anne M; Martelotto, Luciano G; De Filippo, Maria R; Piscuglio, Salvatore; Ng, Charlotte K Y; Hussein, Yaser R; Reis-Filho, Jorge S; Soslow, Robert A; Weigelt, Britta

    2016-07-01

    Endometrial carcinomas (ECs) are heterogeneous at the genetic level. Although TP53 mutations are highly recurrent in serous endometrial carcinomas (SECs), these are also present in a subset of endometrioid endometrial carcinomas (EECs). Here, we sought to define the frequency, pattern, distribution, and type of TP53 somatic mutations in ECs by performing a reanalysis of the publicly available data from The Cancer Genome Atlas (TCGA). A total of 228 EECs (n=186) and SECs (n=42) from the TCGA data set, for which an integrated genomic characterization was performed, were interrogated for the presence and type of TP53 mutations, and for mutations in genes frequently mutated in ECs. TP53 mutations were found in 15% of EECs and 88% of SECs, and in 91% of copy-number-high and 35% of polymerase (DNA directed), epsilon, catalytic subunit (POLE) integrative genomic subtypes. In addition to differences in prevalence, variations in the type and pattern of TP53 mutations were observed between histologic types and between integrative genomic subtypes. TP53 hotspot mutations were significantly more frequently found in SECs (46%) than in EECs (15%). TP53-mutant EECs significantly more frequently harbored a co-occurring PTEN mutation than TP53-mutant SECs. Finally, a subset of TP53-mutant ECs (22%) was found to harbor frameshift or nonsense mutations. Given that nonsense and frameshift TP53 mutations result in distinct p53 immunohistochemical results that require careful interpretation, and that EECs and SECs display different patterns, types, and distributions of TP53 mutations, the use of the TP53/p53 status alone for the differential diagnosis of EECs and SECs may not be sufficient.

  5. The TP53 tumour suppressor gene in colorectal carcinomas. I. Genetic alterations on chromosome 17.

    PubMed Central

    Meling, G. I.; Lothe, R. A.; Børresen, A. L.; Graue, C.; Hauge, S.; Clausen, O. P.; Rognum, T. O.

    1993-01-01

    In 231 colorectal carcinomas, allele variation at four restriction fragments length polymorphisms (RFLP) loci on chromosome 17 have been studied by Southern analysis. Heterozygous loss of the TP53 gene was found in 68% (129/189) of the carcinomas informative on both chromosome arms. In 41% (77/189) of the carcinomas the loss was found only on 17p. Two probes were used to detect alterations on 17p, pBHP53 and pYNZ22. When loss was demonstrated with pYNZ22, pBHP53 also always showed loss (n = 45), whereas when loss was demonstrated with pBHP53, only 45 of 54 (83%) showed loss with pYNZ22. Loss on 17q was found in 34% (64/189) of the carcinomas, and 6% (12/189) had loss on this chromosome arm, only. Loss on 17q was significantly associated with loss on 17p (P < 0.01). These data confirm that the TP53 gene is the target of loss on chromosome arm 17p in colorectal carcinomas, and demonstrate that loss of the TP53 gene is most frequently part of limited, subchromosomal loss. Furthermore, the results do not suggest any additional tumour suppressor gene(s) on chromosome 17 involved in colorectal carcinogenesis. Images Figure 2 PMID:8094008

  6. Association between Mutation and Expression of TP53 as a Potential Prognostic Marker of Triple-Negative Breast Cancer

    PubMed Central

    Kim, Ji-Yeon; Park, Kyunghee; Jung, Hae Hyun; Lee, Eunjin; Cho, Eun Yoon; Lee, Kwang Hee; Bae, Soo Youn; Lee, Se Kyung; Kim, Seok Won; Lee, Jeong Eon; Nam, Seok Jin; Ahn, Jin Seok; Im, Young-Hyuck; Park, Yeon Hee

    2016-01-01

    Purpose TP53, the most frequently mutated gene in breast cancer, is more frequently altered in HER2-enriched and basal-like breast cancer. However, no studies have clarified the role of TP53 status as a prognostic and predictive marker of triple-negative breast cancer (TNBC). Materials and Methods We performed p53 immunohistochemistry (IHC), nCounter mRNA expression assay, and DNA sequencing to determine the relationship between TP53 alteration and clinical outcomes of TNBC patients. Results Seventy-seven of 174 TNBC patients were found to harbor a TP53 mutation. Patients with missense mutations showed high protein expression in contrast to patients with deletion mutations (positivity of IHC: wild type vs. missense vs. deletion mutation, 53.6% vs. 89.8% vs. 25.0%, respectively; p < 0.001). TP53 mRNA expression was influenced by mutation status (mRNA expression [median]: wild type vs. missense vs. deletion mutation, 207.36± 132.73 vs. 339.61±143.21 vs. 99.53±99.57, respectively; p < 0.001). According to survival analysis, neither class of mutation nor protein or mRNA expression status had any impact on patient prognosis. In subgroup analysis, low mRNA expression was associated with poor prognosis in patients with a TP53 missense mutation (5-year distant recurrence-free survival [5Y DRFS]: low vs. high, 50.0% vs. 87.8%; p=0.009), while high mRNA expression with a TP53 deletion mutation indicated poor prognosis (5Y DRFS: low vs. high, 91.7% vs. 75.0%; p=0.316). Conclusion Association between TP53 mutation and expression indicates a potential prognostic marker of TNBC; hence both DNA sequencing and mRNA expression analysis may be required to predict the prognosis of TNBC patients. PMID:26910472

  7. TP53 alterations in pancreatic acinar cell carcinoma: new insights into the molecular pathology of this rare cancer.

    PubMed

    La Rosa, Stefano; Bernasconi, Barbara; Frattini, Milo; Tibiletti, Maria Grazia; Molinari, Francesca; Furlan, Daniela; Sahnane, Nora; Vanoli, Alessandro; Albarello, Luca; Zhang, Lizhi; Notohara, Kenji; Casnedi, Selenia; Chenard, Marie-Pierre; Adsay, Volkan; Asioli, Sofia; Capella, Carlo; Sessa, Fausto

    2016-03-01

    The molecular alterations of pancreatic acinar cell carcinomas (ACCs) are poorly understood and have been reported as being different from those in ductal adenocarcinomas. Loss of TP53 gene function in the pathogenesis of ACCs is controversial since contradictory findings have been published. A comprehensive analysis of the different possible genetic and epigenetic mechanisms leading to TP53 alteration in ACC has never been reported and hence the role of TP53 in the pathogenesis and/or progression of ACC remains unclear. We investigated TP53 alterations in 54 tumor samples from 44 patients, including primary and metastatic ACC, using sequencing analysis, methylation-specific multiplex ligation probe amplification, fluorescence in situ hybridization, and immunohistochemistry. TP53 mutations were found in 13 % of primary ACCs and in 31 % of metastases. Primary ACCs and metastases showed the same mutational profile, with the exception of one case, characterized by a wild-type sequence in the primary carcinoma and a mutation in the corresponding metastasis. FISH analysis revealed deletion of the TP53 region in 53 % of primary ACCs and in 50 % of metastases. Promoter hypermethylation was found in one case. The molecular alterations correlated well with the immunohistochemical findings. A statistically significant association was found between the combination of mutation of one allele and loss of the other allele of TP53 and worse survival.

  8. Prenatal diagnosis of interstitial deletion of 17(p11.2p11.2) (Smith-Magenis Syndrome)

    SciTech Connect

    1994-01-15

    Interstitial deletion of 17p11.2 is associated with Smith-Magenis syndrome. This is a recognizable chromosomal deletion syndrome, characterized by brachycephaly, midface hypoplasia, growth and mental retardation, behavioral problems, and ocular abnormalities. Molecular analysis indicates it is a contiguous gene syndrome. Over 50 patients have been reported since the deletion was first described by Smith et al. [1982]. Cases include one with mosaicism and a familial example. None were prenatally diagnosed. The authors report on the prenatal detection of interstitial deletion of 17p11.2. 11 refs., 1 fig.

  9. TP53 — EDRN Public Portal

    Cancer.gov

    TP53, also widely known as p53, acts as a tumor suppressor in many tumor types, responding to diverse cellular stresses to regulate target genes that induce cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. It is involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. p53 protein is expressed at low level in normal cells and at a high level in a variety of transformed cell lines, where it's believed to contribute to transformation and malignancy. p53 is a DNA-binding protein containing transcription activation, DNA-binding, and oligomerization domains. It is postulated to bind to a p53-binding site and activate expression of downstream genes that inhibit growth and/or invasion, and thus function as a tumor suppressor. Mutants of p53 that frequently occur in a number of different human cancers fail to bind the consensus DNA binding site, and hence cause the loss of tumor suppressor activity. Multiple p53 variants due to alternative promoters and multiple alternative splicing have been found. These variants encode distinct isoforms, which can regulate p53 transcriptional activity.

  10. Knockdown of HSPA9 induces TP53-dependent apoptosis in human hematopoietic progenitor cells.

    PubMed

    Liu, Tuoen; Krysiak, Kilannin; Shirai, Cara Lunn; Kim, Sanghyun; Shao, Jin; Ndonwi, Matthew; Walter, Matthew J

    2017-01-01

    Myelodysplastic syndromes (MDS) are the most common adult myeloid blood cancers in the US. Patients have increased apoptosis in their bone marrow cells leading to low peripheral blood counts. The full complement of gene mutations that contribute to increased apoptosis in MDS remains unknown. Up to 25% of MDS patients harbor and acquired interstitial deletion on the long arm of chromosome 5 [del(5q)], creating haploinsufficiency for a large set of genes including HSPA9. Knockdown of HSPA9 in primary human CD34+ hematopoietic progenitor cells significantly inhibits growth and increases apoptosis. We show here that HSPA9 knockdown is associated with increased TP53 expression and activity, resulting in increased expression of target genes BAX and p21. HSPA9 protein interacts with TP53 in CD34+ cells and knockdown of HSPA9 increases nuclear TP53 levels, providing a possible mechanism for regulation of TP53 by HSPA9 haploinsufficiency in hematopoietic cells. Concurrent knockdown of TP53 and HSPA9 rescued the increased apoptosis observed in CD34+ cells following knockdown of HSPA9. Reduction of HSPA9 below 50% results in severe inhibition of cell growth, suggesting that del(5q) cells may be preferentially sensitive to further reductions of HSPA9 below 50%, thus providing a genetic vulnerability to del(5q) cells. Treatment of bone marrow cells with MKT-077, an HSPA9 inhibitor, induced apoptosis in a higher percentage of cells from MDS patients with del(5q) compared to non-del(5q) MDS patients and normal donor cells. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to TP53 activation and increased apoptosis observed in del(5q)-associated MDS.

  11. Knockdown of HSPA9 induces TP53-dependent apoptosis in human hematopoietic progenitor cells

    PubMed Central

    Liu, Tuoen; Krysiak, Kilannin; Shirai, Cara Lunn; Kim, Sanghyun; Shao, Jin; Ndonwi, Matthew; Walter, Matthew J.

    2017-01-01

    Myelodysplastic syndromes (MDS) are the most common adult myeloid blood cancers in the US. Patients have increased apoptosis in their bone marrow cells leading to low peripheral blood counts. The full complement of gene mutations that contribute to increased apoptosis in MDS remains unknown. Up to 25% of MDS patients harbor and acquired interstitial deletion on the long arm of chromosome 5 [del(5q)], creating haploinsufficiency for a large set of genes including HSPA9. Knockdown of HSPA9 in primary human CD34+ hematopoietic progenitor cells significantly inhibits growth and increases apoptosis. We show here that HSPA9 knockdown is associated with increased TP53 expression and activity, resulting in increased expression of target genes BAX and p21. HSPA9 protein interacts with TP53 in CD34+ cells and knockdown of HSPA9 increases nuclear TP53 levels, providing a possible mechanism for regulation of TP53 by HSPA9 haploinsufficiency in hematopoietic cells. Concurrent knockdown of TP53 and HSPA9 rescued the increased apoptosis observed in CD34+ cells following knockdown of HSPA9. Reduction of HSPA9 below 50% results in severe inhibition of cell growth, suggesting that del(5q) cells may be preferentially sensitive to further reductions of HSPA9 below 50%, thus providing a genetic vulnerability to del(5q) cells. Treatment of bone marrow cells with MKT-077, an HSPA9 inhibitor, induced apoptosis in a higher percentage of cells from MDS patients with del(5q) compared to non-del(5q) MDS patients and normal donor cells. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to TP53 activation and increased apoptosis observed in del(5q)-associated MDS. PMID:28178280

  12. Loss of function tp53 mutations do not accelerate the onset of myc-induced T-cell acute lymphoblastic leukaemia in the zebrafish.

    PubMed

    Gutierrez, Alejandro; Feng, Hui; Stevenson, Kristen; Neuberg, Donna S; Calzada, Oscar; Zhou, Yi; Langenau, David M; Look, A Thomas

    2014-07-01

    The TP53 tumour suppressor is activated in response to distinct stimuli, including an ARF-dependent response to oncogene stress and an ATM/ATR-dependent response to DNA damage. In human T-cell acute lymphoblastic leukaemia (T-ALL), TP53-dependent tumour suppression is typically disabled via biallelic ARF deletions. In murine models, loss of Arf (Cdkn2a) or Tp53 markedly accelerates the onset of Myc-induced lymphoblastic malignancies. In zebrafish, no ARF ortholog has been identified, but the sequence of ARF is very poorly conserved evolutionarily, making it difficult to exclude the presence of a zebrafish ARF ortholog without functional studies. Here we show that tp53 mutations have no significant influence on the onset of myc-induced T-ALL in zebrafish, consistent with the lack of additional effects of Tp53 loss on lymphomagenesis in Arf-deficient mice. By contrast, irradiation leads to complete T-ALL regression in tp53 wild-type but not homozygous mutant zebrafish, indicating that the tp53-dependent DNA damage response is intact. We conclude that tp53 inactivation has no impact on the onset of myc-induced T-ALL in the zebrafish, consistent with the lack of a functional ARF ortholog linking myc-induced oncogene stress to tp53-dependent tumour suppression. Thus, the zebrafish model is well suited to the study of ARF-independent pathways in T-ALL pathobiology.

  13. TP53 mutations in older adults with acute myeloid leukemia.

    PubMed

    Yanada, Masamitsu; Yamamoto, Yukiya; Iba, Sachiko; Okamoto, Akinao; Inaguma, Yoko; Tokuda, Masutaka; Morishima, Satoko; Kanie, Tadaharu; Mizuta, Shuichi; Akatsuka, Yoshiki; Okamoto, Masataka; Emi, Nobuhiko

    2016-04-01

    The net benefits of induction therapy for older adults with acute myeloid leukemia (AML) remain controversial. Because AML in older adults is a heterogeneous disease, it is important to identify those who are unlikely to benefit from induction therapy based on information available at the initial assessment. We used next-generation sequencing to analyze TP53 mutation status in AML patients aged 60 years or older, and evaluated its effects on outcomes. TP53 mutations were detected in 12 of 77 patients (16 %), and there was a significant association between TP53 mutations and monosomal karyotype. Patients with TP53 mutations had significantly worse survival than those without (P = 0.009), and multivariate analysis identified TP53 mutation status as the most significant prognostic factor for survival. Neverthelsess, TP53-mutated patients had a 42 % chance of complete remission and a median survival of 8.0 months, which compares favorably with those who did not undergo induction therapy, even in the short term. These results suggest that screening for TP53 mutations at diagnosis is useful for identifying older adults with AML who are least likely to respond to chemotherapy, although the presence of this mutation alone does not seem to justify rejecting induction therapy.

  14. Germline TP53 mutations and single nucleotide polymorphisms in children.

    PubMed

    Valva, Pamela; Becker, Pablo; Streitemberger, Patricia; Lombardi, García Mercedes; Rey, Guadalupe; Guzman, Carlos A; Preciado, María Victoria

    2009-01-01

    Mutations in the gene TP53, which codifies the tumor suppressor protein p53, are found in about 50% of tumors. These mutations can occur not only at somatic level, but also in germline. Pediatric cancer patients, mostly with additional family history of malignancy, should be considered as potential TP53 germline mutation carriers. Germline TP53 mutations and polymorphisms have been widely studied to determine their relation with different tumors' pathogenesis. Our aim was to analyze the occurrence frequency of germline TP53 mutations and polymorphisms and to relate these to tumor development in a pediatric series. Peripheral blood mononuclear cell samples from 26 children with solid tumors [PST] and 21 pediatric healthy donors [HD] were analyzed for germline mutations and polymorphisms in TP53 gene spanning from exon 5 to 8 including introns 5 and 7. These PCR amplified fragments were sequenced to determine variations. A heterozygous mutation at codon 245 was found in 1/26 PST and 0/21 HD. Comparative polymorphisms distribution, at position 14181 and 14201(intron 7), between HD and PST revealed a trend of association (p= 0.07) with cancer risk. HD group disclosed a similar polymorphism distribution as published data for Caucasian and Central/South American populations. This is the first study about TP53 variant frequency and distribution in healthy individuals and cancer patients in Argentina.

  15. Immunohistochemical correlates of TP53 somatic mutations in cancer

    PubMed Central

    Murnyák, Balázs; Hortobágyi, Tibor

    2016-01-01

    Despite controversy on the correlation between p53 accumulation and TP53 mutational status, ihas long been used as a surrogate method for mutation analysis. The aim of our study was to characterise the IHC expression features of TP53 somatic mutations and define their occurrence in human cancers. A large-scale database analysis was conducted in the IARC TP53 Database (R17); 7878 mutations with IHC features were retrieved representing 60 distinct tumour sites. The majority of the alterations were immunopositive (p <0.001). Sex was known for 4897 mutations showing a female dominance (57.2%) and females carrying negative mutations were significantly younger. TP53 mutations were divided into three IHC groups according to mutation frequency and IHC positivity. Each group had female dominance. Among the IHC groups, significant correlations were observed with age at diagnosis in breast, bladder, liver, haematopoietic system and head & neck cancers. An increased likelihood of false negative IHC associated with rare nonsense mutations was observed in certain tumour sites. Our study demonstrates that p53 immunopositivity largely correlates with TP53 mutational status but expression is absent in certain mutation types.Besides, describing the complex IHC expression of TP53 somatic mutations, our results reveal some caveats for the diagnostic practice. PMID:27626311

  16. Immunohistochemical correlates of TP53 somatic mutations in cancer.

    PubMed

    Murnyák, Balázs; Hortobágyi, Tibor

    2016-10-04

    Despite controversy on the correlation between p53 accumulation and TP53 mutational status, immunohistochemical (IHC) detection of overexpressed protein has long been used as a surrogate method for mutation analysis. The aim of our study was to characterise the IHC expression features of TP53 somatic mutations and define their occurrence in human cancers. A large-scale database analysis was conducted in the IARC TP53 Database (R17); 7878 mutations with IHC features were retrieved representing 60 distinct tumour sites. The majority of the alterations were immunopositive (p <0.001). Sex was known for 4897 mutations showing a female dominance (57.2%) and females carrying negative mutations were significantly younger. TP53 mutations were divided into three IHC groups according to mutation frequency and IHC positivity. Each group had female dominance. Among the IHC groups, significant correlations were observed with age at diagnosis in breast, bladder, liver, haematopoietic system and head & neck cancers. An increased likelihood of false negative IHC associated with rare nonsense mutations was observed in certain tumour sites. Our study demonstrates that p53 immunopositivity largely correlates with TP53 mutational status but expression is absent in certain mutation types.Besides, describing the complex IHC expression of TP53 somatic mutations, our results reveal some caveats for the diagnostic practice.

  17. The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes

    PubMed Central

    McGraw, K L; Zhang, L M; Rollison, D E; Basiorka, A A; Fulp, W; Rawal, B; Jerez, A; Billingsley, D L; Lin, H-Y; Kurtin, S E; Yoder, S; Zhang, Y; Guinta, K; Mallo, M; Solé, F; Calasanz, M J; Cervera, J; Such, E; González, T; Nevill, T J; Haferlach, T; Smith, A E; Kulasekararaj, A; Mufti, G; Karsan, A; Maciejewski, J P; Sokol, L; Epling-Burnette, P K; Wei, S; List, A F

    2015-01-01

    Nonsynonymous TP53 exon 4 single-nucleotide polymorphism (SNP), R72P, is linked to cancer and mutagen susceptibility. R72P associations with specific cancer risk, particularly hematological malignancies, have been conflicting. Myelodysplastic syndrome (MDS) with chromosome 5q deletion is characterized by erythroid hypoplasia arising from lineage-specific p53 accumulation resulting from ribosomal insufficiency. We hypothesized that apoptotically diminished R72P C-allele may influence predisposition to del(5q) MDS. Bone marrow and blood DNA was sequenced from 705 MDS cases (333 del(5q), 372 non-del(5q)) and 157 controls. Genotype distribution did not significantly differ between del(5q) cases (12.6% CC, 38.1% CG, 49.2% GG), non-del(5q) cases (9.7% CC, 44.6% CG, 45.7% GG) and controls (7.6% CC, 37.6% CG, 54.8% GG) (P=0.13). Allele frequency did not differ between non-del(5q) and del(5q) cases (P=0.91) but trended towards increased C-allele frequency comparing non-del(5q) (P=0.08) and del(5q) (P=0.10) cases with controls. Median lenalidomide response duration increased proportionate to C-allele dosage in del(5q) patients (2.2 (CC), 1.3 (CG) and 0.89 years (GG)). Furthermore, C-allele homozygosity in del(5q) was associated with prolonged overall and progression-free survival and non-terminal interstitial deletions that excluded 5q34, whereas G-allele homozygozity was associated with inferior outcome and terminal deletions involving 5q34 (P=0.05). These findings comprise the largest MDS R72P SNP analysis. PMID:25768405

  18. A case of gastric cancer with heterogeneous components of EB virus (+)/TP53 (+) and EB virus (-)/TP53 (-).

    PubMed

    Matsuda, Ikuo; Kan, Kazuomi; Doi, Sadayuki; Motoki, Yoshiyuki; Onodera, Masayuki; Hirota, Seiichi

    2015-01-01

    Epstein-Barr virus (EBV)-associated gastric adenocarcinoma is a histological subtype of gastric adenocarcinoma, in which all of the carcinoma cells are basically positive for EBV-encoded small RNA (EBER) by in situ hybridization. Although its typical histology has some overlap with gastric carcinoma with lymphoid stroma, absence of massive lymphoid infiltrate is sometimes observed either in whole or in part. EBV-associated adenocarcinoma is one of the four representative molecular pathological subtypes recently identified by comprehensive genomic analysis of gastric adenocarcinomas. According to the analysis, typical EBV-associated gastric adenocarcinoma constitutes an independent molecular pathological subgroup, which is mutually exclusive to TP53-mutated adenocarcinoma with chromosomal instability, another molecular pathological subtype in gastric adenocarcinomas. Here, we report a rare case of gastric cancer heterogeneously composed of EBER (+)/TP53 (+) and EBER (-)/TP53 (-) portions. The EBER (+)/TP53 (+) component with massive lymphoid infiltrate surrounded the EBER (-)/TP53 (-) component showing well to moderately differentiated tubular adenocarcinoma. Although collision of two independent gastric cancers could be the simplest and most possible explanation for this situation, we discussed another possibility. In the case of gastric collision tumors, concurrent development of EBER (+) gastric adenocarcinomas and EBER (-) gastric adenocarcinomas in a single stomach is a rare incident. Since presence of the EBER (+)/TP53 (+) tumor component is atypical in itself, we also discussed the mechanism of development of the clone.

  19. NOTCH1, TP53, and MAP2K1 Mutations in Splenic Diffuse Red Pulp Small B-cell Lymphoma Are Associated With Progressive Disease.

    PubMed

    Martinez, Daniel; Navarro, Alba; Martinez-Trillos, Alejandra; Molina-Urra, Ricardo; Gonzalez-Farre, Blanca; Salaverria, Itziar; Nadeu, Ferran; Enjuanes, Anna; Clot, Guillem; Costa, Dolors; Carrio, Ana; Villamor, Neus; Colomer, Dolors; Martinez, Antonio; Bens, Susanne; Siebert, Reiner; Wotherspoon, Andrew; Beà, Sílvia; Matutes, Estella; Campo, Elias

    2016-02-01

    Splenic diffuse red pulp small B-cell lymphoma (SDRPL) is considered an indolent neoplasm and its pathogenesis is not well known. We investigated the molecular characteristics of 19 SDRPL patients, 5 of them with progressive disease. IGHV genes were mutated in 9/13 (69%). Cytogenetic and molecular studies identified complex karyotypes in 2 cases, and IGH rearrangements in 3, with PAX5 and potentially TCL1 as partners in each one of them. Copy number arrays showed aberrations in 69% of the tumors, including recurrent losses of 10q23, 14q31-q32, and 17p13 in 3, and 9p21 in 2 cases. Deletion of 7q31.3-q32.3 was present in only 1 case and no trisomies 3 or 18 were detected. NOTCH1 and MAP2K1 were mutated in 2 cases each, whereas BRAF, TP53, and SF3B1 were mutated each in single cases. No mutations were found in NOTCH2 or MYD88. Four of the 5 patients with aggressive disease had mutations in NOTCH1 (2 cases), TP53 (1 case), and MAP2K1 (1 case). The progression-free survival of patients with mutated genes was significantly shorter than in the unmutated (P=0.011). These findings show that SDRPL share some mutated genes but not chromosomal alterations, with other splenic lymphomas, that may confer a more aggressive behavior.

  20. Prognostic significance of TP53 alterations in breast carcinoma.

    PubMed Central

    Andersen, T. I.; Holm, R.; Nesland, J. M.; Heimdal, K. R.; Ottestad, L.; Børresen, A. L.

    1993-01-01

    Constant denaturant gel electrophoresis (CDGE) was used to screen 179 breast carcinomas for mutations in the conserved regions of the TP53 gene (exons 5 through 8). Mutations were found in 35 of 163 primary tumours (21%) and in 5 of 16 metastases (31%) and resided predominantly in exon 7. The majority of the mutations were G:C-->A:T transitions. Immunohistochemistry demonstrated nuclear accumulation of p53 protein in 35 of 162 primary tumours (22%) and in four of 15 metastases (27%). TP53 mutation was strongly associated with nuclear accumulation of p53 protein. In total 42 of 163 primary tumours (26%) and 5 of 16 metastases (31%) were demonstrated to contain TP53 alterations (mutation and/or nuclear protein accumulation). TP53 alteration in primary tumour was significantly associated with the following parameters: positive node status, T status > 1, negative oestrogen receptor status, negative progesterone receptor status, presence of ERBB2 gene amplification, and invasive ductal histology. Furthermore, there were statistically significant associations, independent of other prognostic factors, between TP53 alterations in primary tumour and disease-free and overall survival. Images Figure 1 Figure 2 PMID:8102535

  1. Sequential mutations in Notch1, Fbxw7, and Tp53 in radiation-induced mouse thymic lymphomas.

    PubMed

    Jen, Kuang-Yu; Song, Ihn Young; Banta, Karl Luke; Wu, Di; Mao, Jian-Hua; Balmain, Allan

    2012-01-19

    T-cell acute lymphoblastic lymphomas commonly demonstrate activating Notch1 mutations as well as mutations or deletions in Fbxw7. However, because Fbxw7 targets Notch1 for degradation, genetic alterations in these genes are expected to be mutually exclusive events in lymphomagenesis. Previously, by using a radiation-induced Tp53-deficient mouse model for T-cell acute lymphoblastic lymphoma, we reported that loss of heterozygosity at the Fbxw7 locus occurs frequently in a Tp53-dependent manner. In the current study, we show that these thymic lymphomas also commonly exhibit activating Notch1 mutations in the proline-glutamic acid-serine-threonine (PEST) domain. Moreover, concurrent activating Notch1 PEST domain mutations and single-copy deletions at the Fbxw7 locus occur with high frequency in the same individual tumors, indicating that these changes are not mutually exclusive events. We further demonstrate that although Notch1 PEST domain mutations are independent of Tp53 status, they are completely abolished in mice with germline Fbxw7 haploinsufficiency. Therefore, Notch1 PEST domain mutations only occur when Fbxw7 expression levels are intact. These data suggest a temporal sequence of mutational events involving these important cancer-related genes, with Notch1 PEST domain mutations occurring first, followed by Fbxw7 deletion, and eventually by complete loss of Tp53.

  2. Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith-Magenis syndrome.

    PubMed

    Vieira, Gustavo H; Rodriguez, Jayson D; Carmona-Mora, Paulina; Cao, Lei; Gamba, Bruno F; Carvalho, Daniel R; de Rezende Duarte, Andréa; Santos, Suely R; de Souza, Deise H; DuPont, Barbara R; Walz, Katherina; Moretti-Ferreira, Danilo; Srivastava, Anand K

    2012-02-01

    Smith-Magenis syndrome (SMS) is a complex disorder whose clinical features include mild to severe intellectual disability with speech delay, growth failure, brachycephaly, flat midface, short broad hands, and behavioral problems. SMS is typically caused by a large deletion on 17p11.2 that encompasses multiple genes including the retinoic acid induced 1, RAI1, gene or a mutation in the RAI1 gene. Here we have evaluated 30 patients with suspected SMS and identified SMS-associated classical 17p11.2 deletions in six patients, an atypical deletion of ~139 kb that partially deletes the RAI1 gene in one patient, and RAI1 gene nonsynonymous alterations of unknown significance in two unrelated patients. The RAI1 mutant proteins showed no significant alterations in molecular weight, subcellular localization and transcriptional activity. Clinical features of patients with or without 17p11.2 deletions and mutations involving the RAI1 gene were compared to identify phenotypes that may be useful in diagnosing patients with SMS.

  3. Impact of TP53 Mutations on Outcome in EGFR-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors.

    PubMed

    Canale, Matteo; Petracci, Elisabetta; Delmonte, Angelo; Chiadini, Elisa; Dazzi, Claudio; Papi, Maximilian; Capelli, Laura; Casanova, Claudia; De Luigi, Nicoletta; Mariotti, Marita; Gamboni, Alessandro; Chiari, Rita; Bennati, Chiara; Calistri, Daniele; Ludovini, Vienna; Crinò, Lucio; Amadori, Dino; Ulivi, Paola

    2016-10-25

    Purpose: To analyze the impact of TP53 mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non-small cell lung cancer (NSCLC).Experimental Design: 136 EGFR-mutated NSCLC patients receiving first-line TKIs were analyzed. TP53 mutations were evaluated in 123 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).Results:TP53 mutations were observed in 37 (30.1%), 10 (27.0%), 6 (16.2%), 9 (24.3%), and 12 (32.4%) patients in exons 5, 6, 7, and 8, respectively. DCR was 70% in TP53-mutated patients compared with 88% in TP53-wild type (wt) patients [relative risk, RR, of disease progression: 3.17 (95% CI, 1.21-8.48), P = 0.019]. In particular, a 42% DCR was observed in patients with TP53 exon 8 mutation versus 87% in exon 8 wt patients [RR of disease progression 9.6 (2.71-36.63), P < 0.001]. Shorter median PFS and OS were observed in patients with TP53 exon 8 mutations compared with others (4.2 vs. 12.5, P = 0.058, and 16.2 vs. 32.3, P = 0.114, respectively); these differences became significant in the subgroup with EGFR exon 19 deletion (4.2 vs. 16.8, P < 0.001, and 7.6 vs. not reached, P = 0.006, respectively), HR 6.99 (95% CI, 2.34-20.87, P < 0.001) and HR 4.75 (95% CI, 1.38-16.29, P = 0.013), respectively.Conclusions:TP53 mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions. Clin Cancer Res; 1-8. ©2016 AACR.

  4. Germline mutations of TP53 gene in breast cancer.

    PubMed

    Damineni, Surekha; Rao, Vadlamudi Raghavendra; Kumar, Satish; Ravuri, Rajasekar Reddy; Kagitha, Sailaja; Dunna, Nageswara Rao; Digumarthi, Raghunadharao; Satti, Vishnupriya

    2014-09-01

    Germline alterations of the TP53 gene encoding the p53 protein have been observed in the majority of families with the Li-Fraumeni syndrome, a rare dominantly inherited disorder with breast cancer. Genomic DNA samples of 182 breast cancer cases and 186 controls were sequenced for TP53 mutations in the exon 5-9 and intervening introns 5, 7-9. Direct sequencing was done using Applied Biosystem 3730 DNA analyzer. In the present study, we observed nine mutations in the sequenced region, of which five were novel. Hardy-Weinberg equilibrium (HWE) was done for all the mutations; C14181T, T14201G, and G13203A have shown deviation from HWE. High linkage disequilibrium (LD) was observed between C14181T (rs129547788) and T14201G (rs12951053) (r (2) = 0.98.3; D' = 1.00), whereas other observed mutations do not show strong LD with any of the other mutations. None of the intronic mutations has shown significant association with the breast cancer, two exonic mutations G13203A (rs28934578) and A14572G are significantly (P = 0.04, P = 0.007) associated with breast cancer. Germline mutations observed in DNA-binding domain of the gene showed significant association with breast cancer. This study reports five novel germline mutations in the TP53 gene out of which one mutation may confer significant risk to the breast cancer. Mutations in DNA-binding domain of TP53 gene may play role in the early onset and prognosis of breast cancer. The population-based studies of germline mutations in DNA-binding domain of TP53 gene helps in identification of individuals and families who are at risk of developing cancers.

  5. Two patients with duplication of 17p11.2: The reciprocal of the Smith-Magenis syndrome deletion?

    SciTech Connect

    Brown, A. |; Phelan, M.C.; Rogers, R.C.

    1996-05-17

    J.M. and H.G. are two unrelated male patients with developmental delay. Cytogenetic analysis detected a duplication of 17p11.2 in both patients. The extent of the duplicated region was determined using single copy DNA probes: cen-D17S58-D17S29-D17S258-D17S71-D17S445-D17S122-tel. Four of the six markers, D17S29, D17S258, D17S71, and D17S445, were duplicated by dosage analysis. Fluorescent in situ hybridization (FISH) analysis of H.G., using cosmids for locus D17S29, confirmed the duplication in 17p11.2. Because the deletion that causes the Smith-Magenis syndrome involves the same region of 17p11.2 as the duplication in these patients, the mechanism may be similar to that proposed for the reciprocal deletion/ duplication event observed in Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and Charcot-Marie-Tooth Type 1A disease (CMT1A). 30 refs., 3 figs., 1 tab.

  6. Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents

    PubMed Central

    Takahashi, Koichi; Patel, Keyur; Bueso-Ramos, Carlos; Zhang, Jianhua; Gumbs, Curtis; Jabbour, Elias; Kadia, Tapan; Andreff, Michael; Konopleva, Marina; DiNardo, Courtney; Daver, Naval; Cortes, Jorge; Estrov, Zeev; Futreal, Andrew; Kantarjian, Hagop; Garcia-Manero, Guillermo

    2016-01-01

    We screened TP53 mutations in 168 MDS patients who were treated with HMA and evaluated predictive and prognostic value of TP53 mutations. Overall response to HMA was not different based on TP53 mutation status (45% vs. 32% in TP53-mutated and wild type [WT], respectively, P = 0.13). However, response duration was significantly shorter in TP53-mutated patients compared to WT patients (5.7 months vs. 28.5 months, P = 0.003). Longitudinal analysis of TP53 mutations after HMA showed that TP53 mutations almost always persisted at times of disease progression. TP53-mutated patients showed significantly worse overall survival (OS) compared to WT patients (9.4 months vs. 20.7 months, P <0.001). Further, TP53 mutations distinguished prognosis in the subgroup of patients with complex karyotype and Revised International Prognostic Scoring System (IPSS-R) defined very high-risk disease. Multivariate analysis showed that TP53 mutation status is significantly prognostic for OS after adjusting prognostic effect from other factors. The current study provides evidence that TP53 mutations are independently prognostic in MDS patients treated with HMA. While TP53-mutated MDS patients initially respond well to HMA, their duration of response is significantly shorter than WT patients. Novel strategies to improve duration of response in TP53-mutated MDS are urgently needed. PMID:26871476

  7. Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents.

    PubMed

    Takahashi, Koichi; Patel, Keyur; Bueso-Ramos, Carlos; Zhang, Jianhua; Gumbs, Curtis; Jabbour, Elias; Kadia, Tapan; Andreff, Michael; Konopleva, Marina; DiNardo, Courtney; Daver, Naval; Cortes, Jorge; Estrov, Zeev; Futreal, Andrew; Kantarjian, Hagop; Garcia-Manero, Guillermo

    2016-03-22

    We screened TP53 mutations in 168 MDS patients who were treated with HMA and evaluated predictive and prognostic value of TP53 mutations. Overall response to HMA was not different based on TP53 mutation status (45% vs. 32% in TP53-mutated and wild type [WT], respectively, P = 0.13). However, response duration was significantly shorter in TP53-mutated patients compared to WT patients (5.7 months vs. 28.5 months, P = 0.003). Longitudinal analysis of TP53 mutations after HMA showed that TP53 mutations almost always persisted at times of disease progression. TP53-mutated patients showed significantly worse overall survival (OS) compared to WT patients (9.4 months vs. 20.7 months, P <0.001). Further, TP53 mutations distinguished prognosis in the subgroup of patients with complex karyotype and Revised International Prognostic Scoring System (IPSS-R) defined very high-risk disease. Multivariate analysis showed that TP53 mutation status is significantly prognostic for OS after adjusting prognostic effect from other factors. The current study provides evidence that TP53 mutations are independently prognostic in MDS patients treated with HMA. While TP53-mutated MDS patients initially respond well to HMA, their duration of response is significantly shorter than WT patients. Novel strategies to improve duration of response in TP53-mutated MDS are urgently needed.

  8. De novo duplication of 17p13.1-p13.2 in a patient with intellectual disability and obesity.

    PubMed

    Kuroda, Yukiko; Ohashi, Ikuko; Tominaga, Makiko; Saito, Toshiyuki; Nagai, Jun-Ichi; Ida, Kazumi; Naruto, Takuya; Masuno, Mitsuo; Kurosawa, Kenji

    2014-06-01

    17p13.1 Deletion encompassing TP53 has been described as a syndrome characterized by intellectual disability and dysmorphic features. Only one case with a 17p13.1 duplication encompassing TP53 has been reported in a patient with intellectual disability, seizures, obesity, and diabetes mellitus. Here, we present a patient with a 17p13.1 duplication who exhibited obesity and intellectual disability, similar to the previous report. The 9-year-old proposita was referred for the evaluation of intellectual disability and obesity. She also exhibited insulin resistance and liver dysfunction. She had wide palpebral fissures, upturned nostrils, a long mandible, short and slender fingers, and skin hyperpigmentation. Array comparative genomic hybridization (array CGH) detected a 3.2 Mb duplication of 17p13.1-p13.2 encompassing TP53, FXR2, NLGN2, and SLC2A4, which encodes the insulin-responsive glucose transporter 4 (GLUT4) associated with insulin-stimulated glucose uptake in adipocytes and muscle. We suggest that 17p13.1 duplication may represent a clinically recognizable condition characterized partially by a characteristic facial phenotype, developmental delay, and obesity.

  9. Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf(-/-) mouse model.

    PubMed

    Chapeau, Emilie A; Gembarska, Agnieszka; Durand, Eric Y; Mandon, Emeline; Estadieu, Claire; Romanet, Vincent; Wiesmann, Marion; Tiedt, Ralph; Lehar, Joseph; de Weck, Antoine; Rad, Roland; Barys, Louise; Jeay, Sebastien; Ferretti, Stephane; Kauffmann, Audrey; Sutter, Esther; Grevot, Armelle; Moulin, Pierre; Murakami, Masato; Sellers, William R; Hofmann, Francesco; Jensen, Michael Rugaard

    2017-03-21

    Inhibitors of double minute 2 protein (MDM2)-tumor protein 53 (TP53) interaction are predicted to be effective in tumors in which the TP53 gene is wild type, by preventing TP53 protein degradation. One such setting is represented by the frequent CDKN2A deletion in human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades TP53 tumor suppressor. Here we used piggyBac (PB) transposon insertional mutagenesis to anticipate resistance mechanisms occurring during treatment with the MDM2-TP53 inhibitor HDM201. Constitutive PB mutagenesis in Arf(-/-) mice provided a collection of spontaneous tumors with characterized insertional genetic landscapes. Tumors were allografted in large cohorts of mice to assess the pharmacologic effects of HDM201. Sixteen out of 21 allograft models were sensitive to HDM201 but ultimately relapsed under treatment. A comparison of tumors with acquired resistance to HDM201 and untreated tumors identified 87 genes that were differentially and significantly targeted by the PB transposon. Resistant tumors displayed a complex clonality pattern suggesting the emergence of several resistant subclones. Among the most frequent alterations conferring resistance, we observed somatic and insertional loss-of-function mutations in transformation-related protein 53 (Trp53) in 54% of tumors and transposon-mediated gain-of-function alterations in B-cell lymphoma-extra large (Bcl-xL), Mdm4, and two TP53 family members, resulting in expression of the TP53 dominant negative truncations ΔNTrp63 and ΔNTrp73. Enhanced BCL-xL and MDM4 protein expression was confirmed in resistant tumors, as well as in HDM201-resistant patient-derived tumor xenografts. Interestingly, concomitant inhibition of MDM2 and BCL-xL demonstrated significant synergy in p53 wild-type cell lines in vitro. Collectively, our findings identify several potential mechanisms by which TP53 wild-type tumors may escape MDM2-targeted therapy.

  10. PIN1 in hepatocellular carcinoma is associated with TP53 gene status.

    PubMed

    Bae, Jun Sang; Noh, Sang Jae; Kim, Kyoung Min; Jang, Kyu Yun; Park, Ho Sung; Chung, Myoung Ja; Park, Byung-Hyun; Moon, Woo Sung

    2016-10-01

    Phosphorylation of proteins on serine/threonine residues that precede proline (pSer/Thr-Pro) is specifically catalyzed by the peptidyl-prolyl cis-trans isomerase PIN1. PIN1-mediated prolyl-isomerization induces cell cycle arrest and growth inhibition through the regulation of target proteins, including TP53. We examined whether PIN1 acts in a different manner according to TP53 gene status in hepatocellular carcinoma (HCC). We investigated the expression of PIN1 and TP53 proteins in 119 HCC tissue samples. We also analyzed PIN1 expression in combination with TP53 gene mutation and its correlation with the clinical outcome. In addition, we used synthetic small interfering RNA to silence PIN1 gene expression in TP53 wild-type and TP53 mutant HCC cell lines, and then evaluated cell proliferation, migration and invasion. Expression of PIN1 was strongly associated with expression of TP53 protein or TP53 mutation of HCC samples. PIN1 and TP53 expression in TP53 mutant HCC cell lines was higher than that in TP53 wild-type HCC cell lines. Silencing of PIN1 in HLE cells containing mutant TP53 significantly decreased cell proliferation, migration and invasion. In contrast to PIN1 silencing in HLE cells, PIN1 silencing in HepG2 cells containing functional wild-type TP53 resulted in enhanced tumor cell proliferation. HCC patients bearing PIN1 expression with wild-type TP53 were predicted to demonstrate favorable relapse-free survival. Our results suggest that PIN1 plays a role in cancer cell proliferation, migration and invasion in a different manner according to the TP53 gene mutation status in HCC. In particular, interaction of PIN1 with mutant TP53 can act as a tumor promoter and increase its oncogenic activities in HCC.

  11. Deletion 17p11.2 (Smith-Magenis syndrome) is relatively common among patients having mental retardation and myopia

    SciTech Connect

    Finucane, B.; Jaeger, E.R.; Freitag, S.K.

    1994-09-01

    We recently reported the finding of moderate to severe myopia in 6 of 10 patients with Smith-Magenis syndrome (SMS). To investigate the prevalence of SMS among mentally retarded people having myopia, we surveyed a cohort of patients residing at a facility for individuals with mental retardation (MR). Of 547 institutionalized individuals with MR, 72 (13.2%) had moderate to high myopia defined as a visual acuity of minus 3 diopters or more. It should be noted that our institution does not specifically select for people with visual impairment; rather, the facility serves people with a primary diagnosis of MR. Sixty-five of 72 (90.3%) myopic individuals identified were available for cytogenetic analysis. Seventeen (26.2%) of these patients had trisomy 21. Down syndrome (DS) is well known to be associated with eye abnormalities, including myopia. Of 48 individuals with moderate to high myopia not having DS, 5 (10.4%) were shown to have deletions of 17p11.2. This is a high prevalence considering the relative rarity of SMS. By contrast, in a randomized sample of 48 patients without significant myopia at the same facility, we found no individuals with deletion 17p11.2. We conclude that the diagnosis of SMS should be considered in any non-Down syndrome individual having MR and myopia, and that ophthalmologists serving people with MR should be made aware of this deletion syndrome. Furthermore, our results suggest that significant numbers of people having SMS could be identified through selective institutional screening of patients having a combination of MR and moderate to severe myopia.

  12. Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2)

    SciTech Connect

    Greenberg, F.; Lewis, R.A.; Potocki, L.

    1996-03-29

    Smith-Magenis syndrome (SMS) is a multiple congenital anomaly, mental retardation (MCA/MR) syndrome associated with deletion of chromosome 17 band p11.2. As part of a multi-disciplinary clinical, cytogenetic, and molecular approach to SMS, detailed clinical studies including radiographic neurologic, developmental, ophthalmologic, otolaryngologic, and audiologic evaluations were performed on 27 SMS patients. Significant findings include otolaryngologic abnormalities in 94%, eye abnormalities in 85%, sleep abnormalities (especially reduced REM sleep) in 75%, hearing impairment in 68% (approximately 65% conductive and 35% sensorineural), scoliosis in 65% brain abnormalities (predominantly ventriculomegaly) in 52%, cardiac abnormalities in at least 37%, renal anomalies (especially duplication of the collecting system) in 35%, low thyroxine levels in 29%, low immunoglobulin levels in 23%, and forearm abnormalities in 16%. The measured IQ ranged between 20-78, most patients falling in the moderate range of mental retardation at 40-54, although several patients scored in the mild or borderline range. The frequency of these many abnormalities in SMS suggests that patients should be evaluated thoroughly for associated complications both at the time of diagnosis and at least annually thereafter. 42 refs., 2 figs., 3 tabs.

  13. Detection of submicroscopic deletions in band 17p13 in patients with the Miller-Dieker syndrome

    PubMed Central

    Schwartz, Charles E.; Johnson, John P.; Holycross, Bridget; Mandeville, Tracy M.; Sears, Tena S.; Graul, Elizabeth A.; Carey, John C.; Schroer, Richard J.; Phelan, Mary C.; Szollar, Judith; Flannery, David B.; Stevenson, Roger E.

    1988-01-01

    The Miller-Dieker syndrome (MDS), a syndrome with lissencephaly, distinctive craniofacial features, growth impairment, and profound developmental failure, has been associated with a deletion of the distal part of chromosome band 17p13. A minority of patients with the syndrome do not have a deletion detectable with current cytogenetic techniques. Using three highly polymorphic DNA probes (pYNZ22, pYNH37.3, and p144D6) we have detected microdeletions in three MDS patients, two of whom had no visible abnormalities of chromosome 17. Loci defined by two of the DNA probes, pYNZ22 and pYNH37.3, were deleted in all three patients. The most distal locus, defined by p144D6, was present in one MDS patient, possibly defining the distal limits of the MDS region in band 17pl3.3. None of these loci were absent in one case of lissencephaly without MDS. ImagesFigure 1Figure 2Figure 3Figure 4 PMID:2903661

  14. Molecular Alterations of TP53 are a Defining Feature of Ovarian High-Grade Serous Carcinoma: A Rereview of Cases Lacking TP53 Mutations in The Cancer Genome Atlas Ovarian Study.

    PubMed

    Vang, Russell; Levine, Douglas A; Soslow, Robert A; Zaloudek, Charles; Shih, Ie-Ming; Kurman, Robert J

    2016-01-01

    The Cancer Genome Atlas has reported that 96% of ovarian high-grade serous carcinomas (HGSCs) have TP53 somatic mutations suggesting that mutation of this gene is a defining feature of this neoplasm. In the current study, 5 gynecologic pathologists independently evaluated hematoxylin and eosin slides of 14 available cases from The Cancer Genome Atlas classified as HGSC that lacked a TP53 mutation. The histologic diagnoses rendered by these pathologists and the accompanying molecular genetic data are the subject of this report. Only 1 case (Case 5), which contained a homozygous deletion of TP53, had unanimous interobserver agreement for a diagnosis of pure HGSC. In 1 case (Case 3), all 5 observers (100%) rendered a diagnosis of HGSC; however, 3 observers (60%) noted that the histologic features were not classic for HGSC and suggested this case may have arisen from a low-grade serous carcinoma (arisen from an alternate pathway compared with the usual HGSC). In 2 cases (Cases 4 and 12), only 3 observers (60%) in each case, respectively, interpreted it as having a component of HGSC. In the remaining 10 (71%) of tumors (Cases 1, 2, 6-11, 13, and 14), the consensus diagnosis was not HGSC, with individual diagnoses including low-grade serous carcinoma, high-grade endometrioid carcinoma, HGSC, metastatic carcinoma, clear cell carcinoma, atypical proliferative (borderline) serous tumor, and adenocarcinoma, not otherwise specified. Therefore, 13 (93%) of the tumors (Cases 1-4 and 6-14) were either not a pure HGSC or represented a diagnosis other than HGSC, all with molecular results not characteristic of HGSC. Accordingly, our review of the TP53 wild-type HGSCs reported in The Cancer Genome Atlas suggests that 100% of de novo HGSCs contain TP53 somatic mutations or deletions, with the exception of the rare HGSCs that develop from a low-grade serous tumor precursor. We, therefore, propose that lack of molecular alterations of TP53 are essentially inconsistent with the

  15. c-Myc inhibits TP53INP1 expression via promoter methylation in esophageal carcinoma

    SciTech Connect

    Weng, Wenhao; Yang, Qinyuan; Huang, Miaolong; Qiao, Yongxia; Xie, Yuan; Yu, Yongchun; Jing, An; Li, Zhi

    2011-02-11

    Research highlights: {yields} TP53INP1 expression is down-regulated in esophageal carcinoma and is associated with CGI-131 methylation. {yields} Inhibition of CGI-131 methylation upregulates TP53INP1 expression in ESCC cell lines. {yields} Ectopic expression of TP53INP1 inhibits growth of ESCC cells by inducing apoptosis and inhibiting cell cycle progression. {yields} c-Myc binds to the promoter of TP53INP1 in vivo and vitro and recruits DNMT3A to TP53INP1 promoter for CGI-131 methylation. -- Abstract: Tumor protein p53-induced nuclear protein 1 (TP53INP1) is a well known stress-induced protein that plays a role in both cell cycle arrest and p53-mediated apoptosis. Loss of TP53INP1 expression has been reported in human melanoma, breast carcinoma, and gastric cancer. However, TP53INP1 expression and its regulatory mechanism in esophageal squamous cell carcinoma (ESCC) remain unclear. Our findings are in agreement with previous reports in that the expression of TP53INP1 was downregulated in 28% (10/36 cases) of ESCC lesions, and this was accompanied by significant promoter methylation. Overexpression of TP53INP1 induced G1 cell cycle arrest and increased apoptosis in ESCC cell lines (EC-1, EC-109, EC-9706). Furthermore, our study showed that the oncoprotein c-Myc bound to the core promoter of TP53INP1 and recruited DNA methyltransferase 3A to methylate the local promoter region, leading to the inhibition of TP53INP1 expression. Our findings revealed that TP53INP1 is a tumor suppressor in ESCC and that c-Myc-mediated DNA methylation-associated silencing of TP53INP1 contributed to the pathogenesis of human ESCC.

  16. TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis.

    PubMed

    Loghavi, Sanam; Al-Ibraheemi, Alyaa; Zuo, Zhuang; Garcia-Manero, Guillermo; Yabe, Mariko; Wang, Sa A; Kantarjian, Hagop M; Yin, Cameron C; Miranda, Roberto N; Luthra, Raja; Medeiros, L Jeffrey; Bueso-Ramos, Carlos E; Khoury, Joseph D

    2015-10-01

    Bone marrow (BM) fibrosis is associated with poor prognosis in patients with de novo myelodysplastic syndromes (MDS). TP53 mutations and TP53 (p53) overexpression in MDS are also associated with poor patient outcomes. The prevalence and significance of TP53 mutations and TP53 overexpression in MDS with fibrosis are unknown. We studied 67 patients with de novo MDS demonstrating moderate to severe reticulin fibrosis (MDS-F). Expression of TP53 was evaluated in BM core biopsy specimens using dual-colour CD34/TP53 immunohistochemistry with computer-assisted image analysis. Mutation analysis was performed using next-generation sequencing, or Sanger sequencing methods. TP53 mutations were present in 47·1% of cases. TP53 mutation was significantly associated with TP53 expression (P = 0·0294). High levels of TP53 expression (3 +  in ≥10% cells) were associated with higher BM blast counts (P = 0·0149); alterations of chromosomes 5 (P = 0·0009) or 7 (P = 0·0141); complex karyotype (P = 0·0002); high- and very-high risk IPSS-R groups (P = 0·009); and TP53 mutations (P = 0·0003). High TP53 expression independently predicted shorter overall survival (OS) by multivariate analysis (P = <0·001). Expression of TP53 by CD34-positive cells was associated with shorter OS and leukaemia-free survival (P = 0·0428). TP53 overexpression is a predictor of poor outcome in patients with MDS-F.

  17. TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer.

    PubMed

    Chien, Jeremy; Sicotte, Hugues; Fan, Jian-Bing; Humphray, Sean; Cunningham, Julie M; Kalli, Kimberly R; Oberg, Ann L; Hart, Steven N; Li, Ying; Davila, Jaime I; Baheti, Saurabh; Wang, Chen; Dietmann, Sabine; Atkinson, Elizabeth J; Asmann, Yan W; Bell, Debra A; Ota, Takayo; Tarabishy, Yaman; Kuang, Rui; Bibikova, Marina; Cheetham, R Keira; Grocock, Russell J; Swisher, Elizabeth M; Peden, John; Bentley, David; Kocher, Jean-Pierre A; Kaufmann, Scott H; Hartmann, Lynn C; Shridhar, Viji; Goode, Ellen L

    2015-08-18

    To determine early somatic changes in high-grade serous ovarian cancer (HGSOC), we performed whole genome sequencing on a rare collection of 16 low stage HGSOCs. The majority showed extensive structural alterations (one had an ultramutated profile), exhibited high levels of p53 immunoreactivity, and harboured a TP53 mutation, deletion or inactivation. BRCA1 and BRCA2 mutations were observed in two tumors, with nine showing evidence of a homologous recombination (HR) defect. Combined Analysis with The Cancer Genome Atlas (TCGA) indicated that low and late stage HGSOCs have similar mutation and copy number profiles. We also found evidence that deleterious TP53 mutations are the earliest events, followed by deletions or loss of heterozygosity (LOH) of chromosomes carrying TP53, BRCA1 or BRCA2. Inactivation of HR appears to be an early event, as 62.5% of tumours showed a LOH pattern suggestive of HR defects. Three tumours with the highest ploidy had little genome-wide LOH, yet one of these had a homozygous somatic frame-shift BRCA2 mutation, suggesting that some carcinomas begin as tetraploid then descend into diploidy accompanied by genome-wide LOH. Lastly, we found evidence that structural variants (SV) cluster in HGSOC, but are absent in one ultramutated tumor, providing insights into the pathogenesis of low stage HGSOC.

  18. TP53, MSH4, and LATS1 germline mutations in a family with clustering of nervous system tumors.

    PubMed

    Kim, Young-Ho; Ohta, Takashi; Oh, Ji Eun; Le Calvez-Kelm, Florence; McKay, James; Voegele, Catherine; Durand, Geoffroy; Mittelbronn, Michel; Kleihues, Paul; Paulus, Werner; Ohgaki, Hiroko

    2014-09-01

    Exome DNA sequencing of blood samples from a Li-Fraumeni family with a TP53 germline mutation (codon 236 deletion) and multiple nervous system tumors revealed additional germline mutations. Missense mutations in the MSH4 DNA repair gene (c.2480T>A; p.I827N) were detected in three patients with gliomas (two anaplastic astrocytomas, two glioblastomas). Two family members without a TP53 germline mutation who developed peripheral schwannomas also carried the MSH4 germline mutation, and in addition, a germline mutation of the LATS1 gene (c.286C>T; p.R96W). LATS1 is a downstream mediator of the NF2, but has not previously been found to be related to schwannomas. We therefore screened the entire coding sequence of the LATS1 gene in 65 sporadic schwannomas, 12 neurofibroma/schwannoma hybrid tumors, and 4 cases of schwannomatosis. We only found a single base deletion at codon 827 (exon 5) in a spinal schwannoma, leading to a stop at codon 835 (c.2480delG; p.*R827Kfs*8). Mutational loss of LATS1 function may thus play a role in some inherited schwannomas, but only exceptionally in sporadic schwannomas. This is the first study reporting a germline MSH4 mutation. Since it was present in all patients, it may have contributed to the subsequent acquisition of TP53 and LATS1 germline mutations.

  19. Subgroup-Specific Prognostic Implications of TP53 Mutation in Medulloblastoma

    PubMed Central

    Zhukova, Nataliya; Ramaswamy, Vijay; Remke, Marc; Pfaff, Elke; Shih, David J.H.; Martin, Dianna C.; Castelo-Branco, Pedro; Baskin, Berivan; Ray, Peter N.; Bouffet, Eric; von Bueren, André O.; Jones, David T.W.; Northcott, Paul A.; Kool, Marcel; Sturm, Dominik; Pugh, Trevor J.; Pomeroy, Scott L.; Cho, Yoon-Jae; Pietsch, Torsten; Gessi, Marco; Rutkowski, Stefan; Bognar, Laszlo; Klekner, Almos; Cho, Byung-Kyu; Kim, Seung-Ki; Wang, Kyu-Chang; Eberhart, Charles G.; Fevre-Montange, Michelle; Fouladi, Maryam; French, Pim J.; Kros, Max; Grajkowska, Wieslawa A.; Gupta, Nalin; Weiss, William A.; Hauser, Peter; Jabado, Nada; Jouvet, Anne; Jung, Shin; Kumabe, Toshihiro; Lach, Boleslaw; Leonard, Jeffrey R.; Rubin, Joshua B.; Liau, Linda M.; Massimi, Luca; Pollack, Ian F.; Shin Ra, Young; Van Meir, Erwin G.; Zitterbart, Karel; Schüller, Ulrich; Hill, Rebecca M.; Lindsey, Janet C.; Schwalbe, Ed C.; Bailey, Simon; Ellison, David W.; Hawkins, Cynthia; Malkin, David; Clifford, Steven C.; Korshunov, Andrey; Pfister, Stefan; Taylor, Michael D.; Tabori, Uri

    2013-01-01

    Purpose Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles. Patients and Methods We determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas. Results TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors. Conclusion Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients. PMID:23835706

  20. TP53 status and response to chemotherapy in breast cancer.

    PubMed

    Bertheau, Philippe; Espié, Marc; Turpin, Elisabeth; Lehmann, Jacqueline; Plassa, Louis-François; Varna, Mariana; Janin, Anne; de Thé, Hugues

    2008-01-01

    Despite its central role in the control of apoptosis, senescence and cell cycle arrest, the tumor suppressor protein p53 remains an enigma for its possible role in predicting response to chemotherapy in cancer patients. Many studies remained inconclusive, others showed a better response for tumors with normal p53, and some recent studies showed adverse effects of normal p53 for response to treatment. p53 is not only a powerful pro-apoptotic factor in response to drug-induced DNA damages but also a potential inducer of cell cycle arrest, protecting tumor cells from further cytotoxic damages. Our review describes the classical as well as the more recent concepts. In order to draw definite conclusions, future works should use more reliable methods to assess the TP53 status and should address more homogeneous tumor subpopulations treated with homogeneous chemotherapy regimens.

  1. Targeting acute myeloid leukemia with TP53-independent vosaroxin.

    PubMed

    Benton, Christopher B; Ravandi, Farhad

    2017-01-01

    Vosaroxin is a quinolone compound that intercalates DNA and induces TP53-independent apoptosis, demonstrating activity against acute myeloid leukemia (AML) in Phase I-III trials. Here, we examine vosaroxin's mechanism of action and pharmacology, and we review its use in AML to date, focusing on details of individual clinical trials. Most recently, when combined with cytarabine in a randomized Phase III trial (VALOR), vosaroxin improved outcomes versus cytarabine alone for relapsed/refractory AML in patients older than 60 years and for patients in early relapse. We consider its continued role in the context of a multifaceted strategy against AML, including its current use in clinical trials. Prospective use will define its role in the evolving landscape of AML therapy.

  2. Hypoventilation in REM sleep in a case of 17p11.2 deletion (Smith-Magenis syndrome).

    PubMed

    Leoni, Chiara; Cesarini, Laura; Dittoni, Serena; Battaglia, Domenica; Novelli, Antonio; Bernardini, Laura; Losurdo, Anna; Vollono, Catello; Testani, Elisa; Della Marca, Giacomo; Zampino, Giuseppe

    2010-03-01

    We describe a 2-year-old baby affected by Smith-Magenis syndrome (SMS), due to 17p11.2 deletion, who presented repeated episodes of hemoglobin desaturation during REM sleep. The boy, aged 14 months, presented a phenotype characterized by psychomotor delay, right posterior plagiocephaly, telecanthus, strabismus, upslanting palpebral fissures, broad hypoplastic nasal bridge, short philtrum, deep ring shaped skin creases around the limbs, proximal syndactyly, bilateral hypoacusia. Polysomnographic (PSG) recording showed episodes of REM-related hypoventilation (hemoglobin desaturations without apneas or hypopneas). Sleep disorders are present in almost all the cases of SMS, but very few reports describe the sleep-related respiratory patterns. The finding of REM hypoventilation in SMS does not allow an unequivocal interpretation. It could reflect a subclinical restrictive respiratory impairment or, alternatively, an impairment of central respiratory control during REM sleep. In SMS children, respiratory abnormalities during sleep, and in particular during REM sleep, may cause sleep disruption, reduction of time spent in REM sleep, and daytime sleepiness. We therefore suggest that some sleep abnormalities described in SMS could be consequent to Sleep Disordered Breathing, and in particular to REM hypoventilation. Sleep studies in SMS should include the recording of respiratory parameters.

  3. Roles of TP53 in determining therapeutic sensitivity, growth, cellular senescence, invasion and metastasis.

    PubMed

    McCubrey, James A; Lertpiriyapong, Kvin; Fitzgerald, Timothy L; Martelli, Alberto M; Cocco, Lucio; Rakus, Dariusz; Gizak, Agnieszka; Libra, Massimo; Cervello, Melchiorre; Montalto, Guiseppe; Yang, Li V; Abrams, Stephen L; Steelman, Linda S

    2017-01-01

    TP53 is a critical tumor suppressor gene that regulates cell cycle progression, apoptosis, cellular senescence and many other properties critical for control of normal cellular growth and death. Due to the pleiotropic effects that TP53 has on gene expression and cellular physiology, mutations at this tumor suppressor gene result in diverse physiological effects. T53 mutations are frequently detected in numerous cancers. The expression of TP53 can be induced by various agents used to treat cancer patients such as chemotherapeutic drugs and ionizing radiation. Radiation will induce Ataxia telangiectasia mutated (ATM) and other kinases that results in the phosphorylation and activation of TP53. TP53 is also negatively regulated by other mechanisms, such as ubiquitination by ligases such as MDM2. While TP53 has been documented to control the expression of many "classical" genes (e.g., p21(Cip-1), PUMA, Bax) by transcriptional mechanisms for quite some time, more recently TP53 has been shown to regulate microRNA (miR) gene expression. Different miRs can promote oncogenesis (oncomiR) whereas others act to inhibit tumor progression (tumor suppressor miRs). Targeted therapies to stabilize TP53 have been developed by various approaches, MDM2/MDM4 inhibitors have been developed to stabilize TP53 in TP53-wild type (WT) tumors. In addition, small molecules have been isolated that will reactivate certain mutant TP53s. Both of these types of inhibitors are in clinical trials. Understanding the actions of TP53 may yield novel approaches to suppress cancer, aging and other health problems.

  4. Molecular characterization of near-complete trisomy 17p syndrome from inverted duplication in association with cryptic deletion of 17pter.

    PubMed

    Park, Chang-Hun; Kim, Hee-Jin; Lee, Seung-Tae; Seo, Jeong Meen; Kim, Sun-Hee

    2014-03-10

    Trisomy of the short arm of chromosome 17 (T17P) is a genomic disorder presenting with growth retardation, motor and mental retardation and constitutional physical anomalies including congenital heart defects. Here we report a case of near-complete T17P of which the genomic dosage aberrations were delineated by chromosomal microarray along with conventional diagnostic modalities. A 9-year-old Korean boy was admitted because of esophageal obstruction. He showed clinical manifestations of T17P, along with atypical features of scoliosis, corpus callosum agenesis, and seizure. Chromosome analyses revealed an inverted duplication of the chromosomal segment between 17p11.2 and 17p13.3. Chromosomal microarray revealed a duplication of the most of the short arm of chromosome 17 (size ~19.09 Mb) along with a cryptic deletion of a small segment of 17p terminal end (17pter) (~261 Kb). This is the first report of molecular characterization of near-complete T17P from inverted duplication in association with 17pter microdeletion. The fine delineation of the extent of genomic aberration by SNP-based microarray could help us better understand the molecular mechanism and genotype-phenotype correlations in T17P syndrome.

  5. The TP53 Codon 72 Polymorphism and Risk of Sporadic Prostate Cancer among Iranian Patients

    PubMed Central

    BABAEI, Farhad; AHMADI, Seyed Ali; ABIRI, Ramin; REZAEI, Farhad; NASERI, Maryam; MAHMOUDI, Mahmoud; NATEGH, Rakhshande; MOKHTARI AZAD, Talat

    2014-01-01

    Abstract Background The TP53 gene is one of the most frequently mutated genes amongst human malignancies, particularly TP53 codon 72 polymorphism. Furthermore, an association between the TP53 codon 72 variants and prostate cancer has been reported in several studies. Although some studies have indicated an association between the TP53 Arg/Arg variant and an increased risk for prostate cancer, other studies have shown a positive correlation between the TP53 Pro/Pro genotype instead. Therefore, to clarify if this polymorphism is associated with an increased risk of prostate cancer in Iranian men, we conducted a case-control study of 40 sporadic prostate cancer patients and 80 benign prostate hyperplasia cases. Methods The TP53 codon 72 was genotyped using an allele specific PCR. Results A significant association between the TP53 codon 72 genotype and prostate cancer risk was found (OR = 6.8, 95% CI = [1.8-25.1], P = 0.005). However, the results of this study did not support an association between age, the Gleason score nor TP53 genotype at codon 72 in prostate cancer patients. Conclusions TP53 codon 72 polymorphism may have a great impact in the development of prostate cancer. PMID:26005655

  6. TP53 Mutations and Survival in Osteosarcoma Patients: A Meta-Analysis of Published Data

    PubMed Central

    Chen, Zhe; Guo, Jiayi; Zhang, Kun; Guo, Yanxing

    2016-01-01

    Several research groups have examined the association between TP53 mutations and prognosis in human osteosarcoma. However, the results were controversial. The purpose of this study was to evaluate the prognostic value of TP53 mutations in osteosarcoma patients. A meta-analysis was conducted with all eligible studies which quantitatively evaluated the relationship between TP53 mutations and clinical outcome of osteosarcoma patients. Eight studies with a total of 210 patients with osteosarcoma were included in this meta-analysis. The risk ratio (RR) with a 95% confidence interval (95% CI) was calculated to assess the effect of TP53 mutations on 2-year overall survival. The quantitative synthesis of 8 published studies showed that TP53 mutations were associated with 2-year overall survival in osteosarcoma patients. These data suggested that TP53 mutations had an unfavorable impact on 2-year overall survival when compared to the counterparts with wild type (WT) TP53 (RR: 1.79; 95% CI: 1.12 to 2.84; P = 0.01; I2 = 0%). There was no between-study heterogeneity. TP53 mutations are an effective prognostic marker for survival of patients with osteosarcoma. However, further large-scale prospective trials should be performed to clarify the prognostic value of TP53 mutations on 3- or 5-year survival in osteosarcoma patients. PMID:27239089

  7. Prevalence of germline TP53 mutations in HER2+ breast cancer patients.

    PubMed

    Rath, Michelle G; Masciari, Serena; Gelman, Rebecca; Miron, Alexander; Miron, Penelope; Foley, Kathleen; Richardson, Andrea L; Krop, Ian E; Verselis, Sigitas J; Dillon, Deborah A; Garber, Judy E

    2013-05-01

    Breast cancer is the most frequent tumor in Li-Fraumeni syndrome (LFS), a rare inherited cancer syndrome associated with germline mutations in the TP53 gene. Recent data show that breast cancer in germline TP53 mutation carriers is commonly HER2+ (63-83 %). We assessed the prevalence of germline TP53 mutations in a cohort of women with HER2+ breast cancer diagnosed age ≤50 years. We identified blood specimens from 213 women with primary invasive HER2+ breast cancer age ≤50 years from a single center. Exon grouping analysis sequencing and multiplex ligation-dependent probe amplification techniques were used to screen for germline TP53 mutations. Among 213 women with HER2+ breast cancer age ≤50 years, 3 (ages at diagnosis 23, 32, 44 years) were found to carry a TP53 mutation (1.4 %, 95 % CI 0.3-4.1 %). ER/PR status was not uniform. Two TP53 carriers met Chompret criteria for LFS; none met classic LFS criteria. Although two-thirds of breast cancers in women with TP53 mutations are HER2+, we observed a low prevalence of germline TP53 mutations among unselected young women with HER2+ breast cancer. Given the potential clinical impact, consideration of germline TP53 testing should be given to young women with HER2+ breast cancer, especially if family cancer history is notable.

  8. TP53 Mutations and Survival in Osteosarcoma Patients: A Meta-Analysis of Published Data.

    PubMed

    Chen, Zhe; Guo, Jiayi; Zhang, Kun; Guo, Yanxing

    2016-01-01

    Several research groups have examined the association between TP53 mutations and prognosis in human osteosarcoma. However, the results were controversial. The purpose of this study was to evaluate the prognostic value of TP53 mutations in osteosarcoma patients. A meta-analysis was conducted with all eligible studies which quantitatively evaluated the relationship between TP53 mutations and clinical outcome of osteosarcoma patients. Eight studies with a total of 210 patients with osteosarcoma were included in this meta-analysis. The risk ratio (RR) with a 95% confidence interval (95% CI) was calculated to assess the effect of TP53 mutations on 2-year overall survival. The quantitative synthesis of 8 published studies showed that TP53 mutations were associated with 2-year overall survival in osteosarcoma patients. These data suggested that TP53 mutations had an unfavorable impact on 2-year overall survival when compared to the counterparts with wild type (WT) TP53 (RR: 1.79; 95% CI: 1.12 to 2.84; P = 0.01; I (2) = 0%). There was no between-study heterogeneity. TP53 mutations are an effective prognostic marker for survival of patients with osteosarcoma. However, further large-scale prospective trials should be performed to clarify the prognostic value of TP53 mutations on 3- or 5-year survival in osteosarcoma patients.

  9. MYC, FBXW7 and TP53 copy number variation and expression in Gastric Cancer

    PubMed Central

    2013-01-01

    Background MYC deregulation is a common event in gastric carcinogenesis, usually as a consequence of gene amplification, chromosomal translocations, or posttranslational mechanisms. FBXW7 is a p53-controlled tumor-suppressor that plays a role in the regulation of cell cycle exit and reentry via MYC degradation. Methods We evaluated MYC, FBXW7, and TP53 copy number, mRNA levels, and protein expression in gastric cancer and paired non-neoplastic specimens from 33 patients and also in gastric adenocarcinoma cell lines. We also determined the invasion potential of the gastric cancer cell lines. Results MYC amplification was observed in 51.5% of gastric tumor samples. Deletion of one copy of FBXW7 and TP53 was observed in 45.5% and 21.2% of gastric tumors, respectively. MYC mRNA expression was significantly higher in tumors than in non-neoplastic samples. FBXW7 and TP53 mRNA expression was markedly lower in tumors than in paired non-neoplastic specimens. Moreover, deregulated MYC and FBXW7 mRNA expression was associated with the presence of lymph node metastasis and tumor stage III-IV. Additionally, MYC immunostaining was more frequently observed in intestinal-type than diffuse-type gastric cancers and was associated with MYC mRNA expression. In vitro studies showed that increased MYC and reduced FBXW7 expression is associated with a more invasive phenotype in gastric cancer cell lines. This result encouraged us to investigate the activity of the gelatinases MMP-2 and MMP-9 in both cell lines. Both gelatinases are synthesized predominantly by stromal cells rather than cancer cells, and it has been proposed that both contribute to cancer progression. We observed a significant increase in MMP-9 activity in ACP02 compared with ACP03 cells. These results confirmed that ACP02 cells have greater invasion capability than ACP03 cells. Conclusion In conclusion, FBXW7 and MYC mRNA may play a role in aggressive biologic behavior of gastric cancer cells and may be a useful

  10. TP53 mutations induced by BPDE in Xpa-WT and Xpa-Null human TP53 knock-in (Hupki) mouse embryo fibroblasts

    PubMed Central

    Kucab, Jill E.; van Steeg, Harry; Luijten, Mirjam; Schmeiser, Heinz H.; White, Paul A.; Phillips, David H.; Arlt, Volker M.

    2015-01-01

    Somatic mutations in the tumour suppressor gene TP53 occur in more than 50% of human tumours; in some instances exposure to environmental carcinogens can be linked to characteristic mutational signatures. The Hupki (human TP53 knock-in) mouse embryo fibroblast (HUF) immortalization assay (HIMA) is a useful model for studying the impact of environmental carcinogens on TP53 mutagenesis. In an effort to increase the frequency of TP53-mutated clones achievable in the HIMA, we generated nucleotide excision repair (NER)-deficient HUFs by crossing the Hupki mouse with an Xpa-knockout (Xpa-Null) mouse. We hypothesized that carcinogen-induced DNA adducts would persist in the TP53 sequence of Xpa-Null HUFs leading to an increased propensity for mismatched base pairing and mutation during replication of adducted DNA. We found that Xpa-Null Hupki mice, and HUFs derived from them, were more sensitive to the environmental carcinogen benzo[a]pyrene (BaP) than their wild-type (Xpa-WT) counterparts. Following treatment with the reactive metabolite of BaP, benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), Xpa-WT and Xpa-Null HUF cultures were subjected to the HIMA. A significant increase in TP53 mutations on the transcribed strand was detected in Xpa-Null HUFs compared to Xpa-WT HUFs, but the TP53-mutant frequency overall was not significantly different between the two genotypes. BPDE induced mutations primarily at G:C base pairs, with approximately half occurring at CpG sites, and the predominant mutation type was G:C > T:A in both Xpa-WT and Xpa-Null cells. Further, several of the TP53 mutation hotspots identified in smokers’ lung cancer were mutated by BPDE in HUFs (codons 157, 158, 245, 248, 249, 273). Therefore, the pattern and spectrum of BPDE-induced TP53 mutations in the HIMA are consistent with TP53 mutations detected in lung tumours of smokers. While Xpa-Null HUFs exhibited increased sensitivity to BPDE-induced damage on the transcribed strand, NER-deficiency did not

  11. TP53 mutations induced by BPDE in Xpa-WT and Xpa-Null human TP53 knock-in (Hupki) mouse embryo fibroblasts.

    PubMed

    Kucab, Jill E; van Steeg, Harry; Luijten, Mirjam; Schmeiser, Heinz H; White, Paul A; Phillips, David H; Arlt, Volker M

    2015-03-01

    Somatic mutations in the tumour suppressor gene TP53 occur in more than 50% of human tumours; in some instances exposure to environmental carcinogens can be linked to characteristic mutational signatures. The Hupki (human TP53 knock-in) mouse embryo fibroblast (HUF) immortalization assay (HIMA) is a useful model for studying the impact of environmental carcinogens on TP53 mutagenesis. In an effort to increase the frequency of TP53-mutated clones achievable in the HIMA, we generated nucleotide excision repair (NER)-deficient HUFs by crossing the Hupki mouse with an Xpa-knockout (Xpa-Null) mouse. We hypothesized that carcinogen-induced DNA adducts would persist in the TP53 sequence of Xpa-Null HUFs leading to an increased propensity for mismatched base pairing and mutation during replication of adducted DNA. We found that Xpa-Null Hupki mice, and HUFs derived from them, were more sensitive to the environmental carcinogen benzo[a]pyrene (BaP) than their wild-type (Xpa-WT) counterparts. Following treatment with the reactive metabolite of BaP, benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), Xpa-WT and Xpa-Null HUF cultures were subjected to the HIMA. A significant increase in TP53 mutations on the transcribed strand was detected in Xpa-Null HUFs compared to Xpa-WT HUFs, but the TP53-mutant frequency overall was not significantly different between the two genotypes. BPDE induced mutations primarily at G:C base pairs, with approximately half occurring at CpG sites, and the predominant mutation type was G:C>T:A in both Xpa-WT and Xpa-Null cells. Further, several of the TP53 mutation hotspots identified in smokers' lung cancer were mutated by BPDE in HUFs (codons 157, 158, 245, 248, 249, 273). Therefore, the pattern and spectrum of BPDE-induced TP53 mutations in the HIMA are consistent with TP53 mutations detected in lung tumours of smokers. While Xpa-Null HUFs exhibited increased sensitivity to BPDE-induced damage on the transcribed strand, NER-deficiency did not enhance TP53

  12. A 1.5-Mb deletion in 17p11.2-p12 is frequently observed in Italian families with hereditary neuropathy with liability to pressure palsies

    SciTech Connect

    Lorenzetti, D.; Pandolfo, M. |; Pareyson, D.; Sghirlanzoni, A.; Di Donato, S.; Roa, B.B.; Abbas, N.E.; Lupski, J.R.

    1995-01-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathies. A 1.5-Mb deletion in chromosome 17p11.2-p12 has been associated with HNPP. Duplication of the same 1.5-Mb region is known to be associated with Charcot-Marie-Tooth disease type 1 (CMT1A), a more severe peripheral neuropathy characterized by symmetrically slowed nerve conduction velocity (NCV). The CMT1A duplication and HNPP deletion appear to be the reciprocal products of a recombination event involving a repeat element (CMT1A-REP) that flanks the 1.5-Mb region involved in the duplication/deletion. Patients from nine unrelated Italian families who were diagnosed with HNPP on the basis of clinical, electrophysiological, and histological evaluations were analyzed by molecular methods for DNA deletion on chromosome 17p. In all nine families, Southern analysis using a CMT1A-REP probe detected a reduced hybridization signal of a 6.0-kb EcoRI fragment mapping within the distal CMT1A-REP, indicating deletion of one copy of CMT1A-REP in these HNPP patients. Families were also typed with a polymorphic (CA){sub n} repeat and with RFLPs corresponding to loci D17S122, D17S125, and D17S61, which all map within the deleted region. Lack of allelic transmission from affected parent to affected offspring was observed in four informative families, providing an independent indication for deletion. Furthermore, pulsed-field gel electrophoresis analysis of SacII-digested genomic DNA detected junction fragments specific to the 1.5-Mb HNPP deletion in seven of nine Italian families included in this study. These findings suggest that a 1.5-Mb deletion on 17p11.2-p12 is the most common mutation associated with HNPP. 51 refs., 5 figs., 1 tab.

  13. A 1.5-Mb deletion in 17p11.2-p12 is frequently observed in Italian families with hereditary neuropathy with liability to pressure palsies.

    PubMed Central

    Lorenzetti, D; Pareyson, D; Sghirlanzoni, A; Roa, B B; Abbas, N E; Pandolfo, M; Di Donato, S; Lupski, J R

    1995-01-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathies. A 1.5-Mb deletion in chromosome 17p11.2-p12 has been associated with HNPP. Duplication of the same 1.5-Mb region is known to be associated with Charcot-Marie-Tooth disease type 1 (CMT1A), a more severe peripheral neuropathy characterized by symmetrically slowed nerve conduction velocity (NCV). The CMT1A duplication and HNPP deletion appear to be the reciprocal products of a recombination event involving a repeat element (CMT1A-REP) that flanks the 1.5-Mb region involved in the duplication/deletion. Patients from nine unrelated Italian families who were diagnosed with HNPP on the basis of clinical, electrophysiological, and histological evaluations were analyzed by molecular methods for DNA deletion on chromosome 17p. In all nine families, Southern analysis using a CMT1A-REP probe detected a reduced hybridization signal of a 6.0-kb EcoRI fragment mapping within the distal CMT1A-REP, indicating deletion of one copy of CMT1A-REP in these HNPP patients. Families were also typed with a polymorphic (CA)n repeat and with RFLPs corresponding to loci D17S122, D17S125, and D17S61, which all map within the deleted region. Lack of allelic transmission from affected parent to affected offspring was observed in four informative families, providing an independent indication for deletion. Furthermore, pulsed-field gel electrophoresis analysis of SacII-digested genomic DNA detected junction fragments specific to the 1.5-Mb HNPP deletion in seven of nine Italian families included in this study. These findings suggest that a 1.5-Mb deletion on 17p11.2-p12 is the most common mutation associated with HNPP. Images Figure 2 Figure 4 Figure 5 PMID:7825607

  14. TP53/MicroRNA Interplay in Hepatocellular Carcinoma

    PubMed Central

    Pollutri, Daniela; Gramantieri, Laura; Bolondi, Luigi; Fornari, Francesca

    2016-01-01

    The role of microRNAs as oncogenes and tumor suppressor genes has emerged in several cancers, including hepatocellular carcinoma (HCC). The pivotal tumor suppressive role of p53-axis is indicated by the presence of inactivating mutations in TP53 gene in nearly all cancers. A close interaction between these two players, as well as the establishment of complex p53/miRNAs loops demonstrated the strong contribution of p53-effector miRNAs in enhancing the p53-mediated tumor suppression program. On the other hand, the direct and indirect targeting of p53, as well as the regulation of its stability and activity by specific microRNAs, underlie the importance of the fine-tuning of p53 pathway, affecting the cell fate of damaged/transformed cells. The promising results of miRNAs-based therapeutic approaches in preclinical studies and their entrance in clinical trials demonstrate the feasibility of this strategy in several diseases, including cancer. Molecularly targeted drugs approved so far for HCC treatment show intrinsic or acquired resistances with disease progression in many cases, therefore the identification of effective and non-toxic agents for the treatment of HCC is actually an unmet clinical need. The knowledge of p53/miRNA inter-relations in HCC may provide useful elements for the identification of novel combined approaches in the context of the “personalized-medicine” era. PMID:27918441

  15. Bioinformatic dissecting of TP53 regulation pathway underlying butyrate-induced histone modification in epigenetic regulation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Butyrate affects cell proliferation, differentiation and motility. Butyrate inhibits histone deacetylase (HDAC) activities and induces cell cycle arrest and apoptosis. TP53 is one of the most active upstream regulators discovered by IPA in our RNA sequencing data set. The TP53 signaling pathway pl...

  16. Alterations of the TP53 Gene in Gastric and Esophageal Carcinogenesis

    PubMed Central

    Bellini, Marilanda Ferreira; Cadamuro, Aline Cristina Targa; Succi, Maysa; Proença, Marcela Alcântara; Silva, Ana Elizabete

    2012-01-01

    TP53 genes is one of more important tumor suppressor gene, which acts as a potent transcription factor with fundamental role in the maintenance of genetic stability. The development of esophageal and gastric cancers is a multistep process resulting in successive accumulation of genetic alterations that culminates in the malignant transformation. Thus, this study highlights the participation of the main genetic alterations of the TP53 gene in esophageal and gastric carcinogenesis. Among these changes, high frequency of TP53 mutations, loss of heterozygosity (LOH), overexpression of the p53 protein, and consequently loss of p53 function, which would be early events in esophageal and gastric cancers, as well as an important biomarker of the prognosis and treatment response. Furthermore, Single Nucleotide Polymorphisms (SNPs) of TP53 have been implicated in the development and prognosis of several cancers, mainly TP53 codon 72 polymorphism whose role has been extensively studied in relation to susceptibility for esophageal and gastric cancer development. PMID:22919278

  17. Identification of Nine New RAI1-Truncating Mutations in Smith-Magenis Syndrome Patients without 17p11.2 Deletions

    PubMed Central

    Dubourg, C.; Bonnet-Brilhault, F.; Toutain, A.; Mignot, C.; Jacquette, A.; Dieux, A.; Gérard, M.; Beaumont-Epinette, M.-P.; Julia, S.; Isidor, B.; Rossi, M.; Odent, S.; Bendavid, C.; Barthélémy, C.; Verloes, A.; David, V.

    2014-01-01

    Smith-Magenis syndrome (SMS) is an intellectual disability syndrome with sleep disturbance, self-injurious behaviors and dysmorphic features. It is estimated to occur in 1/25,000 births, and in 90% of cases it is associated with interstitial deletions of chromosome 17p11.2. RAI1 (retinoic acid induced 1; OMIM 607642) mutations are the second most frequent molecular etiology, with this gene being located in the SMS locus at 17p11.2. Here, we report 9 new RAI1-truncating mutations in nonrelated individuals referred for molecular analysis due to a possible SMS diagnosis. None of these patients carried a 17p11.2 deletion. The 9 mutations include 2 nonsense mutations and 7 heterozygous frameshift mutations leading to protein truncation. All mutations map in exon 3 of RAI1 which codes for more than 98% of the protein. RAI1 regulates gene transcription, and its targets are themselves involved in transcriptional regulation, cell growth and cell cycle regulation, bone and skeletal development, lipid and glucide metabolisms, neurological development, behavioral functions, and circadian activity. We report the clinical features of the patients carrying these deleterious mutations in comparison with those of patients carrying 17p11.2 deletions. PMID:24715852

  18. Identification of Nine New RAI1-Truncating Mutations in Smith-Magenis Syndrome Patients without 17p11.2 Deletions.

    PubMed

    Dubourg, C; Bonnet-Brilhault, F; Toutain, A; Mignot, C; Jacquette, A; Dieux, A; Gérard, M; Beaumont-Epinette, M-P; Julia, S; Isidor, B; Rossi, M; Odent, S; Bendavid, C; Barthélémy, C; Verloes, A; David, V

    2014-02-01

    Smith-Magenis syndrome (SMS) is an intellectual disability syndrome with sleep disturbance, self-injurious behaviors and dysmorphic features. It is estimated to occur in 1/25,000 births, and in 90% of cases it is associated with interstitial deletions of chromosome 17p11.2. RAI1 (retinoic acid induced 1; OMIM 607642) mutations are the second most frequent molecular etiology, with this gene being located in the SMS locus at 17p11.2. Here, we report 9 new RAI1-truncating mutations in nonrelated individuals referred for molecular analysis due to a possible SMS diagnosis. None of these patients carried a 17p11.2 deletion. The 9 mutations include 2 nonsense mutations and 7 heterozygous frameshift mutations leading to protein truncation. All mutations map in exon 3 of RAI1 which codes for more than 98% of the protein. RAI1 regulates gene transcription, and its targets are themselves involved in transcriptional regulation, cell growth and cell cycle regulation, bone and skeletal development, lipid and glucide metabolisms, neurological development, behavioral functions, and circadian activity. We report the clinical features of the patients carrying these deleterious mutations in comparison with those of patients carrying 17p11.2 deletions.

  19. TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth.

    PubMed

    Haricharan, Svasti; Brown, Powel

    2015-06-23

    Breast cancer is a leading cause of cancer-related death, and it is important to understand pathways that drive the disease to devise effective therapeutic strategies. Our results show that Toll-like receptor 4 (TLR4) drives breast cancer cell growth differentially based on the presence of TP53, a tumor suppressor. TP53 is mutationally inactivated in most types of cancer and is mutated in 30-50% of diagnosed breast tumors. We demonstrate that TLR4 activation inhibits growth of TP53 wild-type cells, but promotes growth of TP53 mutant breast cancer cells by regulating proliferation. This differential effect is mediated by changes in tumor cell cytokine secretion. Whereas TLR4 activation in TP53 mutant breast cancer cells increases secretion of progrowth cytokines, TLR4 activation in TP53 wild-type breast cancer cells increases type I IFN (IFN-γ) secretion, which is both necessary and sufficient for mediating TLR4-induced growth inhibition. This study identifies a novel dichotomous role for TLR4 as a growth regulator and a modulator of tumor microenvironment in breast tumors. These results have translational relevance, demonstrating that TP53 mutant breast tumor growth can be suppressed by pharmacologic TLR4 inhibition, whereas TLR4 inhibitors may in fact promote growth of TP53 wild-type tumors. Furthermore, using data generated by The Cancer Genome Atlas consortium, we demonstrate that the effect of TP53 mutational status on TLR4 activity may extend to ovarian, colon, and lung cancers, among others, suggesting that the viability of TLR4 as a therapeutic target depends on TP53 status in many different tumor types.

  20. TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

    PubMed Central

    Haricharan, Svasti; Brown, Powel

    2015-01-01

    Breast cancer is a leading cause of cancer-related death, and it is important to understand pathways that drive the disease to devise effective therapeutic strategies. Our results show that Toll-like receptor 4 (TLR4) drives breast cancer cell growth differentially based on the presence of TP53, a tumor suppressor. TP53 is mutationally inactivated in most types of cancer and is mutated in 30–50% of diagnosed breast tumors. We demonstrate that TLR4 activation inhibits growth of TP53 wild-type cells, but promotes growth of TP53 mutant breast cancer cells by regulating proliferation. This differential effect is mediated by changes in tumor cell cytokine secretion. Whereas TLR4 activation in TP53 mutant breast cancer cells increases secretion of progrowth cytokines, TLR4 activation in TP53 wild-type breast cancer cells increases type I IFN (IFN-γ) secretion, which is both necessary and sufficient for mediating TLR4-induced growth inhibition. This study identifies a novel dichotomous role for TLR4 as a growth regulator and a modulator of tumor microenvironment in breast tumors. These results have translational relevance, demonstrating that TP53 mutant breast tumor growth can be suppressed by pharmacologic TLR4 inhibition, whereas TLR4 inhibitors may in fact promote growth of TP53 wild-type tumors. Furthermore, using data generated by The Cancer Genome Atlas consortium, we demonstrate that the effect of TP53 mutational status on TLR4 activity may extend to ovarian, colon, and lung cancers, among others, suggesting that the viability of TLR4 as a therapeutic target depends on TP53 status in many different tumor types. PMID:26063617

  1. TP53 mutation-correlated genes predict the risk of tumor relapse and identify MPS1 as a potential therapeutic kinase in TP53-mutated breast cancers.

    PubMed

    Győrffy, Balázs; Bottai, Giulia; Lehmann-Che, Jacqueline; Kéri, György; Orfi, László; Iwamoto, Takayuki; Desmedt, Christine; Bianchini, Giampaolo; Turner, Nicholas C; de Thè, Hugues; André, Fabrice; Sotiriou, Christos; Hortobagyi, Gabriel N; Di Leo, Angelo; Pusztai, Lajos; Santarpia, Libero

    2014-05-01

    Breast cancers (BC) carry a complex set of gene mutations that can influence their gene expression and clinical behavior. We aimed to identify genes driven by the TP53 mutation status and assess their clinical relevance in estrogen receptor (ER)-positive and ER-negative BC, and their potential as targets for patients with TP53 mutated tumors. Separate ROC analyses of each gene expression according to TP53 mutation status were performed. The prognostic value of genes with the highest AUC were assessed in a large dataset of untreated, and neoadjuvant chemotherapy treated patients. The mitotic checkpoint gene MPS1 was the most significant gene correlated with TP53 status, and the most significant prognostic marker in all ER-positive BC datasets. MPS1 retained its prognostic value independently from the type of treatment administered. The biological functions of MPS1 were investigated in different BC cell lines. We also assessed the effects of a potent small molecule inhibitor of MPS1, SP600125, alone and in combination with chemotherapy. Consistent with the gene expression profiling and siRNA assays, the inhibition of MPS1 by SP600125 led to a reduction in cell viability and a significant increase in cell death, selectively in TP53-mutated BC cells. Furthermore, the chemical inhibition of MPS1 sensitized BC cells to conventional chemotherapy, particularly taxanes. Our results collectively demonstrate that TP53-correlated kinase MPS1, is a potential therapeutic target in BC patients with TP53 mutated tumors, and that SP600125 warrant further development in future clinical trials.

  2. A de novo case of hereditary neuropathy with liability to pressure palsies (HNPP) of maternal origin: a new mechanism for deletion in 17p11.2?

    PubMed

    LeGuern, E; Gouider, R; Ravisé, N; Lopes, J; Tardieu, S; Gugenheim, M; Abbas, N; Bouche, P; Agid, Y; Brice, A

    1996-01-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant neuropathy, most often associated with a deletion of the 17p11.2 region, which is duplicated in 70% of patients with Charcot-Marie-Tooth type 1 (CMT1A). Most de novo CMT1A and HNPP cases have been of paternal origin. A rare case of de novo HNPP of maternal origin was analysed to determine the underlying mechanism. Affected individuals in the family carried a deletion corresponding to the CMT1A/HNPP monomer unit associated with a rearrangement of the CMT1A-REP sequences. Segregation analysis of 17p11-p12 markers in the family indicated that the deletion was not generated by unequal crossing over between homologous 17 chromosomes, as in de novo cases from paternal origin, but rather by an intrachromosomal rearrangement. Two distinct mechanisms can therefore lead to the same 17p11.2 deletion. This result suggests that intrachromosomal rearrangement may be specific to maternal transmissions.

  3. CYP1A1, GSTM1, GSTT1 and TP53 Polymorphisms and Risk of Gallbladder Cancer in Bolivians.

    PubMed

    Sakai, Kazuaki; Loza, Ernesto; Roig, Guido Villa-Gomez; Nozaki, Ryoko; Asai, Takao; Ikoma, Toshikazu; Tsuchiya, Yasuo; Kiyohara, Chikako; Yamamoto, Masaharu; Nakamura, Kazutoshi

    2016-01-01

    The Plurinational State of Bolivia (Bolivia) has a high incidence rate of gallbladder cancer (GBC). However, the genetic and environmental risk factors for GBC development are not well understood. We aimed to assess whether or not cytochrome P450 (CYP1A1), glutathione S-transferase mu 1 (GSTM1), theta 1 (GSTT1) and tumor suppressor protein p53 (TP53) genetic polymorphisms modulate GBC susceptibility in Bolivians. This case-control study covered 32 patients with GBC and 86 healthy subjects. GBC was diagnosed on the basis of histological analysis of tissues at the Instituto de Gastroenterologia Boliviano-Japones (IGBJ); the healthy subjects were members of the staff at the IGBJ. Distributions of the CYP1A1 rs1048943 and TP53 rs1042522 polymorphisms were assayed using PCR-restriction fragment length polymorphism assay. GSTM1 and GSTT1 deletion polymorphisms were detected by a multiplex PCR assay. The frequency of the GSTM1 null genotype was significantly higher in GBC patients than in the healthy subjects (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.03-5.37; age-adjusted OR, 3.53; 95% CI, 1.29-9.66; age- and sex-adjusted OR, 3.40; 95% CI, 1.24-9.34). No significant differences were observed in the frequencies of CYP1A1, GSTT1, or TP53 polymorphisms between the two groups. The GSTM1 null genotype was associated with increased GBC risk in Bolivians. Additional studies with larger control and case populations are warranted to confirm the association between the GSTM1 deletion polymorphism and GBC risk suggested in the present study.

  4. TP53 drives invasion through expression of its Δ133p53β variant

    PubMed Central

    Gadea, Gilles; Arsic, Nikola; Fernandes, Kenneth; Diot, Alexandra; Joruiz, Sébastien M; Abdallah, Samer; Meuray, Valerie; Vinot, Stéphanie; Anguille, Christelle; Remenyi, Judit; Khoury, Marie P; Quinlan, Philip R; Purdie, Colin A; Jordan, Lee B; Fuller-Pace, Frances V; de Toledo, Marion; Cren, Maïlys; Thompson, Alastair M

    2016-01-01

    TP53 is conventionally thought to prevent cancer formation and progression to metastasis, while mutant TP53 has transforming activities. However, in the clinic, TP53 mutation status does not accurately predict cancer progression. Here we report, based on clinical analysis corroborated with experimental data, that the p53 isoform Δ133p53β promotes cancer cell invasion, regardless of TP53 mutation status. Δ133p53β increases risk of cancer recurrence and death in breast cancer patients. Furthermore Δ133p53β is critical to define invasiveness in a panel of breast and colon cell lines, expressing WT or mutant TP53. Endogenous mutant Δ133p53β depletion prevents invasiveness without affecting mutant full-length p53 protein expression. Mechanistically WT and mutant Δ133p53β induces EMT. Our findings provide explanations to 2 long-lasting and important clinical conundrums: how WT TP53 can promote cancer cell invasion and reciprocally why mutant TP53 gene does not systematically induce cancer progression. DOI: http://dx.doi.org/10.7554/eLife.14734.001 PMID:27630122

  5. TP53 mutants in the tower of babel of cancer progression.

    PubMed

    Bisio, Alessandra; Ciribilli, Yari; Fronza, Gilberto; Inga, Alberto; Monti, Paola

    2014-06-01

    Loss-of-function, partial-function, altered-function, dominant-negative, temperature sensitive, interfering, contact, structural, unfolded, misfolded, dimeric, monomeric, non-cooperative, unstable, supertrans, superstable, intragenic suppressor. TP53 mutants are many, more than 2,000 in fact, and they can be very diverse. Sporadic; germline; gain-of-function (GoF); oncogenic; rebel-angel; yin and yang; prion-like; metastasis-inducer; mediator of chemo-resistance; modifier of stemness. TP53 mutants can impact important cancer clinical variables, in multiple, often subtle ways, as revealed by cell-based assays as well as animal models. Here, we review studies investigating TP53 mutants for their effect on sequence-specific transactivation function, and especially recent findings on how TP53 mutants can exhibit GoF properties. We also review reports on TP53 mutants' impact on cancer cell transcriptomes and studies with Li-Fraumeni patients trying to classify and predict phenotypes in relation to experimentally determined transcription fingerprints. Finally, we provide an example of the complexity of correlating TP53 mutant functionality to clinical variables in sporadic cancer patients. Conflicting results and limitations of experimental approaches notwithstanding, the study of TP53 mutants has provided a rich body of knowledge, mostly available in the public domain and accessible through databases, which is beginning to impact cancer intervention strategies.

  6. TP53 mutations predict decitabine-induced complete responses in patients with myelodysplastic syndromes.

    PubMed

    Chang, Chun-Kang; Zhao, You-Shan; Xu, Feng; Guo, Juan; Zhang, Zheng; He, Qi; Wu, Dong; Wu, Ling-Yun; Su, Ji-Ying; Song, Lu-Xi; Xiao, Chao; Li, Xiao

    2017-02-01

    To identify the molecular signatures that predict responses to decitabine (DAC), we examined baseline gene mutations (28 target genes) in 109 myelodysplastic syndrome (MDS) patients at diagnosis. We determined that TP53 mutations predicted complete response (CR), as 10 of 15 patients (66·7%) who possessed TP53 mutations achieved a CR. Univariate and multivariate analyses showed that TP53 mutations are the only molecular signatures predictive of a CR to DAC in MDS. Among the ten patients with TP53 mutations who achieved a CR, nine presented with complex karyotypes due to abnormalities involving chromosome 5 and/or chromosome 7, and eight possessed monosomies. Although TP53 mutations were associated with a higher frequency of CRs, they were not associated with improved survival. Poor outcomes were attributed to early relapses and transformation to acute myeloid leukaemia after CR. Post-DAC therapy patient gene mutation profiles showed that most CR patients exhibited fewer gene mutations after achieving a CR. It seems that suppression of these gene mutations was facilitated by DAC, resulting in a CR. In summary, TP53 mutations might predict decitabine-induced complete responses in patients with MDS. DAC-induced responses may result from partial suppression of malignant clones containing mutated TP53 genes.

  7. Comprehensive characterization of genes associated with the TP53 signal transduction pathway in various tumors.

    PubMed

    Ohnami, Shumpei; Ohshima, Keiichi; Nagashima, Takeshi; Urakami, Kenichi; Shimoda, Yuji; Saito, Junko; Naruoka, Akane; Hatakeyama, Keiichi; Mochizuki, Tohru; Serizawa, Masakuni; Ohnami, Sumiko; Kusuhara, Masatoshi; Yamaguchi, Ken

    2017-03-03

    The TP53 signal transduction pathway is an attractive target for cancer treatments. In this study, we conducted a comprehensive molecular evaluation of 907 patients with cancer in Japan to identify genomic alterations in the TP53 pathway. TP53 mutations were frequently detected in many cancers, except melanoma, thymic tumors, gastrointestinal stromal tumors, and renal cancers. The frequencies of non-synonymous single nucleotide variants (SNVs) in the TP53 family members TP63 and TP73 were relatively low, although genes with increased frequencies of SNVs were as follows: PTEN (11.7%) in breast cancer, CDKN2A (11.1 and 9.6%) in pancreas and head and neck cancers, and ATM (18.0 and 11.1%) in liver and esophageal cancers. MDM2 expression was decreased or increased in patients with mutant or wild-type TP53, respectively. CDKN1A expression was increased with mutant TP53 in head and neck cancers. Moreover, TP63 overexpression was characteristically observed in squamous cell carcinomas of the lung, esophagus, and head and neck region. Additionally, overexpression of TP63 and TP73 was frequently observed in thymomas. Our results reveal a spectrum of genomic alterations in the TP53 pathway that is characteristic of many tumor types, and these data may be useful in the trials of targeted therapies.

  8. Prevalence of low-penetrant germline TP53 D49H mutation in Japanese cancer patients.

    PubMed

    Yamaguchi, Ken; Urakami, Kenichi; Nagashima, Takeshi; Shimoda, Yuji; Ohnami, Shumpei; Ohnami, Sumiko; Ohshima, Keiichi; Mochizuki, Tohru; Hatakeyama, Keiichi; Serizawa, Masakuni; Akiyama, Yasuto; Maruyama, Kouji; Katagiri, Hirohisa; Ishida, Yuji; Takahashi, Kaoru; Nishimura, Seiichiro; Terashima, Masanori; Kawamura, Taiichi; Kinugasa, Yusuke; Yamakawa, Yushi; Onitsuka, Tetsuro; Ohde, Yasuhisa; Sugino, Takashi; Ito, Ichiro; Matsubayashi, Hiroyuki; Horiuchi, Yasue; Mizuguchi, Maki; Yamazaki, Mutsumi; Inoue, Kengo; Wakamatsu, Kimiko; Sugiyama, Misato; Uesaka, Katsuhiko; Kusuhara, Masatoshi

    2016-01-01

    Using whole exome sequencing data obtained from 1,685 Japanese cancer patients, we examined genetic variations of germline TP53 and found 10 types of non-synonymous single nucleotide variants. In the present study, we focused on 6 patients with germline D49H mutation located in the transactivation domain 2 of p53 protein, since the mutation seemed to be prevalent in cancer patients and to be pathogenic. According to the initial survey for family history of the proband with the germline TP53 D49H mutation, one osteosarcoma patient and his pedigree fulfill the criteria for Li-Fraumeni-like syndrome and the 2009 Chompret criteria for germline TP53 mutation screening. Since this patient possesses double germline mutations of TP53 D49H and A159D, further studies are required to evaluate contribution of the D49H mutation in this morbidity. The remaining 5 patients had family histories of cancer, but none fulfills the criteria either for the Li-Fraumeni/Li-Fraumeni-like syndromes or the 2009 Chompret criteria for germline TP53 mutation screening. It is possible to postulate that the germline TP53 D49H mutation is likely to be low-penetrant in some pedigrees. The present study also indicates that the survey for the germline TP53 mutation plays an important role in clinical practice as it will prevent mistaking cancer patients with unusual heredities for sporadic cases.

  9. LAMP3 and TP53 overexpression predicts poor outcome in laryngeal squamous cell carcinoma.

    PubMed

    Qiu, Xiaoxia; You, Yiwen; Huang, Jianfei; Wang, Xudong; Zhu, Huijun; Wang, Zhiwei

    2015-01-01

    Lysosomal associated membrane protein 3 (LAMP3) is a newly identified tumor-specific and hypoxia-induced protein. It is a downstream target gene of tumor suppressor TP53 and its expression has been associated with hypoxia-induced metastasis and poor overall survival in cervical, breast and gastrointestinal cancers. However, little is known of LAMP3 protein expression in laryngeal squamous cell carcinoma (LSCC) and its prognostic value. We determined protein expression of LAMP3 and TP53 in LSCC tissues (n=117) by immunohistochemistry analysis on tissue microarray (TMA), their expression was correlated with patients' clinical parameters and overall survival. LAMP3 and TP53 protein expression was significantly higher in cancerous tissues compared to adjacent normal surgical margin tissues. Both high LAMP3 and high TP53 protein expression was significantly associated with tumor stage and size. Significant correlation between LAMP3 and TP53 expression was observed. Patients with high LAMP3 or high TP53 expression had a poor overall survival. Our data suggest that both epithelial LAMP3 expression and TP53 expression are independent prognostic markers for LSCC.

  10. Tracking sub-clonal TP53 mutated tumor cells in human metastatic renal cell carcinoma.

    PubMed

    Bousquet, Guilhem; El Bouchtaoui, Morad; Leboeuf, Christophe; Battistella, Maxime; Varna, Mariana; Ferreira, Irmine; Plassa, Louis-François; Hamdan, Diaddin; Bertheau, Philippe; Feugeas, Jean-Paul; Damotte, Diane; Janin, Anne

    2015-08-07

    Renal Cell Carcinomas (RCCs) are heterogeneous tumors with late acquisition of TP53 abnormalities during their evolution. They harbor TP53 abnormalities in their metastases. We aimed to study TP53 gene alterations in tissue samples from primary and metastatic RCCs in 36 patients followed up over a median of 4.2 years, and in xenografted issued from primary RCCs. In 36 primary RCCs systematically xenografted in mice, and in biopsies of metastases performed whenever possible during patient follow-up, we studied p53-expressing tumor cells and TP53 gene abnormalities.We identified TP53 gene alterations in primary tumors, metastases and xenografts. Quantification of tumors cells with TP53 gene alterations showed a significant increase in the metastases compared to the primary RCCs, and, strikingly, the xenografts were similar to the metastases and not to the primary RCCs from which they were derived.Using laser-microdissection of p53-expressing tumor cells, we identified TP53-mutated tumor cells in the xenografts derived from the primary RCC, and in a lung metastasis later developed in one patient. The mutation enabled us to track back their origin to a minority sub-clone in the primary heterogeneous RCC. Combining in situ and molecular analyses, we demonstrated a clonal expansion in a living patient with metastatic RCC.

  11. Transglutaminase 2 contributes to a TP53-induced autophagy program to prevent oncogenic transformation.

    PubMed

    Yeo, Shi Yun; Itahana, Yoko; Guo, Alvin Kunyao; Han, Rachel; Iwamoto, Kozue; Nguyen, Hung Thanh; Bao, Yi; Kleiber, Kai; Wu, Ya Jun; Bay, Boon Huat; Voorhoeve, Mathijs; Itahana, Koji

    2016-03-09

    Genetic alterations which impair the function of the TP53 signaling pathway in TP53 wild-type human tumors remain elusive. To identify new components of this pathway, we performed a screen for genes whose loss-of-function debilitated TP53 signaling and enabled oncogenic transformation of human mammary epithelial cells. We identified transglutaminase 2 (TGM2) as a putative tumor suppressor in the TP53 pathway. TGM2 suppressed colony formation in soft agar and tumor formation in a xenograft mouse model. The depletion of growth supplements induced both TGM2 expression and autophagy in a TP53-dependent manner, and TGM2 promoted autophagic flux by enhancing autophagic protein degradation and autolysosome clearance. Reduced expression of both CDKN1A, which regulates the cell cycle downstream of TP53, and TGM2 synergized to promote oncogenic transformation. Our findings suggest that TGM2-mediated autophagy and CDKN1A-mediated cell cycle arrest are two important barriers in the TP53 pathway that prevent oncogenic transformation.

  12. Molecular analysis of the Retinoic Acid Induced 1 gene (RAI1) in patients with suspected Smith-Magenis syndrome without the 17p11.2 deletion.

    PubMed

    Vilboux, Thierry; Ciccone, Carla; Blancato, Jan K; Cox, Gerald F; Deshpande, Charu; Introne, Wendy J; Gahl, William A; Smith, Ann C M; Huizing, Marjan

    2011-01-01

    Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder characterized by multiple congenital anomalies. The syndrome is primarily ascribed to a ∼3.7 Mb de novo deletion on chromosome 17p11.2. Haploinsufficiency of multiple genes likely underlies the complex clinical phenotype. RAI1 (Retinoic Acid Induced 1) is recognized as a major gene involved in the SMS phenotype. Extensive genetic and clinical analyses of 36 patients with SMS-like features, but without the 17p11.2 microdeletion, yielded 10 patients with RAI1 variants, including 4 with de novo deleterious mutations, and 6 with novel missense variants, 5 of which were familial. Haplotype analysis showed two major RAI1 haplotypes in our primarily Caucasian cohort; the novel RAI1 variants did not occur in a preferred haplotype. RNA analysis revealed that RAI1 mRNA expression was significantly decreased in cells of patients with the common 17p11.2 deletion, as well as in those with de novo RAI1 variants. Expression levels varied in patients with familial RAI1 variants and in non-17p11.2 deleted patients without identified RAI1 defects. No correlation between SNP haplotype and RAI1 expression was found. Two clinical features, ocular abnormalities and polyembolokoilomania (object insertion), were significantly correlated with decreased RAI1 expression. While not significantly correlated, the presence of hearing loss, seizures, hoarse voice, childhood onset of obesity and specific behavioral aspects and the absence of immunologic abnormalities and cardiovascular or renal structural anomalies, appeared to be specific for the de novo RAI1 subgroup. Recognition of the combination of these features will assist in referral for RAI1 analysis of patients with SMS-like features without detectable microdeletion of 17p11.2. Moreover, RAI1 expression emerged as a genetic target for development of therapeutic interventions for SMS.

  13. TP53 Alterations Correlate with Response to VEGF/VEGFR Inhibitors: Implications for Targeted Therapeutics.

    PubMed

    Wheler, Jennifer J; Janku, Filip; Naing, Aung; Li, Yali; Stephen, Bettzy; Zinner, Ralph; Subbiah, Vivek; Fu, Siqing; Karp, Daniel; Falchook, Gerald S; Tsimberidou, Apostolia M; Piha-Paul, Sarina; Anderson, Roosevelt; Ke, Danxia; Miller, Vincent; Yelensky, Roman; Lee, J Jack; Hong, David; Kurzrock, Razelle

    2016-10-01

    TP53 tumor-suppressor gene mutations are among the most frequent abnormalities in cancer, affecting approximately 40% of patients. Yet, there is no accepted way to target these alterations in the clinic. At the same time, antagonists of VEGFR or its ligand are best-selling oncology drugs, with multiple, expensive compounds approved. Although only a subset of patients benefit from these antiangiogenesis agents, no relevant biomarker has been identified. Interestingly, TP53 mutations upregulate VEGF-A and VEGFR2. We prospectively enrolled 500 patients, to be interrogated by comprehensive genomic profiling (CGP) (next-generation sequencing, 236 genes), and to be matched, whenever possible, with targeted agents. Herein, we analyze outcomes based on VEGF/VEGFR inhibitor treatment and presence of TP53 mutations. Of the 500 patients, 188 (37.6%; with ≥1 alteration) were treated; 106 (56% of 188) had tumors that harbored TP53 mutations. VEGF/VEGFR inhibitor therapy was independently associated with improvement in all outcome parameters [rate of stable disease (SD) ≥6 months/partial and complete remission (PR/CR); (31% versus 7%; TP53-mutant patients (who received no other molecular-matched agents) treated with versus without VEGF/VEGFR inhibitors), time-to-treatment failure, and overall survival (multivariate analysis: all P ≤ 0.01)] for the patients harboring TP53-mutant cancers, but improvement was not seen in any of these parameters for patients with TP53 wild-type neoplasms. We conclude that TP53 mutations predict sensitivity to VEGF/VEGFR inhibitors in the clinic. TP53 alterations may therefore be a ready biomarker for treatment with antiangiogenesis agents, a finding of seminal importance across the cancer field. Mol Cancer Ther; 15(10); 2475-85. ©2016 AACR.

  14. Integrative post-genome-wide association analysis of CDKN2A and TP53 SNPs and risk of esophageal adenocarcinoma

    PubMed Central

    Buas, Matthew F.; Levine, David M.; Makar, Karen W.; Utsugi, Heidi; Onstad, Lynn; Li, Xiaohong; Galipeau, Patricia C.; Shaheen, Nicholas J.; Hardie, Laura J.; Romero, Yvonne; Bernstein, Leslie; Gammon, Marilie D.; Casson, Alan G.; Bird, Nigel C.; Risch, Harvey A.; Ye, Weimin; Liu, Geoffrey; Corley, Douglas A.; Blount, Patricia L.; Fitzgerald, Rebecca C.; Whiteman, David C.; Wu, Anna H.; Reid, Brian J.; Vaughan, Thomas L.

    2014-01-01

    Incidence of esophageal adenocarcinoma (EA) in Western countries has increased markedly in recent decades. Although several risk factors have been identified for EA and its precursor, Barrett’s esophagus (BE), including reflux, Caucasian race, male gender, obesity, and smoking, less is known about the role of inherited genetic variation. Frequent somatic mutations in the tumor suppressor genes CDKN2A and TP53 were recently reported in EA tumors, while somatic alterations at 9p (CDKN2A) and 17p (TP53) have been implicated as predictors of progression from BE to EA. Motivated by these findings, we used data from a genome-wide association study of 2515 EA cases and 3207 controls to analyze 37 germline single nucleotide polymorphisms at the CDKN2A and TP53 loci. Three CDKN2A polymorphisms were nominally associated (P < 0.05) with reduced risk of EA: rs2518720 C>T [intronic, odds ratio 0.90, P = 0.0121, q = 0.3059], rs3088440 G>A (3′UTR, odds ratio 0.84, P = 0.0186, q = 0.3059), and rs4074785 C>T (intronic, odds ratio 0.85, P = 0.0248, q = 0.3059). None of the TP53 single nucleotide polymorphisms reached nominal significance. Two of the CDKN2A variants identified were also associated with reduced risk of progression from BE to EA, when assessed in a prospective cohort of 408 BE patients: rs2518720 (hazard ratio 0.57, P = 0.0095, q = 0.0285) and rs3088440 (hazard ratio 0.34, P = 0.0368, q = 0.0552). In vitro functional studies of rs3088440, a single nucleotide polymorphism located in the seed sequence of a predicted miR-663b binding site, suggested a mechanism whereby the G>A substitution may attenuate miR-663b-mediated repression of the CDKN2A transcript. This study provides the first evidence that germline variation at the CDKN2A locus may influence EA susceptibility. PMID:25280564

  15. TP53 and lacZ mutagenesis induced by 3-nitrobenzanthrone in Xpa-deficient human TP53 knock-in mouse embryo fibroblasts.

    PubMed

    Kucab, Jill E; Zwart, Edwin P; van Steeg, Harry; Luijten, Mirjam; Schmeiser, Heinz H; Phillips, David H; Arlt, Volker M

    2016-03-01

    3-Nitrobenzanthrone (3-NBA) is a highly mutagenic compound and possible human carcinogen found in diesel exhaust. 3-NBA forms bulky DNA adducts following metabolic activation and induces predominantly G:CT:A transversions in a variety of experimental systems. Here we investigated the influence of nucleotide excision repair (NER) on 3-NBA-induced mutagenesis of the human tumour suppressor gene TP53 and the reporter gene lacZ. To this end we utilised Xpa -knockout (Xpa-Null) human TP53 knock-in (Hupki) embryo fibroblasts (HUFs). As Xpa is essential for NER of bulky DNA adducts, we hypothesized that DNA adducts induced by 3-NBA would persist in the genomes of Xpa-Null cells and lead to an increased frequency of mutation. The HUF immortalisation assay was used to select for cells harbouring TP53 mutations following mutagen exposure. We found that Xpa-Null Hupki mice and HUFs were more sensitive to 3-NBA treatment than their wild-type (Xpa-WT) counterparts. However, following 3-NBA treatment and immortalisation, a similar frequency of TP53-mutant clones arose from Xpa-WT and Xpa-Null HUF cultures. In cells from both Xpa genotypes G:CT:A transversion was the predominant TP53 mutation type and mutations exhibited bias towards the non-transcribed strand. Thirty-two percent of 3-NBA-induced TP53 mutations occurred at CpG sites, all of which are hotspots for mutation in smokers' lung cancer (codons 157, 158, 175, 245, 248, 273, 282). We also examined 3-NBA-induced mutagenesis of an integrated lacZ reporter gene in HUFs, where we again observed a similar mutant frequency in Xpa-WT and Xpa-Null cells. Our findings suggest that 3-NBA-DNA adducts may evade removal by global genomic NER; the persistence of 3-NBA adducts in DNA may be an important factor in its mutagenicity.

  16. Inhibition of autophagy attenuates pancreatic cancer growth independent of TP53/TRP53 status.

    PubMed

    Yang, Annan; Kimmelman, Alec C

    2014-09-01

    Basal levels of autophagy are elevated in most pancreatic ductal adenocarcinomas (PDAC). Suppressing autophagy pharmacologically using chloroquine (CQ) or genetically with RNAi to essential autophagy genes inhibits human pancreatic cancer growth in vitro and in vivo, which presents possible treatment opportunities for PDAC patients using the CQ-derivative hydroxychloroquine (HCQ). Indeed, such clinical trials are ongoing. However, autophagy is a complex cellular mechanism to maintain cell homeostasis under stress. Based on its biological role, a dual role of autophagy in tumorigenesis has been proposed: at tumor initiation, autophagy helps maintain genomic stability and prevent tumor initiation; while in advanced disease, autophagy degrades and recycles cellular components to meet the metabolic needs for rapid growth. This model was proven to be the case in mouse lung tumor models. However, in contrast to prior work in various PDAC model systems, loss of autophagy in PDAC mouse models with embryonic homozygous Trp53 deletion does not inhibit tumor growth and paradoxically increases progression. This raised concerns whether there may be a genotype-dependent reliance of PDAC on autophagy. In a recent study, our group used a Trp53 heterozygous mouse PDAC model and human PDX xenografts to address the question. Our results demonstrate that autophagy inhibition was effective against PDAC tumors irrespective of TP53/TRP53 status.

  17. TP53 alterations and colorectal cancer predisposition in south Indian population: a case-control study.

    PubMed

    Singamsetty, Gopi Krishna; Malempati, Sravanthi; Bhogadhi, Srichandana; Kondreddy, Ravinder; Govatati, Suresh; Tangudu, Naveen Kumar; Govatati, Sowdamani; kuraganti, Anil Kumar; Bhanoori, Manjula; Kassetty, Kondaiah

    2014-03-01

    The objective of the present study was to investigate the association between TP53 gene single nucleotide polymorphisms (SNPs) and colorectal cancer (CRC) predisposition in south Indian population and to evaluate the role of TP53 expression in the pathophysiology of CRC. A genetic association study was conducted in 103 CRC cases and 107 controls of south Indian origin. We genotyped ten selected TP53 SNPs by polymerase chain reaction-sequencing analysis. Haplotype frequencies for multiple loci and the standardized disequilibrium coefficient (D') for pairwise linkage disequilibrium (LD) were assessed by Haploview Software. In addition, to better understand the role of TP53 in the pathophysiology of CRC, the expression pattern was evaluated in analogous tumor and normal tissues from 23 CRC patients by Western blot analysis. The frequencies of Pro72Pro (P = 0.0033) genotype and Ser47/Pro72 (P = 0.00171) haplotype were significantly higher in patients as compared to controls. Strong LD was observed between codon 47 and 72 in cases (D' = 0.32) as compared to controls (D' = 0.21). The polymorphism was not observe at the remaining eight SNPs loci analyzed. Furthermore, increased TP53 expression was observed in tumor tissue than in analogous normal tissue of CRC patients. Interestingly, advanced stage tumors showed more elevated TP53 expression compared to early stage tumors. In conclusion, the TP53 Pro72Pro genotype and Ser47/Pro72 haplotype has an increased risk for CRC predisposition in south Indian population. In addition, elevated TP53 expression appears to be useful prognostic marker for CRC.

  18. Mutation spectrum of TP53 gene predicts clinicopathological features and survival of gastric cancer

    PubMed Central

    Tahara, Tomomitsu; Shibata, Tomoyuki; Okamoto, Yasuyuki; Yamazaki, Jumpei; Kawamura, Tomohiko; Horiguchi, Noriyuki; Okubo, Masaaki; Nakano, Naoko; Ishizuka, Takamitsu; Nagasaka, Mitsuo; Nakagawa, Yoshihito; Ohmiya, Naoki

    2016-01-01

    Background and aim TP53 gene is frequently mutated in gastric cancer (GC), but the relationship with clinicopathological features and prognosis is conflicting. Here, we screened TP53 mutation spectrum of 214 GC patients in relation to their clinicopathological features and prognosis. Results TP53 nonsilent mutations were detected in 80 cases (37.4%), being frequently occurred as C:G to T:A single nucleotide transitions at 5′-CpG-3′ sites. TP53 mutations occurred more frequently in differentiated histologic type than in undifferentiated type in the early stage (48.6% vs. 7%, P=0.0006), while the mutations correlated with venous invasion among advanced stage (47.7% vs. 20.7%, P=0.04). Subset of GC with TP53 hot spot mutations (R175, G245, R248, R273, R282) presented significantly worse overall survival and recurrence free survival compared to others (both P=0.001). Methods Matched biopsies from GC and adjacent tissues from 214 patients were used for the experiment. All coding regions of TP53 gene (exon2 to exon11) were examined using Sanger sequencing. Conclusion Our data suggest that GC with TP53 mutations seems to develop as differentiated histologic type and show aggressive biological behavior such as venous invasion. Moreover, our data emphasizes the importance of discriminating TP53 hot spot mutations (R175, G245, R248, R273, R282) to predict worse overall survival and recurrence free survival of GC patients. PMID:27323394

  19. Mutational profile of TP53 in esophageal squamous cell carcinoma associated with chagasic megaesophagus.

    PubMed

    Lacerda, C F; Cruvinel-Carloni, A; de Oliveira, A T Torres; Scapulatempo-Neto, C; López, R V M; Crema, E; Adad, S J; Rodrigues, M A M; Henry, M A C A; Guimarães, D P; Reis, R M

    2017-04-01

    Chaga's disease is an important communicable neglected disease that is gaining wider attention due to its increasing incidence worldwide. Achalasia due to chagasic megaesophagus (CM), a complication of this disease, is a known-yet, poorly understood-etiological factor for esophageal squamous cell carcinoma (ESCC) development. In this study, we aimed to perform the analysis of TP53 mutations in a series of Brazilian patients with ESCC that developed in the context CM (ESCC/CM), and to compare with the TP53 mutation profile of patients with benign CM and patients with nonchagasic ESCC. Additionally, we intended to correlate the TP53 mutation results with patient's clinical pathological features. By polymerase chain reaction (PCR) followed by direct sequencing of the hotspot regions of TP53 (exon 5 to 8), we found that TP53 mutations were present in 40.6% (13/32) of the ESCC/CM group, 45% (18/40) of the nonchagasic ESCC group, and in only 3% (1/33) of the benign CM group. Missense mutations were the most common in the three groups, yet, the type and mutated exon mutation varied significantly among the groups. Clinically, the groups exhibited distinct features, with both cancer groups (ESCC and ESCC/CM) been significantly associated higher consumption of alcohol and tobacco, older age, worse Karnofsky performance status, poor outcome than the patients with benign CM. No significant association was found between TP53 mutation profile and clinical-pathological features in any of the three groups. We describe first the time the analysis of TP53 mutations in ESCC that developed in the context of CM, and the observed high frequency of mutations, suggest that TP53 also plays an important role in the tumorigenic process of this unexplored etiological condition.

  20. Superior verbal ability and nonverbal learning disability in a child with a novel 17p12p13.1 deletion.

    PubMed

    Steele, D L; Chisholm, A K; McGhie, J D R; Gardner, R J M; Scheffer, I E; Slater, H R; Dawson, G

    2005-04-05

    We report the case of a 10-year-old girl with the karyotype 46,XX,del(17)(p12p13.1) who presented a remarkable incongruence in higher cerebral functioning. Certain language skills were very superior, with reading and spelling at a 17-19 year-old level of proficiency. Nonverbal skills, however, were mostly below average, executive functioning and socialization were impaired, and a diagnosis of "nonverbal learning disability" is applied. We speculate that the genes deleted include one or some which code for certain specific categories of neural substrate that subserve aspects of visual processing and higher functioning, but that no "language loci" have been deleted. The particular neuropsychological profile that we describe may assist diagnosis of this chromosomal deletion.

  1. TP53 mutation hits energy metabolism and increases glycolysis in breast cancer

    PubMed Central

    Munkácsy, Gyöngyi; Horváth, Gergő; Nagy, Ádám M.; Ambrus, Attila; Hauser, Péter; Szabó, András; Tretter, László; Győrffy, Balázs

    2016-01-01

    Promising new hallmarks of cancer is alteration of energy metabolism that involves molecular mechanisms shifting cancer cells to aerobe glycolysis. Our goal was to evaluate the correlation between mutation in the commonly mutated tumor suppressor gene TP53 and metabolism. We established a database comprising mutation and RNA-seq expression data of the TCGA repository and performed receiver operating characteristics (ROC) analysis to compare expression of each gene between TP53 mutated and wild type samples. All together 762 breast cancer samples were evaluated of which 215 had TP53 mutation. Top up-regulated metabolic genes include glycolytic enzymes (e.g. HK3, GPI, GAPDH, PGK1, ENO1), glycolysis regulator (PDK1) and pentose phosphate pathway enzymes (PGD, TKT, RPIA). Gluconeogenesis enzymes (G6PC3, FBP1) were down-regulated. Oxygen consumption and extracellular acidification rates were measured in TP53 wild type and mutant breast cell lines with a microfluorimetric analyzer. Applying metabolic inhibitors in the presence and absence of D-glucose and L-glutamine in cell culture experiments resulted in higher glycolytic and mitochondrial activity in TP53 mutant breast cancer cell lines. In summary, TP53 mutation influences energy metabolism at multiple levels. Our results provide evidence for the synergistic activation of multiple hallmarks linking to these the mutation status of a key driver gene. PMID:27582538

  2. Multiplex enhancer-reporter assays uncover unsophisticated TP53 enhancer logic

    PubMed Central

    Verfaillie, Annelien; Svetlichnyy, Dmitry; Imrichova, Hana; Davie, Kristofer; Fiers, Mark; Kalender Atak, Zeynep; Hulselmans, Gert; Christiaens, Valerie; Aerts, Stein

    2016-01-01

    Transcription factors regulate their target genes by binding to regulatory regions in the genome. Although the binding preferences of TP53 are known, it remains unclear what distinguishes functional enhancers from nonfunctional binding. In addition, the genome is scattered with recognition sequences that remain unoccupied. Using two complementary techniques of multiplex enhancer-reporter assays, we discovered that functional enhancers could be discriminated from nonfunctional binding events by the occurrence of a single TP53 canonical motif. By combining machine learning with a meta-analysis of TP53 ChIP-seq data sets, we identified a core set of more than 1000 responsive enhancers in the human genome. This TP53 cistrome is invariably used between cell types and experimental conditions, whereas differences among experiments can be attributed to indirect nonfunctional binding events. Our data suggest that TP53 enhancers represent a class of unsophisticated cell-autonomous enhancers containing a single TP53 binding site, distinct from complex developmental enhancers that integrate signals from multiple transcription factors. PMID:27197205

  3. A novel TP53 pathway influences the HGS-mediated exosome formation in colorectal cancer

    PubMed Central

    Sun, Yulin; Zheng, Weiwei; Guo, Zhengguang; Ju, Qiang; Zhu, Lin; Gao, Jiajia; Zhou, Lanping; Liu, Fang; Xu, Yang; Zhan, Qimin; Zhou, Zhixiang; Sun, Wei; Zhao, Xiaohang

    2016-01-01

    Tumor-derived exosomes are important for cell-cell communication. However, the role of TP53 in the control of exosome production in colorectal cancer (CRC) is controversial and unclear. The features of exosomes secreted from HCT116 TP53-wild type (WT), TP53-knockout (KO) and constructed TP53 (R273H)-mutant (MT) cells were assessed. The exosomes from the MT and KO cells exhibited significantly reduced sizes compared with the WT cells. A comprehensive proteomic analysis of exosomal proteins was performed using the isobaric tag for relative and absolute quantitation (iTRAQ)-2D-LC-MS/MS strategy. A total of 3437 protein groups with ≥2 matched peptides were identified. Specifically, hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) was consistently down-regulated in the exosomes from the MT and KO cells. Functional studies demonstrated that low HGS levels were responsible for the decreased exosome size. TP53 regulated HGS expression and thus HGS-dependent exosome formation. Furthermore, the HGS expression was gradually increased concomitant with CRC carcinogenesis and was an independent poor prognostic factor. In conclusion, a novel HGS-dependent TP53 mechanism in exosome formation was identified in CRC. HGS may serve as a novel prognostic biomarker and a candidate target for therapeutic interventions. PMID:27312428

  4. Cytotoxic and toxicogenomic effects of silibinin in bladder cancer cells with different TP53 status.

    PubMed

    DE Oliveira, Daiane Teixeira; Savio, Andre Luiz Ventura; Marcondes, Joao Paulo DE Castro; Barros, Tatiane Martins; Barbosa, Ludmila Correia; Salvadori, Daisy Maria Favero; DA Silva, Glenda Nicioli

    2017-03-01

    Silibinin is a natural phenol found in the seeds of the milk thistle plant. Recent data have shown its effectiveness for preventing/treating bladder tumours. Therefore, in this study we investigated the cytotoxic and toxicogenetic activity of silibinin in bladder cancer cells with different TP53 statuses. Two bladder urothelial carcinoma cell lines were used: RT4 (wild-type TP53 gene) and T24 (mutated TP53 gene). Cell proliferation, clonogenic survival, apoptosis rates, genotoxicity and relative expression profile of FRAP/mTOR, FGFR3, AKT2 and DNMT1 genes and of miR100 and miR203 were evaluated. Silibinin promoted decreased proliferation and increased late apoptosis in TP53 mutated cells. Increased early apoptosis rates, primary DNA damage, and decrease of cell colonies in the clonogenic survival assay were detected in both RT4 and T24 cell lines. Down-regulation of FRAP/mTOR, AKT2, FGFR3, DNMT1 and miR100 expression occurred in RT4 cells. Modulation of miR203 was observed in both cell lines. In conclusion, despite the reduction of clone formation in both cell lines, the toxicogenomic effect of silibinin on FRAP/mTOR, AKT2, FGFR3, DNMT1 and miR100 was dependent on the TP53 status. Taken together, the data confirmed the role of silibinin as an antiproliferative compound, whose mechanism of action was related to the TP53 status.

  5. Hereditary neuropathy with liability to pressure palsies (HNPP) patients of Korean ancestry with chromosome 17p11.2-p12 deletion.

    PubMed

    Kim, Seung Min; Chung, Ki Wha; Choi, Byung Ok; Yoon, Eui Soo; Choi, Jung Young; Park, Kee Duk; Sunwoo, Il Nam

    2004-02-29

    Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant inherited disorder characterized by recurrent pressure palsies. Most HNPP patients have a 1.5 mb deletion in chromosome 17p11.2-p12. The present study aimed at evaluating the deletion of the 17p11.2-p12 region in Korean subjects with families exhibiting HNPP phenotype, and to determine the clinical, electrophysiological and morphological aspects specifically associated with this deletion in HNPP patients. By genotyping six microsatellite markers (D17S921, D17S955, D17S1358, D17S839, D17S122 and D17S261), HNPP with the deletion was observed in 79% (19 of 24) of HNPP families. Nerve conduction studies were performed in 35 HNPP patients from these 19 families. The observed HNPP deletion frequency in Koreans is consistent with findings in other populations. Disease onset occurred at a significantly earlier age in patients with recurrent pressure palsies than in those with a single attack (P < 0.01). Nerve conduction studies demonstrated diffuse mild to moderate slowing of nerve conduction velocities that were worse over the common entrapment sites, regardless of the clinical manifestations. A long duration of compound muscle action potentials without a conduction block or a temporal dispersion is a characteristic of this disease. A sural nerve biopsy with teasing was performed in four patients, and tomacula of the myelin sheath was found in 56.4%. Our findings appear to support the existence of a phenotype/genotype correlation in HNPP patients of Korean ancestry with the deletion, and suggest that HNPP patients with earlier symptom onset face an increased chance of having recurrent attacks.

  6. Molecular diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP) by detection of 17p11.2 deletion in Italian patients.

    PubMed

    Mandich, P; James, R; Nassani, S; Defferrari, R; Bellone, E; Mancardi, G; Schenone, A; Abbruzzese, M; Rocchi, M; Ajmar, F

    1995-05-01

    Hereditary neuropathy with a liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent pressure palsies generally precipitated by minor trauma; weakness and paraesthesia usually improve and recover completely in a few months. By Southern blotting and fluorescent in situ hybridization analysis we confirm the presence of a 17p11.2 deletion in familial and in isolated cases of HNPP, suggesting that molecular analysis of the 17p11.2 region could also be a reliable and non-invasive method of diagnosis in sporadic cases, where a correct diagnosis usually requires a nerve biopsy. Although HNPP is a mild disease and not all patients seek medical attention, a presymptomatic diagnosis is useful for assessing the risk during genetic counselling, due to the inheritance of the mutation.

  7. Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations

    PubMed Central

    Tirode, Franck; Surdez, Didier; Ma, Xiaotu; Parker, Matthew; Le Deley, Marie Cécile; Bahrami, Armita; Zhang, Zhaojie; Lapouble, Eve; Grossetête-Lalami, Sandrine; Rusch, Michael; Reynaud, Stéphanie; Rio-Frio, Thomas; Hedlund, Erin; Wu, Gang; Chen, Xiang; Pierron, Gaelle; Oberlin, Odile; Zaidi, Sakina; Lemmon, Gordon; Gupta, Pankaj; Vadodaria, Bhavin; Easton, John; Gut, Marta; Ding, Li; Mardis, Elaine R.; Wilson, Richard K.; Shurtleff, Sheila; Laurence, Valérie; Michon, Jean; Marec-Bérard, Perrine; Gut, Ivo; Downing, James; Dyer, Michael; Zhang, Jinghui; Delattre, Olivier

    2014-01-01

    Ewing sarcoma is a primary bone tumor initiated by EWSR1–ETS gene fusions. To identify secondary genetic lesions that contribute to tumor progression, we performed whole-genome sequencing of 112 Ewing sarcoma samples and matched germline DNA. Overall, Ewing sarcoma tumors had relatively few single-nucleotide variants, indels, structural variants and copy-number alterations. Apart from whole chromosome arm copy-number changes, the most common somatic mutations were detected in STAG2 (17%), CDKN2A (12%), TP53 (7%), EZH2, BCOR, and ZMYM3 (2.7% each). Strikingly, STAG2 mutations and CDKN2A deletions were mutually exclusive, as confirmed in Ewing sarcoma cell lines. In an expanded cohort of 299 patients with clinical data, we discovered that STAG2 and TP53 mutations are often concurrent and are associated with poor outcome. Finally, we detected subclonal STAG2 mutations in diagnostic tumors and expansion of STAG2 immuno-negative cells in relapsed tumors as compared with matched diagnostic samples. PMID:25223734

  8. Optimized p53 immunohistochemistry is an accurate predictor of TP53 mutation in ovarian carcinoma.

    PubMed

    Köbel, Martin; Piskorz, Anna M; Lee, Sandra; Lui, Shuhong; LePage, Cecile; Marass, Francesco; Rosenfeld, Nitzan; Mes Masson, Anne-Marie; Brenton, James D

    2016-10-01

    TP53 mutations are ubiquitous in high-grade serous ovarian carcinomas (HGSOC), and the presence of TP53 mutation discriminates between high and low-grade serous carcinomas and is now an important biomarker for clinical trials targeting mutant p53. p53 immunohistochemistry (IHC) is widely used as a surrogate for TP53 mutation but its accuracy has not been established. The objective of this study was to test whether improved methods for p53 IHC could reliably predict TP53 mutations independently identified by next generation sequencing (NGS). Four clinical p53 IHC assays and tagged-amplicon NGS for TP53 were performed on 171 HGSOC and 80 endometrioid carcinomas (EC). p53 expression was scored as overexpression (OE), complete absence (CA), cytoplasmic (CY) or wild type (WT). p53 IHC was evaluated as a binary classifier where any abnormal staining predicted deleterious TP53 mutation and as a ternary classifier where OE, CA or WT staining predicted gain-of-function (GOF or nonsynonymous), loss-of-function (LOF including stopgain, indel, splicing) or no detectable TP53 mutations (NDM), respectively. Deleterious TP53 mutations were detected in 169/171 (99%) HGSOC and 7/80 (8.8%) EC. The overall accuracy for the best performing IHC assay for binary and ternary prediction was 0.94 and 0.91 respectively, which improved to 0.97 (sensitivity 0.96, specificity 1.00) and 0.95 after secondary analysis of discordant cases. The sensitivity for predicting LOF mutations was lower at 0.76 because p53 IHC detected mutant p53 protein in 13 HGSOC with LOF mutations. CY staining associated with LOF was seen in 4 (2.3%) of HGSOC. Optimized p53 IHC can approach 100% specificity for the presence of TP53 mutation and its high negative predictive value is clinically useful as it can exclude the possibility of a low-grade serous tumour. 4.1% of HGSOC cases have detectable WT staining while harboring a TP53 LOF mutation, which limits sensitivity for binary prediction of mutation to 96%.

  9. TP53 and lacZ mutagenesis induced by 3-nitrobenzanthrone in Xpa-deficient human TP53 knock-in mouse embryo fibroblasts

    PubMed Central

    Kucab, Jill E.; Zwart, Edwin P.; van Steeg, Harry; Luijten, Mirjam; Schmeiser, Heinz H.; Phillips, David H.; Arlt, Volker M.

    2016-01-01

    3-Nitrobenzanthrone (3-NBA) is a highly mutagenic compound and possible human carcinogen found in diesel exhaust. 3-NBA forms bulky DNA adducts following metabolic activation and induces predominantly G:C > T:A transversions in a variety of experimental systems. Here we investigated the influence of nucleotide excision repair (NER) on 3-NBA-induced mutagenesis of the human tumour suppressor gene TP53 and the reporter gene lacZ. To this end we utilised Xpa -knockout (Xpa-Null) human TP53 knock-in (Hupki) embryo fibroblasts (HUFs). As Xpa is essential for NER of bulky DNA adducts, we hypothesized that DNA adducts induced by 3-NBA would persist in the genomes of Xpa-Null cells and lead to an increased frequency of mutation. The HUF immortalisation assay was used to select for cells harbouring TP53 mutations following mutagen exposure. We found that Xpa-Null Hupki mice and HUFs were more sensitive to 3-NBA treatment than their wild-type (Xpa-WT) counterparts. However, following 3-NBA treatment and immortalisation, a similar frequency of TP53-mutant clones arose from Xpa-WT and Xpa-Null HUF cultures. In cells from both Xpa genotypes G:C > T:A transversion was the predominant TP53 mutation type and mutations exhibited bias towards the non-transcribed strand. Thirty-two percent of 3-NBA-induced TP53 mutations occurred at CpG sites, all of which are hotspots for mutation in smokers’ lung cancer (codons 157, 158, 175, 245, 248, 273, 282). We also examined 3-NBA-induced mutagenesis of an integrated lacZ reporter gene in HUFs, where we again observed a similar mutant frequency in Xpa-WT and Xpa-Null cells. Our findings suggest that 3-NBA-DNA adducts may evade removal by global genomic NER; the persistence of 3-NBA adducts in DNA may be an important factor in its mutagenicity. PMID:26723900

  10. The TP53 dependence of radiation-induced chromosome instability in human lymphoblastoid cells

    NASA Technical Reports Server (NTRS)

    Schwartz, Jeffrey L.; Jordan, Robert; Evans, Helen H.; Lenarczyk, Marek; Liber, Howard

    2003-01-01

    The dose and TP53 dependence for the induction of chromosome instability were examined in cells of three human lymphoblastoid cell lines derived from WIL2 cells: TK6, a TP53-normal cell line, NH32, a TP53-knockout created from TK6, and WTK1, a WIL2-derived cell line that spontaneously developed a TP53 mutation. Cells of each cell line were exposed to (137)Cs gamma rays, and then surviving clones were isolated and expanded in culture for approximately 35 generations before the frequency and characteristics of the instability were analyzed. The presence of dicentric chromosomes, formed by end-to-end fusions, served as a marker of chromosomal instability. Unexposed TK6 cells had low levels of chromosomal instability (0.002 +/- 0.001 dicentrics/cell). Exposure of TK6 cells to doses as low as 5 cGy gamma rays increased chromosome instability levels nearly 10-fold to 0.019 +/- 0.008 dicentrics/cell. There was no further increase in instability levels beyond 5 cGy. In contrast to TK6 cells, unexposed cultures of WTK1 and NH32 cells had much higher levels of chromosome instability of 0.034 +/- 0.007 and 0.041 +/- 0.009, respectively, but showed little if any effect of radiation on levels of chromosome instability. The results suggest that radiation exposure alters the normal TP53-dependent cell cycle checkpoint controls that recognize alterations in telomere structure and activate apoptosis.

  11. Survival of patients with structurally-grouped TP53 mutations in ovarian and breast cancers.

    PubMed

    Seagle, Brandon-Luke L; Eng, Kevin H; Dandapani, Monica; Yeh, Judy Y; Odunsi, Kunle; Shahabi, Shohreh

    2015-07-30

    The objective of this study was to determine if ovarian cancer patients with a TP53 mutation grouped by location of the mutation within the p53 protein structure exhibit differential survival outcomes. Data from patients with high grade serous ovarian cancer (HGS OvCa) (N = 316) or breast cancer (BrCa) (N = 981) sequenced by The Cancer Genome Atlas (TCGA) was studied by Kaplan-Meier and Cox proportional hazards survival analysis. A TP53 DNA binding domain (BD) missense mutation (MM) occurred in 58.5% (185/316) of HGS OvCas and 16.8% (165/981) of BrCas. Patients with a TP53 DNA BD MM grouped by structural location had significantly different overall survival (OS) and progression free survival (PFS). Median OS (months) of HGS OvCa patients by structural group were: Sheet-loop-helix stabilizers, 31.1; DNA minor groove residue R248, 33.6; Wild-type, 34.2; all other MMs, 44.5; DNA major groove residues, 84.1, and zinc ion coordinating residues, 87.0 (log-rank p = 0.006). PFS of DNA major groove MM cases was longer than TP53 wild-type cases (19.1 versus 10.1 months, log-rank p = 0.038). HGS OvCa and BrCa patients with structurally-grouped TP53 DNA BD MMs have different survival outcomes.

  12. TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome

    PubMed Central

    Edison; Teo, Audrey S.M.; Madan, Babita; Zhang, Kang; Kohlmann, Wendy K.; Yao, Fei; Lee, Wah Heng; Hoi, Qiangze; Cai, Shaojiang; Woo, Xing Yi; Tan, Patrick; Jundt, Gernot; Smida, Jan; Nathrath, Michaela; Sung, Wing-Kin; Schiffman, Joshua D.; Virshup, David M.; Hillmer, Axel M.

    2015-01-01

    Somatic mutations of TP53 are among the most common in cancer and germline mutations of TP53 (usually missense) can cause Li-Fraumeni syndrome (LFS). Recently, recurrent genomic rearrangements in intron 1 of TP53 have been described in osteosarcoma (OS), a highly malignant neoplasm of bone belonging to the spectrum of LFS tumors. Using whole-genome sequencing of OS, we found features of TP53 intron 1 rearrangements suggesting a unique mechanism correlated with transcription. Screening of 288 OS and 1,090 tumors of other types revealed evidence for TP53 rearrangements in 46 (16%) OS, while none were detected in other tumor types, indicating this rearrangement to be highly specific to OS. We revisited a four-generation LFS family where no TP53 mutation had been identified and found a 445 kb inversion spanning from the TP53 intron 1 towards the centromere. The inversion segregated with tumors in the LFS family. Cancers in this family had loss of heterozygosity, retaining the rearranged allele and resulting in TP53 expression loss. In conclusion, intron 1 rearrangements cause p53-driven malignancies by both germline and somatic mechanisms and provide an important mechanism of TP53 inactivation in LFS, which might in part explain the diagnostic gap of formerly classified “TP53 wild-type” LFS. PMID:25762628

  13. TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome.

    PubMed

    Ribi, Sebastian; Baumhoer, Daniel; Lee, Kristy; Edison; Teo, Audrey S M; Madan, Babita; Zhang, Kang; Kohlmann, Wendy K; Yao, Fei; Lee, Wah Heng; Hoi, Qiangze; Cai, Shaojiang; Woo, Xing Yi; Tan, Patrick; Jundt, Gernot; Smida, Jan; Nathrath, Michaela; Sung, Wing-Kin; Schiffman, Joshua D; Virshup, David M; Hillmer, Axel M

    2015-04-10

    Somatic mutations of TP53 are among the most common in cancer and germline mutations of TP53 (usually missense) can cause Li-Fraumeni syndrome (LFS). Recently, recurrent genomic rearrangements in intron 1 of TP53 have been described in osteosarcoma (OS), a highly malignant neoplasm of bone belonging to the spectrum of LFS tumors. Using whole-genome sequencing of OS, we found features of TP53 intron 1 rearrangements suggesting a unique mechanism correlated with transcription. Screening of 288 OS and 1,090 tumors of other types revealed evidence for TP53 rearrangements in 46 (16%) OS, while none were detected in other tumor types, indicating this rearrangement to be highly specific to OS. We revisited a four-generation LFS family where no TP53 mutation had been identified and found a 445 kb inversion spanning from the TP53 intron 1 towards the centromere. The inversion segregated with tumors in the LFS family. Cancers in this family had loss of heterozygosity, retaining the rearranged allele and resulting in TP53 expression loss. In conclusion, intron 1 rearrangements cause p53-driven malignancies by both germline and somatic mechanisms and provide an important mechanism of TP53 inactivation in LFS, which might in part explain the diagnostic gap of formerly classified "TP53 wild-type" LFS.

  14. Reciprocal deletion and duplication of 17p11.2-11.2: Korean patients with Smith-Magenis syndrome and Potocki-Lupski syndrome.

    PubMed

    Lee, Cha Gon; Park, Sang-Jin; Yun, Jun-No; Yim, Shin-Young; Sohn, Young Bae

    2012-12-01

    Deletion and duplication of the -3.7-Mb region in 17p11.2 result in two reciprocal syndrome, Smith-Magenis syndrome and Potocki-Lupski syndrome. Smith-Magenis syndrome is a well-known developmental disorder. Potocki-Lupski syndrome has recently been recognized as a microduplication syndrome that is a reciprocal disease of Smith-Magenis syndrome. In this paper, we report on the clinical and cytogenetic features of two Korean patients with Smith-Magenis syndrome and Potocki-Lupski syndrome. Patient 1 (Smith-Magenis syndrome) was a 2.9-yr-old boy who showed mild dysmorphic features, aggressive behavioral problems, and developmental delay. Patient 2 (Potocki-Lupski syndrome), a 17-yr-old boy, had only intellectual disabilities and language developmental delay. We used array comparative genomic hybridization (array CGH) and found a 2.6 Mb-sized deletion and a reciprocal 2.1 Mb-sized duplication involving the 17p11.2. These regions overlapped in a 2.1 Mb size containing 11 common genes, including RAI1 and SREBF.

  15. TP53 exon-6 truncating mutations produce separation of function isoforms with pro-tumorigenic functions

    PubMed Central

    Shirole, Nitin H; Pal, Debjani; Kastenhuber, Edward R; Senturk, Serif; Boroda, Joseph; Pisterzi, Paola; Miller, Madison; Munoz, Gustavo; Anderluh, Marko; Ladanyi, Marc; Lowe, Scott W; Sordella, Raffaella

    2016-01-01

    TP53 truncating mutations are common in human tumors and are thought to give rise to p53-null alleles. Here, we show that TP53 exon-6 truncating mutations occur at higher than expected frequencies and produce proteins that lack canonical p53 tumor suppressor activities but promote cancer cell proliferation, survival, and metastasis. Functionally and molecularly, these p53 mutants resemble the naturally occurring alternative p53 splice variant, p53-psi. Accordingly, these mutants can localize to the mitochondria where they promote tumor phenotypes by binding and activating the mitochondria inner pore permeability regulator, Cyclophilin D (CypD). Together, our studies reveal that TP53 exon-6 truncating mutations, contrary to current beliefs, act beyond p53 loss to promote tumorigenesis, and could inform the development of strategies to target cancers driven by these prevalent mutations. DOI: http://dx.doi.org/10.7554/eLife.17929.001 PMID:27759562

  16. Low penetrance susceptibility to glioma is caused by the TP53 variant rs78378222

    PubMed Central

    Enciso-Mora, V; Hosking, F J; Di Stefano, A L; Zelenika, D; Shete, S; Broderick, P; Idbaih, A; Delattre, J-Y; Hoang-Xuan, K; Marie, Y; Labussière, M; Alentorn, A; Ciccarino, P; Rossetto, M; Armstrong, G; Liu, Y; Gousias, K; Schramm, J; Lau, C; Hepworth, S J; Schoemaker, M; Strauch, K; Müller-Nurasyid, M; Schreiber, S; Franke, A; Moebus, S; Eisele, L; Swerdlow, A; Simon, M; Bondy, M; Lathrop, M; Sanson, M; Houlston, R S

    2013-01-01

    Background: Most of the heritable risk of glioma is presently unaccounted for by mutations in known genes. In addition to rare inactivating germline mutations in TP53 causing glioma in the context of the Li-Fraumeni syndrome, polymorphic variation in TP53 may also contribute to the risk of developing glioma. Methods: To comprehensively evaluate the impact of variation in TP53 on risk, we analysed 23 tagSNPs and imputed 2377 unobserved genotypes in four series totaling 4147 glioma cases and 7435 controls. Results: The strongest validated association signal was shown by the imputed single-nucleotide polymorphism (SNP) rs78378222 (P=6.86 × 10−24, minor allele frequency ∼0.013). Confirmatory genotyping confirmed the high quality of the imputation. The association between rs78378222 and risk was seen for both glioblastoma multiforme (GBM) and non-GBM tumours. We comprehensively examined the relationship between rs78378222 and overall survival in two of the case series totaling 1699 individuals. Despite employing statistical tests sensitive to the detection of differences in early survival, no association was shown. Conclusion: Our data provided strong validation of rs78378222 as a risk factor for glioma but do not support the tenet that the polymorphism being a clinically useful prognostic marker. Acquired TP53 inactivation is a common feature of glioma. As rs78378222 changes the polyadenylation signal of TP53 leading to impaired 3′-end processing of TP53 mRNA, the SNP has strong plausibility for being directly functional contributing to the aetiological basis of glioma. PMID:23571737

  17. KRAS and TP53 mutations in bronchoscopy samples from former lung cancer patients.

    PubMed

    Gao, Weimin; Jin, Jide; Yin, Jinling; Land, Stephanie; Gaither-Davis, Autumn; Christie, Neil; Luketich, James D; Siegfried, Jill M; Keohavong, Phouthone

    2017-02-01

    Mutations in the KRAS and TP53 genes have been found frequently in lung tumors and specimens from individuals at high risk for lung cancer and have been suggested as predictive markers for lung cancer. In order to assess the prognostic value of these two genes' mutations in lung cancer recurrence, we analyzed mutations in codon 12 of the KRAS gene and in hotspot codons of the TP53 gene in 176 bronchial biopsies obtained from 77 former lung cancer patients. Forty-seven patients (61.0%) showed mutations, including 35/77 (45.5%) in the KRAS gene and 25/77 (32.5%) in the TP53 gene, among them 13/77 (16.9%) had mutations in both genes. When grouped according to past or current smoking status, a higher proportion of current smokers showed mutations, in particular those in the TP53 gene (P = 0.07), compared with ex-smokers. These mutations were found in both abnormal lesions (8/20 or 40%) and histologically normal tissues (70/156 or 44.9%) (P = 0.812). They consisted primarily of G to A transition and G to T transversion in both the KRAS (41/56 or 73.2%) and TP53 (24/34 or 70.6%) genes, consistent with mutations found in lung tumors of smoking lung cancer patients. Overall, recurrence-free survival (RFS) among all subjects could be explained by age at diagnosis, tumor stage, tumor subtype, and smoking (P < 0.05, Cox proportional hazard). Therefore, KRAS and TP53 mutations were frequently detected in bronchial tissues of former lung cancer patients. However, the presence of mutation of bronchial biopsies was not significantly associated with a shorter RFS time. © 2016 Wiley Periodicals, Inc.

  18. TP53 Mutational Status and Prediction of Benefit from Adjuvant 5-Fluorouracil in Stage III Colon Cancer Patients.

    PubMed

    Kandioler, Daniela; Mittlböck, Martina; Kappel, Sonja; Puhalla, Harald; Herbst, Friedrich; Langner, Cord; Wolf, Brigitte; Tschmelitsch, Jörg; Schippinger, Walter; Steger, Günther; Hofbauer, Friedrich; Samonigg, Hellmut; Gnant, Michael; Teleky, Bela; Kührer, Irene

    2015-08-01

    We investigated the hypothesis that the varying treatment efficacy of adjuvant 5-fluorouracil (5FU) in stage III colon cancer is linked to the TP53 mutational status. ABCSG-90 was a prospective randomized trial in which effect of adjuvant 5FU was studied in stage III colon cancer patients. Tumor material of 70% of these patients (389/572) was available for analysis of the biomarker TP53 using a TP53-gene-specific Sanger sequencing protocol. Median follow-up was 88 months. TP53 mutation frequency was 33%. A significant interaction between TP53 status, outcomes and nodal category was found (P = 0.0095). In the N1 category, TP53 wildtype patients had significantly better overall survival than TP53 mutated (81.0% vs. 62.0% overall survival at 5 years; HR = 2.131; 95% CI: 1.344-3.378; P = 0.0010). In the N2 category, the TP53 status did not affect survival (P = 0.4992). In TP53 wildtype patients, the prognostic significance of N category was significantly enhanced (P = 0.0002). In TP53 mutated patients, survival curves of N1 and N2 patients overlapped and nodal category was no longer prognostic. The biomarker TP53 independently predicted effect of adjuvant 5FU in N1 colon cancer patients. TP53 was not predictive in N2 patients, in whom 5FU is known to have no effect.

  19. Review of disrupted sleep patterns in Smith-Magenis syndrome and normal melatonin secretion in a patient with an atypical interstitial 17p11.2 deletion.

    PubMed

    Boudreau, Eilis A; Johnson, Kyle P; Jackman, Angela R; Blancato, Jan; Huizing, Marjan; Bendavid, Claude; Jones, Marypat; Chandrasekharappa, Settara C; Lewy, Alfred J; Smith, Ann C M; Magenis, R Ellen

    2009-07-01

    Smith-Magenis syndrome (SMS) is a disorder characterized by multiple congenital anomalies and behavior problems, including abnormal sleep patterns. It is most commonly due to a 3.5 Mb interstitial deletion of chromosome 17 band p11.2. Secretion of melatonin, a hormone produced by the pineal gland, is the body's signal for nighttime darkness. Published reports of 24-hr melatonin secretion patterns in two independent SMS cohorts (US and France) document an inverted endogenous melatonin pattern in virtually all cases (96%), suggesting that this finding is pathognomic for the syndrome. We report on a woman with SMS due to an atypical large proximal deletion ( approximately 6Mb; cen<->TNFRSFproteinB) of chromosome band (17)(p11.2p11.2) who presents with typical sleep disturbances but a normal pattern of melatonin secretion. We further describe a melatonin light suppression test in this patient. This is the second reported patient with a normal endogenous melatonin rhythm in SMS associated with an atypical large deletion. These two patients are significant because they suggest that the sleep disturbances in SMS cannot be solely attributed to the abnormal diurnal melatonin secretion versus the normal nocturnal pattern.

  20. Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian Breast Cancer Family Study.

    PubMed

    Mouchawar, Judy; Korch, Christopher; Byers, Tim; Pitts, Todd M; Li, Efang; McCredie, Margaret R E; Giles, Graham G; Hopper, John L; Southey, Melissa C

    2010-06-15

    Although germline TP53 mutations have been identified in women with breast cancer from families meeting Li-Fraumeni criteria, their contribution to breast cancer per se is not well known, but is thought to be minimal. We aimed to determine the prevalence of germline TP53 mutations in subgroups of early-onset breast cancer. Germline TP53 mutation status was assessed by DNA sequencing, screening for heterozygous single-nucleotide polymorphisms, and Multiplex Ligation-Dependent Probe Amplification analyses. From an Australian population-based series of invasive breast cancers, we studied (a) 52 women diagnosed before age 30 years unselected for family history [very early-onset (VEO)] and (b) 42 women diagnosed in their 30s with two or more first- or second-degree relatives with breast or ovarian cancer [early-onset family history (EO-FH)]. Of the VEO group, two (4%) had a mutation: G13203A (exon 6 missense) in a 24-year-old and a large 5,338-bp genomic deletion in a 26-year-old. Neither had a family cancer history that met Li-Fraumeni criteria. Of the EO-FH group, three (7%) had a mutation: T13240G (a known intron 5 splicing mutation) in a 36-year-old from a classic Li-Fraumeni family; G12299A (exon 4 missense) in a 33-year-old from a Li-Fraumeni-like family; and 14058delG (exon 7 frame-shift) in a 39-year-old with a family cancer history that did not meet Li-Fraumeni criteria. Germline TP53 mutations play a larger role in early-onset breast cancer than previously thought, and in this context, can be evident outside clinically defined Li-Fraumeni families.

  1. microRNA fingerprinting of CLL patients with chromosome 17p deletion identify a miR-21 score that stratifies early survival.

    PubMed

    Rossi, Simona; Shimizu, Masayoshi; Barbarotto, Elisa; Nicoloso, Milena S; Dimitri, Federica; Sampath, Deepa; Fabbri, Muller; Lerner, Susan; Barron, Lynn L; Rassenti, Laura Z; Jiang, Li; Xiao, Lianchun; Hu, Jianhua; Secchiero, Paola; Zauli, Giorgio; Volinia, Stefano; Negrini, Massimo; Wierda, William; Kipps, Thomas J; Plunkett, William; Coombes, Kevin R; Abruzzo, Lynne V; Keating, Michael J; Calin, George A

    2010-08-12

    Aberrant expression of microRNAs (miRNAs) has been associated with clinical outcome in patients with chronic lymphocytic leukemia (CLL). To identify a powerful and easily assessable miRNA bio-marker of prognosis and survival, we performed quantitative reverse-transcription polymerase chain reaction (qRT-PCR) profiling in 104 CLL patients with a well-defined chromosome 17p status, and we validated our findings with miRNA microarray data from an independent cohort of 80 patients. We found that miR-15a, miR-21, miR-34a, miR-155, and miR-181b were differentially expressed between CLLs with chromosome 17p deletion and CLLs with normal 17p and normal karyotype, and that miR-181b was down-regulated in therapy-refractory cases. miR-21 expression levels were significantly higher in patients with poor prognosis and predicted overall survival (OS), and miR-181b expression levels significantly predicted treatment-free survival. We developed a 21FK score (miR-21 qRT-PCR, fluorescence in situ hybridization, Karyotype) to stratify patients according to OS and found that patients with a low score had a significantly longer OS time. When we evaluated the relative power of the 21FK score with the most used prognostic factors, the score was the most significant in both CLL cohorts. We conclude that the 21FK score represents a useful tool for distinguishing between good-prognosis and poor-prognosis CLL patients.

  2. Effect of hypoxia and TP53 mutation status and cytogenetics of normal and malignant mammary epithelium.

    PubMed

    Vidarsson, Hilmar; Steinarsdóttir, Margrét; Jónasson, Jón Gunnlaugur; Júlíusdóttir, Hildur; Hauksdóttir, Halla; Hilmarsdóttir, Hólmfrídur; Halldórsdóttir, Kristín; Ogmundsdóttir, Helga M

    2006-03-01

    It has been proposed that hypoxia favors the growth of tumor cells over normal cells, particularly tumor cells carrying TP53 mutations. Cytogenetic studies of breast cancer have shown that highly complex karyotypes seen in direct harvest preparations are rarely detected after short-term culture. In this study, 34 paired samples of breast carcinomas and grossly nontumorous tissue from the same breast were cultured at 20 and 5% (12 samples) or 20 and 0% oxygen (22 samples). Both carcinoma samples and nontumorous tissue survived at 0% oxygen. Recovery for 24 hours at 20% produced good yields for cytogenetic analysis. Lower oxygen levels did not specifically stimulate growth of tumor cells. Samples with TP53 mutations showed a consistently increased growth under anaerobic hypoxic conditions. Culture at 5% oxygen did not generally reveal more karyotypic abnormalities than found at 20%. In the samples cultured at 0 and 20%, karyotypic abnormalities were detected only in anaerobic hypoxic culture in two cases. Of the only four samples where more complex karyotypes were detected in the low-oxygen culture, two were TP53 mutated. Hypoxic treatment followed by recovery at 20% oxygen may thus increase the yield of complex karyotypes from a subset of breast carcinomas, particularly those with mutated TP53.

  3. Development and translational imaging of a TP53 porcine tumorigenesis model

    PubMed Central

    Sieren, Jessica C.; Meyerholz, David K.; Wang, Xiao-Jun; Davis, Bryan T.; Newell, John D.; Hammond, Emily; Rohret, Judy A.; Rohret, Frank A.; Struzynski, Jason T.; Goeken, J. Adam; Naumann, Paul W.; Leidinger, Mariah R.; Taghiyev, Agshin; Van Rheeden, Richard; Hagen, Jussara; Darbro, Benjamin W.; Quelle, Dawn E.; Rogers, Christopher S.

    2014-01-01

    Cancer is the second deadliest disease in the United States, necessitating improvements in tumor diagnosis and treatment. Current model systems of cancer are informative, but translating promising imaging approaches and therapies to clinical practice has been challenging. In particular, the lack of a large-animal model that accurately mimics human cancer has been a major barrier to the development of effective diagnostic tools along with surgical and therapeutic interventions. Here, we developed a genetically modified porcine model of cancer in which animals express a mutation in TP53 (which encodes p53) that is orthologous to one commonly found in humans (R175H in people, R167H in pigs). TP53R167H/R167H mutant pigs primarily developed lymphomas and osteogenic tumors, recapitulating the tumor types observed in mice and humans expressing orthologous TP53 mutant alleles. CT and MRI imaging data effectively detected developing tumors, which were validated by histopathological evaluation after necropsy. Molecular genetic analyses confirmed that these animals expressed the R167H mutant p53, and evaluation of tumors revealed characteristic chromosomal instability. Together, these results demonstrated that TP53R167H/R167H pigs represent a large-animal tumor model that replicates the human condition. Our data further suggest that this model will be uniquely suited for developing clinically relevant, noninvasive imaging approaches to facilitate earlier detection, diagnosis, and treatment of human cancers. PMID:25105366

  4. A Pathogenic Mosaic TP53 Mutation in Two Germ Layers Detected by Next Generation Sequencing

    PubMed Central

    Williams, Richard D.; Side, Lucy; Hubank, Mike; West, Rebecca; Pearson, Katie; Sebire, Neil; Tarpey, Patrick; Futreal, Andrew; Brooks, Tony; Stratton, Michael R.; Anderson, John

    2014-01-01

    Background Li-Fraumeni syndrome is caused by germline TP53 mutations and is clinically characterized by a predisposition to a range of cancers, most commonly sarcoma, brain tumours and leukemia. Pathogenic mosaic TP53 mutations have only rarely been described. Methods and Findings We describe a 2 years old child presenting with three separate cancers over a 6 month period; two soft tissue mesenchymal tumors and an aggressive metastatic neuroblastoma. As conventional testing of blood DNA by Sanger sequencing for mutations in TP53, ALK, and SDH was negative, whole exome sequencing of the blood DNA of the patient and both parents was performed to screen more widely for cancer predisposing mutations. In the patient's but not the parents' DNA we found a c.743 G>A, p.Arg248Gln (CCDS11118.1) TP53 mutation in 3–20% of sequencing reads, a level that would not generally be detectable by Sanger sequencing. Homozygosity for this mutation was detected in all tumor samples analyzed, and germline mosaicism was demonstrated by analysis of the child's newborn blood spot DNA. The occurrence of separate tumors derived from different germ layers suggests that this de novo mutation occurred early in embryogenesis, prior to gastrulation. Conclusion The case demonstrates pathogenic mosaicim, detected by next generation deep sequencing, that arose in the early stages of embryogenesis. PMID:24810334

  5. hTERT, MYC and TP53 deregulation in gastric preneoplastic lesions

    PubMed Central

    2012-01-01

    Background Gastric cancer is a serious public health problem in Northern Brazil and in the world due to its high incidence and mortality. Despite the severity of the disease, more research is needed to better understand the molecular events involved in this intestinal-type gastric carcinogenesis process. Since precancerous lesions precede intestinal-type gastric cancer, here, we evaluated the hTERT, MYC, and TP53 mRNA and protein expression, as well as TP33 copy number, in gastric preneoplastic lesions. Methods We evaluated 19 superficial gastritis, 18 atrophic gastritis, and 18 intestinal metaplasia from cancer-free individuals of Northern Brazil. Quantitative reverse transcription PCR was used to analyze the mRNA expression and immunohistochemical methods were used to assess protein immunoreactivity in tissue samples. The number of TP53 gene copies was investigated in gastric diseases by quantitative PCR. Results We observed hTERT, MYC, and p53 immunoreactivity only in intestinal metaplasia samples. The immunoreactivity of these proteins was strongly associated with each other. A significantly higher MYC mRNA expression was observed in intestinal metaplasia compared to gastritis samples. Loss of TP53 was also only detected in intestinal metaplasia specimens. Conclusions We demonstrated that hTERT, MYC, and TP53 are deregulated in intestinal metaplasia of individuals from Northern Brazil and these alterations may facilitate tumor initiation. PMID:22768805

  6. The TP53 gene rs1042522 C>G polymorphism and neuroblastoma risk in Chinese children.

    PubMed

    He, Jing; Wang, Fenghua; Zhu, Jinhong; Zhang, Zhuorong; Zou, Yan; Zhang, Ruizhong; Yang, Tianyou; Xia, Huimin

    2017-03-08

    TP53, a tumor suppressor gene, plays a critical role in cell cycle control, apoptosis, and DNA damage repair. Previous studies have indicated that the TP53 gene Arg72Pro (rs1042522 C>G) polymorphism is associated with susceptibility to various types of cancer. We evaluated the association of the TP53 gene rs1042522 C>G polymorphism with neuroblastoma susceptibility in a hospital-based study among the Chinese Han population. Enrolled were 256 patients and 531 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) generated using logistic regression models were used to determine the strength of the association of interest. No association was detected between rs1042522 C>G polymorphism and neuroblastoma risk. In our stratification analysis of age, gender, sites of origin, and clinical stages, we observed that subjects with rs1042522 CG/GG genotypes had a lower risk of developing neuroblastoma in the mediastinum (Adjusted OR=0.52, 95% CI=0.33-0.82, P=0.005) than those carrying the CC genotype. These results indicate that TP53 gene rs1042522 C>G polymorphism may exert a weak and site-specific effect on neuroblastoma risk in Southern Chinese children and warrant further confirmation.

  7. Extremely High Tp53 Mutation Load in Esophageal Squamous Cell Carcinoma in Golestan Province, Iran

    PubMed Central

    Abedi-Ardekani, Behnoush; Kamangar, Farin; Sotoudeh, Masoud; Villar, Stephanie; Islami, Farhad; Aghcheli, Karim; Nasrollahzadeh, Dariush; Taghavi, Noushin; Dawsey, Sanford M.; Abnet, Christian C.; Hewitt, Stephen M.; Fahimi, Saman; Saidi, Farrokh; Brennan, Paul; Boffetta, Paolo; Malekzadeh, Reza; Hainaut, Pierre

    2011-01-01

    Background Golestan Province in northeastern Iran has one of the highest incidences of esophageal squamous cell carcinoma (ESCC) in the world with rates over 50 per 100,000 person-years in both sexes. We have analyzed TP53 mutation patterns in tumors from this high-risk geographic area in search of clues to the mutagenic processes involved in causing ESCC. Methodology/Principal Findings Biopsies of 119 confirmed ESCC tumor tissue from subjects enrolled in a case-control study conducted in Golestan Province were analyzed by direct sequencing of TP53 exons 2 through 11. Immunohistochemical staining for p53 was carried out using two monoclonal antibodies, DO7 and 1801. A total of 120 TP53 mutations were detected in 107/119 cases (89.9%), including 11 patients with double or triple mutations. The mutation pattern was heterogeneous with infrequent mutations at common TP53 “hotspots” but frequent transversions potentially attributable to environmental carcinogens forming bulky DNA adducts, including 40% at bases known as site of mutagenesis by polycyclic aromatic hydrocarbons (PAHs). Mutations showed different patterns according to the reported temperature of tea consumption, but no variation was observed in relation to ethnicity, tobacco or opium use, and alcoholic beverage consumption or urban versus rural residence. Conclusion/Significance ESCC tumors in people from Golestan Province show the highest rate of TP53 mutations ever reported in any cancer anywhere. The heterogeneous mutation pattern is highly suggestive of a causative role for multiple environmental carcinogens, including PAHs. The temperature and composition of tea may also influence mutagenesis. PMID:22216294

  8. A 1.5-Mb cosmid contig of the CMT1A duplication/HNPP deletion critical region in 17p11.2-p12

    SciTech Connect

    Murakami, Tatsufumi; Lupski, J.R.

    1996-05-15

    Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with a 1.5-Mb tandem duplication in chromosome 17p11.2-p12, and hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a 1.5-Mb deletion at this locus. Both diseases appear to result from an altered copy number of the peripheral myelin protein-22 gene, PMP22, which maps within the critical region. To identify additional genes and characterize chromosomal elements, a 1.5-Mb cosmid contig of the CMT1A duplication/HNPP deletion critical region was assembled using a yeast artificial chromosome (YAC)-based isolation and binning strategy. Whole YAC probes were used for screening a high-density arrayed chromosome 17-specific cosmid library. Selected cosmids were spotted on dot blots and assigned to bins defined by YACs. This binning of cosmids facilitated the subsequent fingerprint analysis. The 1.5-Mb region was covered by 137 cosmids with a minimum overlap set of 52 cosmids assigned to 17 bins and 9 contigs. 20 refs., 2 figs.

  9. Coexistence of a T118M PMP22 missense mutation and chromosome 17 (17p11.2-p12) deletion

    PubMed Central

    Jerath, Nivedita U.; Kamholz, John; Grider, Tiffany; Harper, Amy; Swenson, Andrea; Shy, Michael E.

    2015-01-01

    We describe a 6-year-old girl with a T118M PMP22 mutation and heterozygous deletion of PMP22 on chromosome 17 (17p11.2-p12) resulting in a severe sensorimotor polyneuropathy. Methods Case Report Results Foot pain, cavovarus feet, tibialis anterior atrophy, absent reflexes, and inability to walk were found at age 6. Nerve conduction studies showed evidence of a sensorimotor polyneuropathy and compressive mononeuropathies of bilateral median nerves at the wrist and ulnar nerves at the elbow. Genetic testing revealed a deletion of a PMP22 allele and T118M PMP22 mutation in the remaining allele. Conclusions The severe presentation of sensory motor polyneuropathy and HNPP in this patient is likely a consequence of both decreased expression of PMP22 causing features consistent with HNPP, and unopposed expression of the T118M mutant form of PMP22 that is relatively benign in the heterozygous state. The T118M mutant form of PMP22 can be disease-modifying in the appropriate circumstances. PMID:26012543

  10. A 1.5-Mb cosmid contig of the CMT1A duplication/HNPP deletion critical region in 17p11.2-p12.

    PubMed

    Murakami, T; Lupski, J R

    1996-05-15

    Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with a 1. 5-Mb tandem duplication in chromosome 17p11.2-p12, and hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a 1.5-Mb deletion at this locus. Both diseases appear to result from an altered copy number of the peripheral myelin protein-22 gene, PMP22, which maps within the critical region. To identify additional genes and characterize chromosomal elements, a 1.5-Mb cosmid contig of the CMT1A duplication/HNPP deletion critical region was assembled using a yeast artificial chromosome (YAC)-based isolation and binning strategy. Whole YAC probes were used for screening a high-density arrayed chromosome 17-specific cosmid library. Selected cosmids were spotted on dot blots and assigned to bins defined by YACs. This binning of cosmids facilitated the subsequent fingerprint analysis. The 1.5-Mb region was covered by 137 cosmids with a minimum overlap set of 52 cosmids assigned to 17 bins and 9 contigs.

  11. [Frequency, spectrum, and functional significance of TP53 mutations in patients with diffuse large B-cell lymphoma].

    PubMed

    Voropaeva, E N; Pospelova, T I; Voevoda, M I; Maksimov, V N

    2017-01-01

    A comparative analysis of oncogene mutations shows that variations in their frequency, spectrum, and hot-spot locations depends on the type of tumor and the ethnic origin of the population studied. The current version of the IARC TP53 Mutation Database lacks information about the frequency and spectrum of TP53 mutations in patients with DLBCL in Russia. The aim of this study was to assess the frequency and functional significance of TP53 mutations in patients with DLBCL in Novosibirsk. The TP53 coding sequence and the adjacent intron regions were analyzed by direct sequencing in the tumor material from 74 patients with DLBCL. Mutations of the TP53 coding sequence were found in 18 (24.3%) patients. These data are consistent with the frequency of TP53  mutations observed in other studies. The spectrum of nucleotide substitutions found in DLBCL specimens corresponded to that described in the IARC TP53 Mutation Database. According to bioinformatic data and to reported experiments in vitro, most of the mutations detected result in the production of functionally inactive p53. Our results show that DLBCL progression is accompanied by the functional selection for mutations in TP53 exons 5-8.

  12. A FISH comparison of variant derivatives of the recurrent dic(17;20) of myelodysplastic syndromes and acute myeloid leukemia: Obligatory retention of genes on 17p and 20q may explain the formation of dicentric chromosomes.

    PubMed

    MacKinnon, Ruth N; Patsouris, Cris; Chudoba, Ilse; Campbell, Lynda J

    2007-01-01

    The dic(17;20) is a recurrent unbalanced translocation occurring rarely in myelodysplastic syndromes and acute myeloid leukemia. We have studied eleven cases with the dic(17;20) or a more complex derivative, all of which showed deletion of 17p and 20q material. The tumor suppressor gene TP53 was not always lost, supporting a more distal gene as the target of these 17p deletions. All derivatives could be interpreted as having initially been formed as a dicentric chromosome, those with a larger amount of material between the centromeres having undergone further rearrangement to stabilize the chromosome while retaining proximal 17p and proximal 20q material. We propose that critical sequences on both 17p and 20q proximal to the sites of deletion must be retained during the critical 17p and 20q deletions. This would explain the excess of dicentric chromosomes resulting from 17;20 translocation, and the apparent stabilization of the unstable derivatives by further rearrangements which preserve 17p and 20q material.

  13. Isolation of novel genes from the CMT1A duplication/HNPP deletion critical region in 17p11.2-p12.

    PubMed

    Murakami, T; Sun, Z S; Lee, C C; Lupski, J R

    1997-01-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with a 1.5-Mb tandem DNA duplication in chromosome 17p11.2-p12, while hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a 1.5-Mb deletion at this locus. The 1.5-Mb CMT1A monomer unit duplicated in CMT1A and deleted in HNPP is flanked by low-copy repeats termed CMT1A-REPs. Both diseases appear to be caused by an altered copy number of the peripheral myelin protein 22 gene (PMP22), which lies within the critical region. To identify additional genes rapidly, we used a cosmid contig of this region and reciprocal probing of arrayed chromosome 17-specific cosmid and cDNA libraries. Three cDNA clones were identified within the CMT1A duplication/HNPP deletion region and one just proximal to the critical region. The cDNA for human heme A:farnesyltransferase (COX10) mapped 10 kb centromeric to the distal CMT1A-REP. The other two cDNA clones from within the critical interval mapped to cosmid 126D1 at the mfd41 (D17S261) DNA marker, and their conceptual translation showed homology to 60S ribosomal protein L9 (RPL9) and chromosomal protein RMSA-1 (RMSA-1). A gene that is homologous to human peroxisome proliferator activated receptor alpha (hPPARA) was identified near the proximal CMT1A-REP.

  14. Autophagy is induced through the ROS-TP53-DRAM1 pathway in response to mitochondrial protein synthesis inhibition.

    PubMed

    Xie, Xiaolei; Le, Li; Fan, Yanxin; Lv, Lin; Zhang, Junjie

    2012-07-01

    Mitoribosome in mammalian cells is responsible for synthesis of 13 mtDNA-encoded proteins, which are integral parts of four mitochondrial respiratory chain complexes (I, III, IV and V). ERAL1 is a nuclear-encoded GTPase important for the formation of the 28S small mitoribosomal subunit. Here, we demonstrate that knockdown of ERAL1 by RNA interference inhibits mitochondrial protein synthesis and promotes reactive oxygen species (ROS) generation, leading to autophagic vacuolization in HeLa cells. Cells that lack ERAL1 expression showed a significant conversion of LC3-I to LC3-II and an enhanced accumulation of autophagic vacuoles carrying the LC3 marker, all of which were blocked by the autophagy inhibitor 3-MA as well as by the ROS scavenger NAC. Inhibition of mitochondrial protein synthesis either by ERAL1 siRNA or chloramphenicol (CAP), a specific inhibitor of mitoribosomes, induced autophagy in HTC-116 TP53 (+/+) cells, but not in HTC-116 TP53 (-/-) cells, indicating that tumor protein 53 (TP53) is essential for the autophagy induction. The ROS elevation resulting from mitochondrial protein synthesis inhibition induced TP53 expression at transcriptional levels by enhancing TP53 promoter activity, and increased TP53 protein stability by suppressing TP53 ubiquitination through MAPK14/p38 MAPK-mediated TP53 phosphorylation. Upregulation of TP53 and its downstream target gene DRAM1, but not CDKN1A/p21, was required for the autophagy induction in ERAL1 siRNA or CAP-treated cells. Altogether, these data indicate that autophagy is induced through the ROS-TP53-DRAM1 pathway in response to mitochondrial protein synthesis inhibition.

  15. A new quantitative PCR multiplex assay for rapid analysis of chromosome 17p11.2-12 duplications and deletions leading to HMSN/HNPP.

    PubMed

    Thiel, Christian T; Kraus, Cornelia; Rauch, Anita; Ekici, Arif B; Rautenstrauss, Bernd; Reis, André

    2003-02-01

    A 1.4-Mb tandem duplication, including the gene for peripheral myelin protein 22 (PMP22) in chromosome 17p11.2-12 is responsible for 70% of the cases of the demyelinating type 1 of Charcot-Marie-Tooth disease or hereditary motor and sensory neuropathy I (CMT1A/HMSN I). A reciprocal deletion of this CMT1A region causes the hereditary neuropathy with liability to pressure palsies (HNPP). The CMT1A duplication increases the PMP22 gene dosage from two to three, the HNPP deletion reduces the gene dosage from two to one. Currently, routine diagnosis of HMSN/HNPP patients is mainly performed with polymorphic markers in-between the repetitive elements flanking the CMT1A region. These show quantitative and/or qualitative changes in case of a CMT1A duplication and a homozygous allele pattern in case of HNPP deletion. In HNPP patients the deletion is usually confirmed by fluorescence in situ hybridisation (FISH). We now developed a reliable, single tube real-time quantitative PCR assay for rapid determination of PMP22 gene dosage directly. This method involves a multiplex reaction using FAM labelled Taqman-probe with TAMRA quencher derived from PMP22 exon 3 and a VIC labelled probe with non-fluorescent quencher from exon 12 of the albumin gene as internal reference. Copy number of the PMP22 gene was determined by the comparative threshold cycle method (deltadeltaCt). Each sample was run in quadruplicate and analysed at two different threshold levels. The level giving the smallest standard deviation was scored. We evaluated this method through the retrospective analysis of 252 HMSN patients with known genotype and could confirm the previous findings in 99% of cases. Two patients were wrongly diagnosed with microsatellite analysis while quantitative real-time PCR identified the correct genotype, as confirmed by FISH. Thus, this method shows superior sensitivity to microsatellite analysis and has the additional advantage of being a fast and uniform assay for quantitative

  16. Hepatitis B and Hepatitis C Infection Biomarkers and TP53 Mutations in Hepatocellular Carcinomas from Colombia.

    PubMed

    Navas, Maria-Cristina; Suarez, Iris; Carreño, Andrea; Uribe, Diego; Rios, Wilson Alfredo; Cortes-Mancera, Fabian; Martel, Ghyslaine; Vieco, Beatriz; Lozano, Diana; Jimenez, Carlos; Gouas, Doriane; Osorio, German; Hoyos, Sergio; Restrepo, Juan Carlos; Correa, Gonzalo; Jaramillo, Sergio; Lopez, Rocio; Bravo, Luis Eduardo; Arbelaez, Maria Patricia; Scoazec, Jean-Yves; Abedi-Ardekani, Behnoush; Santella, Regina M; Chemin, Isabelle; Hainaut, Pierre

    2011-01-01

    Hepatocellular Carcinoma (HCC) is a leading cause of cancer-related death worldwide. Globally, the most important HCC risk factors are Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV), chronic alcoholism, and dietary exposure to aflatoxins. We have described the epidemiological pattern of 202 HCC samples obtained from Colombian patients. Additionally we investigated HBV/HCV infections and TP53 mutations in 49 of these HCC cases. HBV biomarkers were detected in 58.1% of the cases; HBV genotypes F and D were characterized in three of the samples. The HCV biomarker was detected in 37% of the samples while HBV/HCV coinfection was found in 19.2%. Among TP53 mutations, 10.5% occur at the common aflatoxin mutation hotspot, codon 249. No data regarding chronic alcoholism was available from the cases. In conclusion, in this first study of HCC and biomarkers in a Colombian population, the main HCC risk factor was HBV infection.

  17. Deep sequencing of the TP53 gene reveals a potential risk allele for non-small cell lung cancer and supports the negative prognostic value of TP53 variants.

    PubMed

    Deben, Christophe; Van den Bossche, Jolien; Van Der Steen, Nele; Lardon, Filip; Wouters, An; de Beeck, Ken Op; Hermans, Christophe; Jacobs, Julie; Peeters, Marc; Van Camp, Guy; Rolfo, Christian; Deschoolmeester, Vanessa; Pauwels, Patrick

    2017-02-01

    The TP53 gene remains the most frequently altered gene in human cancer, of which variants are associated with cancer risk, therapy resistance, and poor prognosis in several tumor types. To determine the true prognostic value of TP53 variants in non-small cell lung cancer, this study conducted further research, particularly focusing on subtype and tumor stage. Therefore, we determined the TP53 status of 97 non-small cell lung cancer adenocarcinoma patients using next generation deep sequencing technology and defined the prognostic value of frequently occurring single nucleotide polymorphisms and mutations in the TP53 gene. Inactivating TP53 mutations acted as a predictor for both worse overall and progression-free survival in stage II-IV patients and patients treated with DNA-damaging (neo)adjuvant therapy. In stage I tumors, the Pro-allele of the TP53 R72P polymorphism acted as a predictor for worse overall survival. In addition, we detected the rare R213R (rs1800372, minor allele frequency: 0.0054) polymorphism in 7.2% of the patients and are the first to show the significant association with TP53 mutations in non-small cell lung cancer adenocarcinoma patients (p = 0.003). In conclusion, Our findings show an important role for TP53 variants as negative predictors for the outcome of non-small cell lung cancer adenocarcinoma patients, especially for TP53 inactivating mutations in advanced stage tumors treated with DNA-damaging agents, and provide the first evidence of the R213R G-allele as possible risk factor for non-small cell lung cancer.

  18. Epigenetic modifications, chromatin distribution and TP53 transcription in a model of breast cancer progression.

    PubMed

    Santos, Gilson C; da Silva, Ana P A; Feldman, Lucas; Ventura, Grasiella M; Vassetzky, Yegor; de Moura Gallo, Claudia V

    2015-04-01

    In the present paper we aimed to characterize epigenetic aspects and analyze TP53 transcription in the 21 T series, composed of breast cell lines: non-cancerous H16N2; Atypical Ductal Hyperplasia 21PT; Ductal Carcinoma in situ 21NT and Invasive Metastatic Carcinoma 21MT1. We detected a global genomic hypomethylation in 21NT and 21MT1. The histone modification markers analysis showed an important global decrease of the active chromatin mark H4Ac in 21MT1 relative to the other cell lines while the repressive mark H3K9Me3 were not significantly altered. The mRNA levels of DNA methylation and histone modification key enzymes are consistent with the observed genomic hypomethylation and histone hypoacetylation. The expression of DNMT3A/B increased at the initial stages of oncogenesis and the expression of DNMT1 and HAT1 decreased at the advanced stages of breast cancer. Using a confocal immunofluorescent assay, we observed that H4Ac was mostly located at the periphery and the repressive mark H3K9Me3, at the center of 21NT and 21MT1 cells nuclei. TP53 P1 promoter was found to be in an open chromatin state, with a relatively high enrichment of H4Ac and similar TP53 transcription levels in all 21 T cell lines. In conclusion, we observed epigenetic alterations (global genome hypomethylation, global hypoacetylation and accumulation of pericentric heterochromatin) in metastatic breast cancer cells of the 21 T series. These alterations may act at later stages of breast cancer progression and may not affect TP53 transcription at the P1 promoter.

  19. Deregulation of MYC and TP53 through genetic and epigenetic alterations in gallbladder carcinomas.

    PubMed

    Ishak, Geraldo; Leal, Mariana Ferreira; Dos Santos, Ney Pereira Carneiro; Demachki, Samia; Nunes, Caroline Aquino Moreira; do Nascimento Borges, Barbara; Calcagno, Danielle Queiroz; Smith, Marília Cardoso; Assumpção, Paulo Pimentel; Burbano, Rommel Rodríguez

    2015-08-01

    Gallbladder cancer is a rare malignancy and presents a poor prognosis. MYC and p53 have been implicated in gallbladder carcinogenesis. However, little is known about the molecular mechanisms involved in their regulation in this neoplasia. Here, we evaluated the MYC and TP53 copy numbers in gallbladder tumors and their possible association with protein expression. We also investigated whether MYC may be controlled by mutations and DNA promoter methylation. In the present study, 15 samples of invasive gallbladder carcinomas and six control samples were analyzed. On the other hand, the expression of MYC and p53 was more frequent in gallbladder carcinomas than in control samples (p = 0.002, p = 0.046, respectively). Gain of copies of the MYC and TP53 genes was detected in 86.7 and 50 % of gallbladder carcinomas, respectively. MYC and TP53 amplifications were associated with immunoreactivity of their protein (p = 0.029, p = 0.001, respectively). MYC hypomethylation was only detected in tumoral samples and was associated with its protein expression (p = 0.029). MYC mutations were detected in 80 % of tumor samples. The G allele at rs117856857 was associated with the presence of gallbladder tumors (p = 0.019) and with MYC expression (p = 0.044). Moreover, two tumors presented a pathogenic mutation in MYC exon 2 (rs28933407). Our study highlights that the gain of MYC and TP53 copies seems to be a frequent finding in gallbladder cancer. In addition, gain of copies, hypomethylation and point mutations at MYC may contribute to overexpression of its protein in this type of cancer.

  20. Evaluation of sgRNA target sites for CRISPR-mediated repression of TP53.

    PubMed

    Lawhorn, Ingrid E B; Ferreira, Joshua P; Wang, Clifford L

    2014-01-01

    The CRISPR (clustered regularly interspaced short palindromic repeats) platform has been developed as a general method to direct proteins of interest to gene targets. While the native CRISPR system delivers a nuclease that cleaves and potentially mutates target genes, researchers have recently employed catalytically inactive CRISPR-associated 9 nuclease (dCas9) in order to target and repress genes without DNA cleavage or mutagenesis. With the intent of improving repression efficiency in mammalian cells, researchers have also fused dCas9 with a KRAB repressor domain. Here, we evaluated different genomic sgRNA targeting sites for repression of TP53. The sites spanned a 200-kb distance, which included the promoter, transcript sequence, and regions flanking the endogenous human TP53 gene. We showed that repression up to 86% can be achieved with dCas9 alone (i.e., without use of the KRAB domain) by targeting the complex to sites near the TP53 transcriptional start site. This work demonstrates that efficient transcriptional repression of endogenous human genes can be achieved by the targeted delivery of dCas9. Yet, the efficiency of repression strongly depends on the choice of the sgRNA target site.

  1. KRAS, BRAF, and TP53 deep sequencing for colorectal carcinoma patient diagnostics.

    PubMed

    Rechsteiner, Markus; von Teichman, Adriana; Rüschoff, Jan H; Fankhauser, Niklaus; Pestalozzi, Bernhard; Schraml, Peter; Weber, Achim; Wild, Peter; Zimmermann, Dieter; Moch, Holger

    2013-05-01

    In colorectal carcinoma, KRAS (alias Ki-ras) and BRAF mutations have emerged as predictors of resistance to anti-epidermal growth factor receptor antibody treatment and worse patient outcome, respectively. In this study, we aimed to establish a high-throughput deep sequencing workflow according to 454 pyrosequencing technology to cope with the increasing demand for sequence information at medical institutions. A cohort of 81 patients with known KRAS mutation status detected by Sanger sequencing was chosen for deep sequencing. The workflow allowed us to analyze seven amplicons (one BRAF, two KRAS, and four TP53 exons) of nine patients in parallel in one deep sequencing run. Target amplification and variant calling showed reproducible results with input DNA derived from FFPE tissue that ranged from 0.4 to 50 ng with the use of different targets and multiplex identifiers. Equimolar pooling of each amplicon in a deep sequencing run was necessary to counterbalance differences in patient tissue quality. Five BRAF and 49 TP53 mutations with functional consequences were detected. The lowest mutation frequency detected in a patient tumor population was 5% in TP53 exon 5. This low-frequency mutation was successfully verified in a second PCR and deep sequencing run. In summary, our workflow allows us to process 315 targets a week and provides the quality, flexibility, and speed needed to be integrated as standard procedure for mutational analysis in diagnostics.

  2. Analysis of TP53 mutation spectra reveals the fingerprint of the potent environmental carcinogen, aristolochic acid.

    PubMed

    Hollstein, M; Moriya, M; Grollman, A P; Olivier, M

    2013-01-01

    Genetic alterations in cancer tissues may reflect the mutational fingerprint of environmental carcinogens. Here we review the pieces of evidence that support the role of aristolochic acid (AA) in inducing a mutational fingerprint in the tumor suppressor gene TP53 in urothelial carcinomas of the upper urinary tract (UUT). Exposure to AA, a nitrophenathrene carboxylic acid present in certain herbal remedies and in flour prepared from wheat grain contaminated with seeds of Aristolochia clematitis, has been linked to chronic nephropathy and UUT. TP53 mutations in UUT of individuals exposed to AA reveal a unique pattern of mutations characterized by A to T transversions on the non-transcribed strand, which cluster at hotspots rarely mutated in other cancers. This unusual pattern, originally discovered in UUTs from two different populations, one in Taiwan, and one in the Balkans, has been reproduced experimentally by treating mouse cells that harbor human TP53 sequences with AA. The convergence of molecular epidemiological and experimental data establishes a clear causal association between exposure to the human carcinogen AA and UUT. Despite bans on the sale of herbs containing AA, their use continues, raising global public health concern and an urgent need to identify populations at risk.

  3. TP53 mutation in patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation.

    PubMed

    Middeke, Jan M; Herold, Sylvia; Rücker-Braun, Elke; Berdel, Wolfgang E; Stelljes, Matthias; Kaufmann, Martin; Schäfer-Eckart, Kerstin; Baldus, Claudia D; Stuhlmann, Reingard; Ho, Anthony D; Einsele, Hermann; Rösler, Wolf; Serve, Hubert; Hänel, Mathias; Sohlbach, Kristina; Klesse, Christian; Mohr, Brigitte; Heidenreich, Falk; Stölzel, Friedrich; Röllig, Christoph; Platzbecker, Uwe; Ehninger, Gerhard; Bornhäuser, Martin; Thiede, Christian; Schetelig, Johannes

    2016-03-01

    Treatment success in patients with acute myeloid leukaemia (AML) is heterogeneous. Cytogenetic and molecular alterations are strong prognostic factors, which have been used to individualize treatment. Here, we studied the impact of TP53 mutations on the outcome of AML patients with adverse cytogenetic risk treated with allogeneic haematopoietic stem cell transplantation (HSCT). Samples of 97 patients with AML and adverse-risk cytogenetics who had received a HSCT within three randomized trials were analysed. Complete sequencing of the TP53 coding region was performed using next generation sequencing. The median age was 51 years. Overall, TP53 mutations were found in 40 patients (41%). With a median follow up of 67 months, the three-year probabilities of overall survival (OS) and event-free survival for patients with TP53 wild type were 33% [95% confidence interval (CI), 21% to 45%] and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) (P = 0·002 and P = 0·007) for those with mutated TP53, respectively. In multivariate analysis, the TP53-mutation status had a negative impact on OS (Hazard Ratio = 1·7; P = 0·066). Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in patients with adverse karyotype AML.

  4. Fischer-344 Tp53-knockout rats exhibit a high rate of bone and brain neoplasia with frequent metastasis

    PubMed Central

    Hansen, Sarah A.; Hart, Marcia L.; Busi, Susheel; Parker, Taybor; Goerndt, Angela

    2016-01-01

    ABSTRACT Somatic mutations in the Tp53 tumor suppressor gene are the most commonly seen genetic alterations in cancer, and germline mutations in Tp53 predispose individuals to a variety of early-onset cancers. Development of appropriate translational animal models that carry mutations in Tp53 and recapitulate human disease are important for drug discovery, biomarker development and disease modeling. Current Tp53 mouse and rat models have significant phenotypic and genetic limitations, and often do not recapitulate certain aspects of human disease. We used a marker-assisted speed congenic approach to transfer a well-characterized Tp53-mutant allele from an outbred rat to the genetically inbred Fischer-344 (F344) rat to create the F344-Tp53tm1(EGFP-Pac)Qly/Rrrc (F344-Tp53) strain. On the F344 genetic background, the tumor spectrum shifted, with the primary tumor types being osteosarcomas and meningeal sarcomas, compared to the hepatic hemangiosarcoma and lymphoma identified in the original outbred stock model. The Fischer model is more consistent with the early onset of bone and central nervous system sarcomas found in humans with germline Tp53 mutations. The frequency of osteosarcomas in F344-Tp53 homozygous and heterozygous animals was 57% and 36%, respectively. Tumors were highly representative of human disease radiographically and histologically, with tumors found primarily on long bones with frequent pulmonary metastases. Importantly, the rapid onset of osteosarcomas in this promising new model fills a current void in animal models that recapitulate human pediatric osteosarcomas and could facilitate studies to identify therapeutic targets. PMID:27528400

  5. ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells.

    PubMed

    Kwok, Marwan; Davies, Nicholas; Agathanggelou, Angelo; Smith, Edward; Oldreive, Ceri; Petermann, Eva; Stewart, Grant; Brown, Jeff; Lau, Alan; Pratt, Guy; Parry, Helen; Taylor, Malcolm; Moss, Paul; Hillmen, Peter; Stankovic, Tatjana

    2016-02-04

    TP53 and ataxia telangiectasia mutated (ATM) defects are associated with genomic instability, clonal evolution, and chemoresistance in chronic lymphocytic leukemia (CLL). Currently, therapies capable of providing durable remissions in relapsed/refractory TP53- or ATM-defective CLL are lacking. Ataxia telangiectasia and Rad3-related (ATR) mediates response to replication stress, the absence of which leads to collapse of stalled replication forks into chromatid fragments that require resolution through the ATM/p53 pathway. Here, using AZD6738, a novel ATR kinase inhibitor, we investigated ATR inhibition as a synthetically lethal strategy to target CLL cells with TP53 or ATM defects. Irrespective of TP53 or ATM status, induction of CLL cell proliferation upregulated ATR protein, which then became activated in response to replication stress. In TP53- or ATM-defective CLL cells, inhibition of ATR signaling by AZD6738 led to an accumulation of unrepaired DNA damage, which was carried through into mitosis because of defective cell cycle checkpoints, resulting in cell death by mitotic catastrophe. Consequently, AZD6738 was selectively cytotoxic to both TP53- and ATM-defective CLL cell lines and primary cells. This was confirmed in vivo using primary xenograft models of TP53- or ATM-defective CLL, where treatment with AZD6738 resulted in decreased tumor load and reduction in the proportion of CLL cells with such defects. Moreover, AZD6738 sensitized TP53- or ATM-defective primary CLL cells to chemotherapy and ibrutinib. Our findings suggest that ATR is a promising therapeutic target for TP53- or ATM-defective CLL that warrants clinical investigation.

  6. Analysis of polymorphisms in codons 11, 72 and 248 of TP53 in Brazilian women with breast cancer.

    PubMed

    Almeida, B C; Kleine, J P F O; Camargo-Kosugi, C M; Lisboa, M R; França, C N; França, J P; Silva, I D C G

    2016-02-22

    The association between TP53 gene polymorphisms and breast cancer (BC) in Brazilian women is a controversial topic. In this cross-sectional study, we evaluated the association between clinical pathological variables and three polymorphisms (TP53*11, TP53*72, and TP53*248) in BC patients and controls. Genomic DNA was extracted from the blood cells of 393 participants; the cancer-free control subjects were 26-72 years old (41 ± 11.03) and the BC patients were 28-80 years old (51 ± 10.70). We used standard polymerase chain reaction-restriction fragment length polymorphism and confirmed the results by genetic sequencing. In TP53*11, there was 100% homozygous Glu distribution in both groups. TP53*72 showed genotypic distribution: in the control group, there was 16.10% homozygous Pro, and 42.44% heterozygous and 41.46% homozygous Arg; in the BC group, there was 15.43% homozygous Pro, and 42.55% heterozygous and 42.02% homozygous Arg. The relative frequency of each allele was 0.37% for Pro and 0.63% for Arg in the control group, and 0.37% for Pro and 0.63% for Arg in the BC group. The nuclear grade (P = 0.0084) and adapted histological grade (P = 0.0265) were associated with TP53*72. The distribution of the codon 72 genotypes did not deviate from Hardy-Weinberg equilibrium in either group. In TP53*248, there was 100% homozygous Arg distribution in both groups. In codon 72, the Arg allele is the most prevalent in Brazilian women. TP53*72 may be associated with susceptibility to BC, although more studies are required to evaluate the profile of Brazilian women with BC.

  7. Fischer-344 Tp53-knockout rats exhibit a high rate of bone and brain neoplasia with frequent metastasis.

    PubMed

    Hansen, Sarah A; Hart, Marcia L; Busi, Susheel; Parker, Taybor; Goerndt, Angela; Jones, Kevin; Amos-Landgraf, James M; Bryda, Elizabeth C

    2016-10-01

    Somatic mutations in the Tp53 tumor suppressor gene are the most commonly seen genetic alterations in cancer, and germline mutations in Tp53 predispose individuals to a variety of early-onset cancers. Development of appropriate translational animal models that carry mutations in Tp53 and recapitulate human disease are important for drug discovery, biomarker development and disease modeling. Current Tp53 mouse and rat models have significant phenotypic and genetic limitations, and often do not recapitulate certain aspects of human disease. We used a marker-assisted speed congenic approach to transfer a well-characterized Tp53-mutant allele from an outbred rat to the genetically inbred Fischer-344 (F344) rat to create the F344-Tp53(tm1(EGFP-Pac)Qly)/Rrrc (F344-Tp53) strain. On the F344 genetic background, the tumor spectrum shifted, with the primary tumor types being osteosarcomas and meningeal sarcomas, compared to the hepatic hemangiosarcoma and lymphoma identified in the original outbred stock model. The Fischer model is more consistent with the early onset of bone and central nervous system sarcomas found in humans with germline Tp53 mutations. The frequency of osteosarcomas in F344-Tp53 homozygous and heterozygous animals was 57% and 36%, respectively. Tumors were highly representative of human disease radiographically and histologically, with tumors found primarily on long bones with frequent pulmonary metastases. Importantly, the rapid onset of osteosarcomas in this promising new model fills a current void in animal models that recapitulate human pediatric osteosarcomas and could facilitate studies to identify therapeutic targets.

  8. Different TP53 mutations are associated with specific chromosomal rearrangements, telomere length changes, and remodeling of the nuclear architecture of telomeres.

    PubMed

    Samassekou, Oumar; Bastien, Nathalie; Lichtensztejn, Daniel; Yan, Ju; Mai, Sabine; Drouin, Régen

    2014-11-01

    TP53 mutations are the most common mutations in human cancers, and TP53-R175H and TP53-R273H are the most frequent. The impact of these mutations on genomic instability after tumor initiation is still uncovered. To gain insight into this, we studied the effects of three specific TP53 mutants (TP53-V143A, TP53-R175H, and TP53-R273H) on genomic instability using four isogenic lines of LoVo cells. Multicolor fluorescence in situ hybridization (FISH), three-dimensional (3D) quantitative FISH (Q-FISH) on interphase and Q-FISH on metaphases were used to investigate genomic instability. We found that LoVo cells expressing mutant TP53-R175H displayed the highest level of chromosomal instability among the LoVo cell lines. Furthermore, we observed that mutant TP53-R175H and TP53-V143A showed more alterations in their 3D nuclear architecture of telomeres than the mutant TP53-R273H and the wild type. Moreover, we noted an association between some chromosomal abnormalities and telomere elongation in the mutant TP53-R175H. Taken together, our results indicate that the mutation TP53-R175H is more likely to cause higher levels of genomic instability than the other TP53 mutations. We proposed that the type of TP53 mutations and the genetic background of a cancer cell are major determinants of the TP53-dependent genomic instability.

  9. TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer.

    PubMed

    Fagerholm, Rainer; Khan, Sofia; Schmidt, Marjanka K; García-Closas, Montserrat; Heikkilä, Päivi; Saarela, Jani; Beesley, Jonathan; Jamshidi, Maral; Aittomäki, Kristiina; Liu, Jianjun; Ali, H Raza; Andrulis, Irene L; Beckmann, Matthias W; Behrens, Sabine; Blows, Fiona M; Brenner, Hermann; Chang-Claude, Jenny; Couch, Fergus J; Czene, Kamila; Fasching, Peter A; Figueroa, Jonine; Floris, Giuseppe; Glendon, Gord; Guo, Qi; Hall, Per; Hallberg, Emily; Hamann, Ute; Holleczek, Bernd; Hooning, Maartje J; Hopper, John L; Jager, Agnes; Kabisch, Maria; Keeman, Renske; Kosma, Veli-Matti; Lambrechts, Diether; Lindblom, Annika; Mannermaa, Arto; Margolin, Sara; Provenzano, Elena; Shah, Mitul; Southey, Melissa C; Dennis, Joe; Lush, Michael; Michailidou, Kyriaki; Wang, Qin; Bolla, Manjeet K; Dunning, Alison M; Easton, Douglas F; Pharoah, Paul D P; Chenevix-Trench, Georgia; Blomqvist, Carl; Nevanlinna, Heli

    2017-02-05

    TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.

  10. TP53 suppression promotes erythropoiesis in del(5q) MDS, suggesting a targeted therapeutic strategy in lenalidomide-resistant patients.

    PubMed

    Caceres, Gisela; McGraw, Kathy; Yip, Bon Ham; Pellagatti, Andrea; Johnson, Joseph; Zhang, Ling; Liu, Kenian; Zhang, Lan Min; Fulp, William J; Lee, Ji-Hyun; Al Ali, Najla H; Basiorka, Ashley; Smith, Larry J; Daugherty, F Joseph; Littleton, Neil; Wells, Richard A; Sokol, Lubomir; Wei, Sheng; Komrokji, Rami S; Boultwood, Jacqueline; List, Alan F

    2013-10-01

    Stabilization of p53 in erythroid precursors in response to nucleosomal stress underlies the hypoplastic anemia in myelodysplastic syndromes (MDS) with chromosome 5q deletion [del(5q)]. We investigated whether cenersen, a clinically active 20-mer antisense oligonucleotide complementary to TP53 exon10, could suppress p53 expression and restore erythropoiesis in del(5q) MDS. Cenersen treatment of ribosomal protein S-14-deficient erythroblasts significantly reduced cellular p53 and p53-up-regulated modulator of apoptosis expression compared with controls, accompanied by a significant reduction in apoptosis and increased cell proliferation. In a two-stage erythroid differentiation assay, cenersen significantly suppressed nuclear p53 in bone marrow CD34+ cells isolated from patients with del(5q) MDS, whereas erythroid burst recovery increased proportionally to the magnitude of p53 suppression without evidence of del(5q) clonal suppression (r = -0.6; P = 0.005). To explore the effect of p53 suppression on erythropoiesis in vivo, dexamethasone, a glucocorticoid receptor-dependent p53 antagonist, was added to lenalidomide treatment in eight lower-risk, transfusion-dependent, del(5q) MDS patients with acquired drug resistance. Transfusion independence was restored in five patients accompanied by expansion of erythroid precursors and decreased cellular p53 expression. We conclude that targeted suppression of p53 could support effective erythropoiesis in lenalidomide-resistant del(5q) MDS.

  11. TP53-dependent chromosome instability is associated with transient reductions in telomere length in immortal telomerase-positive cell lines

    NASA Technical Reports Server (NTRS)

    Schwartz, J. L.; Jordan, R.; Liber, H.; Murnane, J. P.; Evans, H. H.

    2001-01-01

    Telomere shortening in telomerase-negative somatic cells leads to the activation of the TP53 protein and the elimination of potentially unstable cells. We examined the effect of TP53 gene expression on both telomere metabolism and chromosome stability in immortal, telomerase-positive cell lines. Telomere length, telomerase activity, and chromosome instability were measured in multiple clones isolated from three related human B-lymphoblast cell lines that vary in TP53 expression; TK6 cells express wild-type TP53, WTK1 cells overexpress a mutant form of TP53, and NH32 cells express no TP53 protein. Clonal variations in both telomere length and chromosome stability were observed, and shorter telomeres were associated with higher levels of chromosome instability. The shortest telomeres were found in WTK1- and NH32-derived cells, and these cells had 5- to 10-fold higher levels of chromosome instability. The primary marker of instability was the presence of dicentric chromosomes. Aneuploidy and other stable chromosome alterations were also found in clones showing high levels of dicentrics. Polyploidy was found only in WTK1-derived cells. Both telomere length and chromosome instability fluctuated in the different cell populations with time in culture, presumably as unstable cells and cells with short telomeres were eliminated from the growing population. Our results suggest that transient reductions in telomere lengths may be common in immortal cell lines and that these alterations in telomere metabolism can have a profound effect on chromosome stability. Copyright 2000 Wiley-Liss, Inc.

  12. FGFR4 polymorphism, TP53 mutation, and their combinations are prognostic factors for oral squamous cell carcinoma.

    PubMed

    Tanuma, Jun-Ichi; Izumo, Toshiyuki; Hirano, Masato; Oyazato, Yoshitaka; Hori, Fumiya; Umemura, Eri; Shisa, Hayase; Hiai, Hiroshi; Kitano, Motoo

    2010-03-01

    The genotype of the fibroblast growth factor receptor 4 (FGFR4) gene and TP53 mutation have been reported as prognostic factors for cancers of the head and neck, bladder, breast and colon. To determine whether they are applicable for oral squamous cell carcinoma (OSCC), we investigated these two genes in OSCC samples from 150 patients who had undergone radical surgery and in 100 cancer-free individuals. In OSCC, the FGFR4 Gly388Arg polymorphism and the presence or absence of mutation in TP53 did not show a significant association with the clinicopathological features of the tumors at surgery. However, the FGFR4 Arg388 allele, as well as mutations in TP53, was found to be closely associated with poor prognosis. Moreover, these two parameters synergistically affected the survival of OSCC patients. During 60 months of observation after radical surgery, a majority of patients with homozygous Arg388 FGFR4 plus mutated TP53 died of cancer, whereas >90% patients carrying homozygous Gly388 FGFR4 plus wild-type TP53 survived. Therefore, the FGFR4 Gly388Arg polymorphism and TP53 mutations, as well as their combinations, are excellent predictors of the prognosis for OSCC patients.

  13. Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer.

    PubMed

    Diaz-Lagares, Angel; Crujeiras, Ana B; Lopez-Serra, Paula; Soler, Marta; Setien, Fernando; Goyal, Ashish; Sandoval, Juan; Hashimoto, Yutaka; Martinez-Cardús, Anna; Gomez, Antonio; Heyn, Holger; Moutinho, Catia; Espada, Jesús; Vidal, August; Paúles, Maria; Galán, Maica; Sala, Núria; Akiyama, Yoshimitsu; Martínez-Iniesta, María; Farré, Lourdes; Villanueva, Alberto; Gross, Matthias; Diederichs, Sven; Guil, Sonia; Esteller, Manel

    2016-11-22

    Long noncoding RNAs (lncRNAs) are important regulators of cellular homeostasis. However, their contribution to the cancer phenotype still needs to be established. Herein, we have identified a p53-induced lncRNA, TP53TG1, that undergoes cancer-specific promoter hypermethylation-associated silencing. In vitro and in vivo assays identify a tumor-suppressor activity for TP53TG1 and a role in the p53 response to DNA damage. Importantly, we show that TP53TG1 binds to the multifaceted DNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. TP53TG1 epigenetic inactivation in cancer cells releases the transcriptional repression of YBX1-targeted growth-promoting genes and creates a chemoresistant tumor. TP53TG1 hypermethylation in primary tumors is shown to be associated with poor outcome. The epigenetic loss of TP53TG1 therefore represents an altered event in an lncRNA that is linked to classical tumoral pathways, such as p53 signaling, but is also connected to regulatory networks of the cancer cell.

  14. Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer

    PubMed Central

    Diaz-Lagares, Angel; Crujeiras, Ana B.; Lopez-Serra, Paula; Soler, Marta; Setien, Fernando; Goyal, Ashish; Sandoval, Juan; Hashimoto, Yutaka; Martinez-Cardús, Anna; Gomez, Antonio; Heyn, Holger; Moutinho, Catia; Espada, Jesús; Vidal, August; Paúles, Maria; Galán, Maica; Sala, Núria; Akiyama, Yoshimitsu; Martínez-Iniesta, María; Farré, Lourdes; Villanueva, Alberto; Gross, Matthias; Diederichs, Sven; Guil, Sonia; Esteller, Manel

    2016-01-01

    Long noncoding RNAs (lncRNAs) are important regulators of cellular homeostasis. However, their contribution to the cancer phenotype still needs to be established. Herein, we have identified a p53-induced lncRNA, TP53TG1, that undergoes cancer-specific promoter hypermethylation-associated silencing. In vitro and in vivo assays identify a tumor-suppressor activity for TP53TG1 and a role in the p53 response to DNA damage. Importantly, we show that TP53TG1 binds to the multifaceted DNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. TP53TG1 epigenetic inactivation in cancer cells releases the transcriptional repression of YBX1-targeted growth-promoting genes and creates a chemoresistant tumor. TP53TG1 hypermethylation in primary tumors is shown to be associated with poor outcome. The epigenetic loss of TP53TG1 therefore represents an altered event in an lncRNA that is linked to classical tumoral pathways, such as p53 signaling, but is also connected to regulatory networks of the cancer cell. PMID:27821766

  15. Gene Coexpression Analyses Differentiate Networks Associated with Diverse Cancers Harboring TP53 Missense or Null Mutations

    PubMed Central

    Oros Klein, Kathleen; Oualkacha, Karim; Lafond, Marie-Hélène; Bhatnagar, Sahir; Tonin, Patricia N.; Greenwood, Celia M. T.

    2016-01-01

    In a variety of solid cancers, missense mutations in the well-established TP53 tumor suppressor gene may lead to the presence of a partially-functioning protein molecule, whereas mutations affecting the protein encoding reading frame, often referred to as null mutations, result in the absence of p53 protein. Both types of mutations have been observed in the same cancer type. As the resulting tumor biology may be quite different between these two groups, we used RNA-sequencing data from The Cancer Genome Atlas (TCGA) from four different cancers with poor prognosis, namely ovarian, breast, lung and skin cancers, to compare the patterns of coexpression of genes in tumors grouped according to their TP53 missense or null mutation status. We used Weighted Gene Coexpression Network analysis (WGCNA) and a new test statistic built on differences between groups in the measures of gene connectivity. For each cancer, our analysis identified a set of genes showing differential coexpression patterns between the TP53 missense- and null mutation-carrying groups that was robust to the choice of the tuning parameter in WGCNA. After comparing these sets of genes across the four cancers, one gene (KIR3DL2) consistently showed differential coexpression patterns between the null and missense groups. KIR3DL2 is known to play an important role in regulating the immune response, which is consistent with our observation that this gene's strongly-correlated partners implicated many immune-related pathways. Examining mutation-type-related changes in correlations between sets of genes may provide new insight into tumor biology. PMID:27536319

  16. TP53 Polymorphisms allow for genetic sub-grouping of the canine transmissible venereal tumor

    PubMed Central

    Sánchez-Servín, Abel; Córdova-Alarcon, Emilio; Fajardo, Raúl

    2009-01-01

    The canine transmissible venereal tumor (CTVT) is found mainly in dogs' sexual organs. Currently, it is widely accepted that all samples of CTVT show similar histopathological characteristics and share common genetic alterations. Despite the common genetic origin of CTVT, mutations in the P53 gene have been reported. In this study, we proposed that tumor samples can be genetically grouped using this gene. The presence of different subgroups of CTVT was determined in Mexican dogs using the TP53 gene sequence in CTVT samples. Four new polymorphisms were found and therefore, the CTVT samples were classified in five subgroups. PMID:19934603

  17. TP53 codon 72 polymorphism affects accumulation of mtDNA damage in human cells

    PubMed Central

    Altilia, Serena; Santoro, Aurelia; Malagoli, Davide; Lanzarini, Catia; Álvarez, Josué Adolfo Ballesteros; Galazzo, Gianluca; Porter, Donald Carl; Crocco, Paolina; Rose, Giuseppina; Passarino, Giuseppe; Roninson, Igor Boris; Franceschi, Claudio; Salvioli, Stefano

    2012-01-01

    Human TP53 gene is characterised by a polymorphism at codon 72 leading to an Arginine-to-Proline (R/P) substitution. The two resulting p53 isoforms have a different subcellular localisation after stress (more nuclear or more mitochondrial for the P or R isoform, respectively). p53P72 variant is more efficient than p53R72 in inducing the expression of genes involved in nuclear DNA repair. Since p53 is involved also in mitochondrial DNA (mtDNA) maintenance, we wondered whether these p53 isoforms are associated with different accumulation of mtDNA damage. We observed that cells bearing p53R72 accumulate lower amount of mtDNA damage upon rotenone stress with respect to cells bearing p53P72, and that p53R72 co-localises with polymerase gamma more than p53P72. We also analysed the in vivo accumulation of heteroplasmy in a 300 bp fragment of mtDNA D-loop of 425 aged subjects. We observed that subjects with heteroplasmy higher than 5% are significantly less than expected in the p53R72/R72 group. On the whole, these data suggest that the polymorphism of TP53 at codon 72 affects the accumulation of mtDNA mutations, likely through the different ability of the two p53 isoforms to bind to polymerase gamma, and may contribute to in vivo accumulation of mtDNA mutations. PMID:22289634

  18. Hepatitis B and Hepatitis C Infection Biomarkers and TP53 Mutations in Hepatocellular Carcinomas from Colombia

    PubMed Central

    Navas, Maria-Cristina; Suarez, Iris; Carreño, Andrea; Uribe, Diego; Rios, Wilson Alfredo; Cortes-Mancera, Fabian; Martel, Ghyslaine; Vieco, Beatriz; Lozano, Diana; Jimenez, Carlos; Gouas, Doriane; Osorio, German; Hoyos, Sergio; Restrepo, Juan Carlos; Correa, Gonzalo; Jaramillo, Sergio; Lopez, Rocio; Bravo, Luis Eduardo; Arbelaez, Maria Patricia; Scoazec, Jean-Yves; Abedi-Ardekani, Behnoush; Santella, Regina M.; Chemin, Isabelle; Hainaut, Pierre

    2011-01-01

    Hepatocellular Carcinoma (HCC) is a leading cause of cancer-related death worldwide. Globally, the most important HCC risk factors are Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV), chronic alcoholism, and dietary exposure to aflatoxins. We have described the epidemiological pattern of 202 HCC samples obtained from Colombian patients. Additionally we investigated HBV/HCV infections and TP53 mutations in 49 of these HCC cases. HBV biomarkers were detected in 58.1% of the cases; HBV genotypes F and D were characterized in three of the samples. The HCV biomarker was detected in 37% of the samples while HBV/HCV coinfection was found in 19.2%. Among TP53 mutations, 10.5% occur at the common aflatoxin mutation hotspot, codon 249. No data regarding chronic alcoholism was available from the cases. In conclusion, in this first study of HCC and biomarkers in a Colombian population, the main HCC risk factor was HBV infection. PMID:22114738

  19. Prevalence and Functional Consequence of TP53 Mutations in Pediatric Adrenocortical Carcinoma: A Children's Oncology Group Study

    PubMed Central

    Wasserman, Jonathan D.; Novokmet, Ana; Eichler-Jonsson, Claudia; Ribeiro, Raul C.; Rodriguez-Galindo, Carlos; Zambetti, Gerard P.; Malkin, David

    2015-01-01

    Purpose Adrenocortical carcinoma (ACC) is a rare pediatric malignancy. It occurs in excess among individuals with the Li-Fraumeni syndrome, which results primarily from germline mutations in the TP53 gene. Prior series exploring frequencies of germline TP53 mutation among children with ACC have been small, geographically limited, or subject to referral bias. The functional consequence of mutations has not been related to phenotype. We provide a genotype-phenotype analysis of TP53 mutations in pediatric ACC and propose a model for tissue-specific effects based on adrenocortical ontogeny. Patients and Methods Eighty-eight consecutive, unrelated children with ACC, unselected for family history, underwent germline TP53 sequencing. Rate and distribution of mutations were identified. Functional analysis was performed for novel TP53 variants. Correlation with the International Agency for Research on Cancer p53 database further delineated mutational distribution, association with family history, and risk for multiple primary malignancies (MPMs). Results Germline mutations were present in 50% of children. These mutations did not correspond to the conventional hotspot mutations. There was a wide range of mutant protein function. Patients bearing alleles encoding protein with higher functionality were less likely to have a strong family cancer history, whereas those with greater loss of function had MPMs and/or positive family history. In patients with MPMs, ACC was the most frequent initial malignancy. Finally, we demonstrated age-dependent rates of TP53 mutation positivity. Conclusion TP53 mutations are prevalent in children with ACC but decline with age. Mutations result in a broad spectrum of functional loss. Effect of individual mutations may predict carrier and familial disease penetrance with potentially broad implications for clinical surveillance and counseling. PMID:25584008

  20. TP53 Mutations in Head and Neck Squamous Cell Carcinoma and Their Impact on Disease Progression and Treatment Response.

    PubMed

    Zhou, Ge; Liu, Zhiyi; Myers, Jeffrey N

    2016-12-01

    Recent studies describing the mutational landscape of head and neck squamous cell carcinoma (HNSCC) on a genomic scale by our group and others, including The Cancer Genome Atlas, have provided unprecedented perspective for understanding the molecular pathogenesis of HNSCC progression and response to treatment. These studies confirmed that mutations of the TP53 tumor suppressor gene were the most frequent of all somatic genomic alterations in HNSCC, alluding to the importance of the TP53 gene in suppressing the development and progression of this disease. Clinically, TP53 mutations are significantly associated with short survival time and tumor resistance to radiotherapy and chemotherapy in HNSCC patients, which makes the TP53 mutation status a potentially useful molecular factor for risk stratification and predictor of clinical response in these patients. In addition to loss of wild-type p53 function and the dominant-negative effect on the remaining wild-type p53, some p53 mutants often gain oncogenic functions to promote tumorigenesis and progression. Different p53 mutants may possess different gain-of-function properties. Herein, we review the most up-to-date information about TP53 mutations available via The Cancer Genome Atlas-based analysis of HNSCC and discuss our current understanding of the potential tumor-suppressive role of p53, focusing on gain-of-function activities of p53 mutations. We also summarize our knowledge regarding the use of the TP53 mutation status as a potential evaluation or stratification biomarker for prognosis and a predictor of clinical response to radiotherapy and chemotherapy in HNSCC patients. Finally, we discuss possible strategies for targeting HNSCCs bearing TP53 mutations. J. Cell. Biochem. 117: 2682-2692, 2016. © 2016 Wiley Periodicals, Inc.

  1. Ultra-deep sequencing detects ovarian cancer cells in peritoneal fluid and reveals somatic TP53 mutations in noncancerous tissues.

    PubMed

    Krimmel, Jeffrey D; Schmitt, Michael W; Harrell, Maria I; Agnew, Kathy J; Kennedy, Scott R; Emond, Mary J; Loeb, Lawrence A; Swisher, Elizabeth M; Risques, Rosa Ana

    2016-05-24

    Current sequencing methods are error-prone, which precludes the identification of low frequency mutations for early cancer detection. Duplex sequencing is a sequencing technology that decreases errors by scoring mutations present only in both strands of DNA. Our aim was to determine whether duplex sequencing could detect extremely rare cancer cells present in peritoneal fluid from women with high-grade serous ovarian carcinomas (HGSOCs). These aggressive cancers are typically diagnosed at a late stage and are characterized by TP53 mutations and peritoneal dissemination. We used duplex sequencing to analyze TP53 mutations in 17 peritoneal fluid samples from women with HGSOC and 20 from women without cancer. The tumor TP53 mutation was detected in 94% (16/17) of peritoneal fluid samples from women with HGSOC (frequency as low as 1 mutant per 24,736 normal genomes). Additionally, we detected extremely low frequency TP53 mutations (median mutant fraction 1/13,139) in peritoneal fluid from nearly all patients with and without cancer (35/37). These mutations were mostly deleterious, clustered in hotspots, increased with age, and were more abundant in women with cancer than in controls. The total burden of TP53 mutations in peritoneal fluid distinguished cancers from controls with 82% sensitivity (14/17) and 90% specificity (18/20). Age-associated, low frequency TP53 mutations were also found in 100% of peripheral blood samples from 15 women with and without ovarian cancer (none with hematologic disorder). Our results demonstrate the ability of duplex sequencing to detect rare cancer cells and provide evidence of widespread, low frequency, age-associated somatic TP53 mutation in noncancerous tissue.

  2. KRAS and TP53 mutations in inflammatory bowel disease-associated colorectal cancer: a meta-analysis.

    PubMed

    Du, Lijun; Kim, John J; Shen, Jinhua; Chen, Binrui; Dai, Ning

    2017-01-07

    Although KRAS and TP53 mutations are common in both inflammatory bowel disease-associated colorectal cancer (IBD-CRC) and sporadic colorectal cancer (S-CRC), molecular events leading to carcinogenesis may be different. Previous studies comparing the frequency of KRAS and TP53 mutations in IBD-CRC and S-CRC were inconsistent. We performed a meta-analysis to compare the presence of KRAS and TP53 mutations among patients with IBD-CRC, S-CRC, and IBD without dysplasia. A total of 19 publications (482 patients with IBD-CRC, 4,222 with S-CRC, 281 with IBD without dysplasia) met the study inclusion criteria. KRAS mutation was less frequent (RR=0.71, 95%CI 0.56-0.90; P=0.004) while TP53 mutation was more common (RR=1.24, 95%CI 1.10-1.39; P<0.001) in patients with IBD-CRC compared to S-CRC. Both KRAS (RR=3.09, 95%CI 1.47-6.51; P=0.003) and TP53 (RR=2.15, 95%CI 1.07-4.31 P=0.03) mutations were more prevalent in patients with IBD-CRC compared to IBD without dysplasia. In conclusion, IBD-CRC and S-CRC appear to have biologically different molecular pathways. TP53 appears to be more important than KRAS in IBD-CRC compared to S-CRC. Our findings suggest possible roles of TP53 and KRAS as biomarkers for cancer and dysplasia screening among patients with IBD and may also provide targeted therapy in patients with IBD-CRC.

  3. A 1.5 Mb submicroscopic deletion in 17p11.2-p12 is frequently observed in Italian families with hereditary neuropathy with liability to pressure palsies

    SciTech Connect

    Lorenzetti, D.; Roa, B.B.; Abbas, N.E.

    1994-09-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathies that was recently associated with a 1.5 Mb deletion in chromosome 17p11.2-p12. Duplication of the same region is known to be associated with Charcot-Marie-Tooth disease type 1A (CMT1A), a more severe peripheral neuropathy characterized by symmetrically slowed nerve conduction velocity. The CMT1A duplication and HNPP deletion are reciprocal recombination products involving a repeat element (CMT1A-REP) which flanks the 1.5 Mb region involved in the duplication/deletion. Patients from 9 unrelated HNPP Italian families were clinically, electrophysiologically and histologically evaluated. Families were typed with a polymorphic (CA){sub n} repeat and with RFLPs corresponding to loci D17S122, D17S125 and D17S61, which all map within the deleted region. Lack of allelic transmission from affected parent to affected offspring was observed in four informative families, suggesting the presence of deletion. Southern blot analysis of EcoRI digested genomic DNA from HNPP patients and control subjects was performed using a probe mapping within the CMT1A-REP elements. A reduced hybridization signal of a 6.0 kb EcoRI fragment, mapping within the distal CMT1A-REP, was observed in all HNPP patients suggesting the loss of one copy of this fragment in the HNPP-deleted chromosome. PFGE analysis of SacII digested genomic DNA from selected HNPP subjects showed the presence of a junction fragment which has previously been found in association with the 1.5 Mb HNPP deletion. Evidence for deletion could be demonstrated in all 9 families suggesting that the 17p11.2-p12 deletion is commonly associated with HNPP.

  4. Involvement of TP53 and TP16 expression in human papillomavirus-associated non-small cell lung cancer

    PubMed Central

    Li, Ming; Zhang, Xiao-Lei; Deng, Fang; Qian, Li-Ting; Meng, Shui-Ping; Shan, Wu-Lin; Wang, Bao-Long

    2016-01-01

    Human papilloma virus (HPV) infection has previously been reported to be associated with TP53 and TP16 expression in Japanese and Taiwanese patients with lung cancer, but data for advanced non-small cell lung cancer (NSCLC) patients is limited. The present study examined the association between HPV infection and TP53 and TP16 expression in Chinese patients with advanced NSCLC. HPV DNA was detected in 20 out of 83 (24%) lung tumors, and was observed more frequently in non-smokers, patients with lymph node metastasis, and patients with poorly differentiated tumors (P=0.048, P=0.044 and P=0.024, respectively). Thirteen (65%) out of 20 HPV-infected tumors were positive for TP53 expression while eight (40%) were positive for TP16 expression. Multivariate analysis revealed that poor differentiation alone (OR=0.163) was an independent predictive factor of HPV infection in NSCLC. TP16-positive patients had a significantly longer survival time when compared with TP16-negative patients (P<0.001, log-rank test), a trend a not observed for TP53. Our results suggest that TP53 and TP16 protein expression is not associated with the expression of HPV DNA, but that TP16 expression may be an independent prognostic factor of long survival in advanced NSCLC. PMID:27900000

  5. TP53 gene expression in HPV-positive oral tongue SCC and its correlation with nodal metastasis.

    PubMed

    Seraj, Jalal Mehdizadeh; Yazdani, Nasrin; Ashtiani, Zahra Ousati; Seraj, Siamak Mehdizadeh; Hasheminasab, Sayed-Mohammad; Memar, Bahram; Mirashrafi, Fatemeh; Borghei, Hasti; Yazdani, Javad; Mostaan, Leila Vazifeh

    2011-12-15

    In this study, we investigated the prevalence of human papilloma virus (HPV) infection and TP53 expression in patients with squamous cell carcinoma (SCC) of the tongue and, subsequently, its significance in cervical lymph node metastases and tumor differentiation. Sections of formalin-fixed, paraffin-embedded tissue blocks from 94 histologically confirmed tongue SCC cases were investigated in this study. Immunohistochemistry was used to study TP53 expression, and polymerase chain reaction (PCR) was performed for the detection of high risk HPV types (16 and 18). The frequency of HPV-16 and HPV-18 infection was 10.6% and 16%, respectively. Overexpression of TP53 was observed in 70.2% of patients. Young patients (aged below 45 years) comprised 20% of all patients. There was no significant association between TP53, HPV-16, or HPV 18 presence and higher stages of the tumor, tumor differentiation, or presence of nodal metastasis. Although an association between head and neck SCC and HPV infection is being recognized and reported, our data implicate that HPV infection or TP53 expression does not play a significant role in oral tongue SCC pathogenesis, differentiation, or metastasis, as seen in our patients.

  6. Recurrent TP53 missense mutation in cancer patients of Arab descent.

    PubMed

    Zick, Aviad; Kadouri, Luna; Cohen, Sherri; Frohlinger, Michael; Hamburger, Tamar; Zvi, Naama; Plaser, Morasha; Avital, Eilat; Breuier, Shani; Elian, Firase; Salah, Azzam; Goldberg, Yael; Peretz, Tamar

    2017-04-01

    Hereditary cancer comprises more than 10% of all breast cancer cases. Identification of germinal mutations enables the initiation of a preventive program that can include early detection or preventive treatment and may also have a major impact on cancer therapy. Several recurrent mutations were identified in the BRCA1/2 genes in Jewish populations however, in other ethnic groups in Israel, no recurrent mutations were identified to date. Our group established panel sequencing in cancer patients to identify recurrent, founder, and new mutations in the heterogeneous and diverse populations in Israel, We evaluated five breast cancer patients of Arab descent diagnosed with cancer before the age of 50 years and identified the previously described TP53 mutation, c.541C>T, R181C (rs587782596), in two women from unrelated Arab families. The two probands were diagnosed with breast cancer at a young age (27 and 34 years) and had significant family history spanning a wide range of tumors (breast cancer (BC), papillary thyroid cancer, glioblastoma multiform (GBM), colon cancer and leukemia). The R181C variant is expected to disrupt p53 at the ASPP2 binding domain but not the DNA binding domain and is defined by Clinvar as likely pathogenic and in HGMD as disease mutation. We further tested 85 unrelated Arab cancer patients and father of a BC carrier patient for TP53 c.541C>T using a real time polymerase chain reaction (RT-PCR) approach and identified four additional carriers, two with BC one with lung cancer, and the father of a BC carrier patient, diagnosed with GBM. Another carrier suffering from BC was identified using a Myriad panel, suggesting a recurrent mutation in this population with a frequency of 5/42 (11.9%) of our selected BC patients. We suggest testing Arab women with a breast cancer at a young age, Arab patients with multiple malignancies, or with suggestive family history for TP53 c.541C>T.

  7. Evaluation of TP53 Pro72Arg and MDM2 SNP285-SNP309 polymorphisms in an Italian cohort of LFS suggestive patients lacking identifiable TP53 germline mutations.

    PubMed

    Ponti, Francesca; Corsini, Serena; Gnoli, Maria; Pedrini, Elena; Mordenti, Marina; Sangiorgi, Luca

    2016-10-01

    Li-Fraumeni syndrome (LFS) is a rare genetic cancer predisposition disease, partly determined by the presence of a TP53 germline mutation; lacking thereof, in presence of a typical LFS phenotype, defines a wide group of 'LFS Suggestive' patients. Alternative LFS susceptibility genes have been investigated without promising results, thus suggesting other genetic determinants involvement in cancer predisposition. Hence, this study explores the single and combined effects of cancer risk, age of onset and cancer type of three single nucleotide polymorphisms (SNPs)-TP53 Pro72Arg, MDM2 SNP285 and SNP309-already described as modifiers on TP53 mutation carriers but not properly investigated in LFS Suggestive patients. This case-control study examines 34 Italian LFS Suggestive lacking of germline TP53 mutations and 95 tumour-free subjects. A significant prevalence of homozygous MDM2 SNP309 G in the LFS Suggestive group (p < 0.0005) confirms its contribute to cancer susceptibility, also highlighted in LFS TP53 positive families. Conversely its anticipating role on tumour onset has not been confirmed, as in our results it was associated with the SNP309 T allele. A strong combined outcome with a 'dosage' effect has also been reported for TP53 P72 and MDM2 SNP309 G allele on cancer susceptibility (p < 0.0005). Whereas the MDM2 SNP285 C allele neutralizing effect on MDM2 SNP309 G variant is not evident in our population. Although it needs further evaluations, obtained results strengthen the role of MDM2 SNP309 as a genetic factor in hereditary predisposition to cancer, so improving LFS Suggestive patients management.

  8. Bilineal T lymphoblastic and myeloid blast transformation in chronic myeloid leukemia with TP53 mutation—an uncommon presentation in adults

    PubMed Central

    Krishnan, S.; Sabai, K.; Chuah, C.; Tan, S.Y.

    2014-01-01

    Bilineal blast transformation of myeloid and T lymphoid type is a rare event in chronic myeloid leukemia. Here, we report a case in which an adult presented with high white cell counts and lymphadenopathy. Bone marrow studies confirmed the presence of 9 and 22 chromosomal translocation, and a diagnosis of chronic myeloid leukemia in chronic phase was made. Examination of a lymph node showed both myeloid and T lymphoblastoid blast crisis. Molecular studies demonstrated the presence of BCR-ABL fusion transcripts in both the myeloid and the T lymphoblastic component, indicating that the myeloid and T lymphoid blast crisis components shared common progenitors. TP53 deletion was demonstrated by fluorescence in situ hybridization. PMID:24523612

  9. TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy.

    PubMed

    Munch-Petersen, Helga D; Asmar, Fazila; Dimopoulos, Konstantinos; Areškevičiūtė, Aušrinė; Brown, Peter; Girkov, Mia Seremet; Pedersen, Anja; Sjö, Lene D; Heegaard, Steffen; Broholm, Helle; Kristensen, Lasse S; Ralfkiaer, Elisabeth; Grønbæk, Kirsten

    2016-04-22

    Primary central nervous system lymphoma (PCNSL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) confined to the CNS. TP53 mutations (MUT-TP53) were investigated in the context of MIR34A/B/C- and DAPK promoter methylation status, and associated with clinical outcomes in PCNSL patients. In a total of 107 PCNSL patients clinical data were recorded, histopathology reassessed, and genetic and epigenetic aberrations of the p53-miR34-DAPK network studied. TP53 mutational status (exon 5-8), with structural classification of single nucleotide variations according to the IARC-TP53-Database, methylation status of MIR34A/B/C and DAPK, and p53-protein expression were assessed. The 57/107 (53.2 %) patients that were treated with combination chemotherapy +/- rituximab (CCT-treated) had a significantly better median overall survival (OS) (31.3 months) than patients treated with other regimens (high-dose methotrexate/whole brain radiation therapy, 6.0 months, or no therapy, 0.83 months), P < 0.0001. TP53 mutations were identified in 32/86 (37.2 %), among which 12 patients had hotspot/direct DNA contact mutations. CCT-treated patients with PCNSL harboring a hotspot/direct DNA contact MUT-TP53 (n = 9) had a significantly worse OS and progression free survival (PFS) compared to patients with non-hotspot/non-direct DNA contact MUT-TP53 or wild-type TP53 (median PFS 4.6 versus 18.2 or 45.7 months), P = 0.041 and P = 0.00076, respectively. Multivariate Cox regression analysis confirmed that hotspot/direct DNA contact MUT-TP53 was predictive of poor outcome in CCT-treated PCNSL patients, P = 0.012 and P = 0.008; HR: 1.86 and 1.95, for OS and PFS, respectively. MIR34A, MIR34B/C, and DAPK promoter methylation were detected in 53/93 (57.0 %), 80/84 (95.2 %), and 70/75 (93.3 %) of the PCNSL patients with no influence on survival. Combined MUT-TP53 and MIR34A methylation was associated with poor PFS (median 6.4 versus 38.0 months), P = 0

  10. Germline TP53 Mutation and Clinical Characteristics of Korean Patients With Li-Fraumeni Syndrome

    PubMed Central

    Park, Kyoung-Jin; Choi, Hyun-Jung; Suh, Soon-Pal; Ki, Chang-Seok

    2016-01-01

    Background Little is known of the mutation and tumor spectrum of Korean patients with Li-Fraumeni syndrome (LFS). Owing to the rarity of LFS, few cases have been reported in Korea thus far. This study aimed to retrospectively review the mutations and clinical characteristics of Korean patients with LFS. Methods TP53 mutation was screened in 89 unrelated individuals at the Samsung Medical Center in Korea, from 2004 to 2015. Six additional mutation carriers were obtained from the literature. Results We identified nine different mutations in 14 Korean patients (male to female ratio=0.3:1). Two such frameshift mutations (p.Pro98Leufs*25, p.Pro27Leufs*17) were novel. The recurrent mutations were located at codons 31 (n=2; p.Val31Ile), 175 (n=3; p.Arg175His), and 273 (n=4; p.Arg273His and p.Arg273Cys). The median age at the first tumor onset was 25 yr. Ten patients (71%) developed multiple primary tumors. A diverse spectrum of tumors was observed, including breast (n=6), osteosarcoma (n=4), brain (n=4), leukemia (n=2), stomach (n=2), thyroid (n=2), lung (n=2), skin (n=2), bladder (n=1), nasal cavity cancer (n=1), and adrenocortical carcinoma (n=1). Conclusions There was considerable heterogeneity in the TP53 mutations and tumor spectrum in Korean patients with LFS. Our results suggest shared and different LFS characteristics between Caucasian and Korean patients. This is the first report on the mutation spectrum and clinical characteristics from the largest series of Korean LFS patients. PMID:27374712

  11. Differential mutation profiles and similar intronic TP53 polymorphisms in asbestos-related lung cancer and pleural mesothelioma.

    PubMed

    Andujar, Pascal; Pairon, Jean-Claude; Renier, Annie; Descatha, Alexis; Hysi, Ilir; Abd-Alsamad, Issam; Billon-Galland, Marie-Annick; Blons, Hélène; Clin, Bénédicte; Danel, Claire; Debrosse, Denis; Galateau-Sallé, Françoise; Housset, Bruno; Laurent-Puig, Pierre; Le Pimpec-Barthes, Françoise; Letourneux, Marc; Monnet, Isabelle; Régnard, Jean-François; Validire, Pierre; Zucman-Rossi, Jessica; Jaurand, Marie-Claude; Jean, Didier

    2013-05-01

    Given the interest in defining biomarkers of asbestos exposure and to provide insights into asbestos-related and cell-specific mechanisms of neoplasia, the identification of gene alterations in asbestos-related cancers can help to a better understanding of exposure risk. To understand the aetiology of asbestos-induced malignancies and to increase our knowledge of mesothelial carcinogenesis, we compared genetic alterations in relevant cancer genes between lung cancer, induced by asbestos and tobacco smoke, and malignant pleural mesothelioma (MPM), a cancer related to asbestos, but not to tobacco smoke. TP53, KRAS, EGFR and NF2 gene alteration analyses were performed in 100 non-small cell lung cancer (NSCLC) patients, 50 asbestos-exposed and 50 unexposed patients, matched for age, gender, histology and smoking habits. Detailed assessment of asbestos exposure was based on both specific questionnaires and asbestos body quantification in lung tissue. Genetic analyses were also performed in 34 MPM patients. TP53, EGFR and KRAS mutations were found in NSCLC with no link with asbestos exposure. NF2 was only altered in MPM. Significant enhancement of TP53 G:C to T:A transversions was found in NSCLC from asbestos-exposed patients when compared with unexposed patients (P = 0.037). Interestingly, TP53 polymorphisms in intron 7 (rs12947788 and rs12951053) were more frequently identified in asbestos-exposed NSCLC (P = 0.046) and MPM patients than in unexposed patients (P < 0.001 and P = 0.012, respectively). These results emphasise distinct genetic alterations between asbestos-related thoracic tumours, but identify common potential susceptibility factors, i.e. single nucleotide polymorphisms in intron 7 of TP53. While genetic changes in NSCLC are dominated by the effects of tobacco smoke, the increase of transversions in TP53 gene is consistent with a synergistic effect of asbestos. These results may help to define cell-dependent mechanisms of action of asbestos and identify

  12. Association between TP53 gene Arg72Pro polymorphism and Wilms’ tumor risk in a Chinese population

    PubMed Central

    Fu, Wen; Zhuo, Zhen-Jian; Jia, Wei; Zhu, Jinhong; Zhu, Shi-Bo; Lin, Ze-Feng; Wang, Feng-Hua; Xia, Huimin; He, Jing; Liu, Guo-Chang

    2017-01-01

    Wilms’ tumor is one of the most prevalent pediatric malignancies, ranking fourth in childhood cancer worldwide. TP53 is a critical tumor suppressor gene, which encodes a 53 kDa protein, p53. The p53 functions to protect against cancer by regulating cell cycle and apoptosis and maintaining DNA integrity. TP53 gene is highly polymorphic. Several TP53 gene polymorphisms have been considered to be associated with cancer risk. Of them, a nonsynonymous polymorphism, Arg72Pro (rs1042522 C>G), has been most extensively studied for the association with cancer risk; however, few studies have investigated its effect on Wilms’ tumor. Because of the central role of p53 in cell cycle control, the TP53 gene Arg72Pro polymorphism is also a good potential candidate predisposition locus for this pediatric cancer. We genotyped this polymorphism in 145 patients and 531 cancer-free controls recruited from Chinese children by Taqman methodology. Overall, our result suggested a lack of association between the TP53 gene Arg72Pro polymorphism and Wilms’ tumor. In the stratified analysis, we found that carriers of CG/GG genotypes had a significantly increased Wilms’ tumor risk in children not older than 18 months (adjusted odds ratio =2.04, 95% confidence interval =1.003–4.13, P=0.049) compared with CC genotype carriers. Our study indicated that the TP53 gene Arg72Pro polymorphism may have a weak, age-related effect on Wilms’ tumor risk in Chinese children. These findings need further validations in other populations with larger sample size. PMID:28260929

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

    PubMed

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

    2017-01-01

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

  14. Association between TP53 gene Arg72Pro polymorphism and Wilms' tumor risk in a Chinese population.

    PubMed

    Fu, Wen; Zhuo, Zhen-Jian; Jia, Wei; Zhu, Jinhong; Zhu, Shi-Bo; Lin, Ze-Feng; Wang, Feng-Hua; Xia, Huimin; He, Jing; Liu, Guo-Chang

    2017-01-01

    Wilms' tumor is one of the most prevalent pediatric malignancies, ranking fourth in childhood cancer worldwide. TP53 is a critical tumor suppressor gene, which encodes a 53 kDa protein, p53. The p53 functions to protect against cancer by regulating cell cycle and apoptosis and maintaining DNA integrity. TP53 gene is highly polymorphic. Several TP53 gene polymorphisms have been considered to be associated with cancer risk. Of them, a nonsynonymous polymorphism, Arg72Pro (rs1042522 C>G), has been most extensively studied for the association with cancer risk; however, few studies have investigated its effect on Wilms' tumor. Because of the central role of p53 in cell cycle control, the TP53 gene Arg72Pro polymorphism is also a good potential candidate predisposition locus for this pediatric cancer. We genotyped this polymorphism in 145 patients and 531 cancer-free controls recruited from Chinese children by Taqman methodology. Overall, our result suggested a lack of association between the TP53 gene Arg72Pro polymorphism and Wilms' tumor. In the stratified analysis, we found that carriers of CG/GG genotypes had a significantly increased Wilms' tumor risk in children not older than 18 months (adjusted odds ratio =2.04, 95% confidence interval =1.003-4.13, P=0.049) compared with CC genotype carriers. Our study indicated that the TP53 gene Arg72Pro polymorphism may have a weak, age-related effect on Wilms' tumor risk in Chinese children. These findings need further validations in other populations with larger sample size.

  15. Germline TP53 alterations in Finnish breast cancer families are rare and occur at conserved mutation-prone sites

    PubMed Central

    Rapakko, K; Allinen, M; Syrjäkoski, K; Vahteristo, P; Huusko, P; Vähäkangas, K; Eerola, H; Kainu, T; Kallioniemi, O-P; Nevanlinna, H; Winqvist, R

    2001-01-01

    We have screened for germline TP53 mutations in Finnish BRCA1 and BRCA2 mutation-negative families. This study represents the largest survey of the entire protein-encoding portion of TP53, and indicates that mutations are only found at conserved domains in breast cancer families also meeting the criteria for Li-Fraumeni/Li-Fraumeni-like syndrome, explaining only a very small additional fraction of the hereditary breast cancer cases. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11139324

  16. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome.

    PubMed

    Rücker, Frank G; Schlenk, Richard F; Bullinger, Lars; Kayser, Sabine; Teleanu, Veronica; Kett, Helena; Habdank, Marianne; Kugler, Carla-Maria; Holzmann, Karlheinz; Gaidzik, Verena I; Paschka, Peter; Held, Gerhard; von Lilienfeld-Toal, Marie; Lübbert, Michael; Fröhling, Stefan; Zenz, Thorsten; Krauter, Jürgen; Schlegelberger, Brigitte; Ganser, Arnold; Lichter, Peter; Döhner, Konstanze; Döhner, Hartmut

    2012-03-01

    To assess the frequency of TP53 alterations and their correlation with other genetic changes and outcome in acute myeloid leukemia with complex karyotype (CK-AML), we performed integrative analysis using TP53 mutational screening and array-based genomic profiling in 234 CK-AMLs. TP53 mutations were found in 141 of 234 (60%) and TP53 losses were identified in 94 of 234 (40%) CK-AMLs; in total, 164 of 234 (70%) cases had TP53 alterations. TP53-altered CK-AML were characterized by a higher degree of genomic complexity (aberrations per case, 14.30 vs 6.16; P < .0001) and by a higher frequency of specific copy number alterations, such as -5/5q-, -7/7q-, -16/16q-, -18/18q-, +1/+1p, and +11/+11q/amp11q13∼25; among CK-AMLs, TP53-altered more frequently exhibited a monosomal karyotype (MK). Patients with TP53 alterations were older and had significantly lower complete remission rates, inferior event-free, relapse-free, and overall survival. In multivariable analysis for overall survival, TP53 alterations, white blood cell counts, and age were the only significant factors. In conclusion, TP53 is the most frequently known altered gene in CK-AML. TP53 alterations are associated with older age, genomic complexity, specific DNA copy number alterations, MK, and dismal outcome. In multivariable analysis, TP53 alteration is the most important prognostic factor in CK-AML, outweighing all other variables, including the MK category.

  17. Microsatellite mapping of the deletion in patients with hereditary neuropathy with liability to pressure palsies (HNPP): new molecular tools for the study of the region 17p12 --> p11 and for diagnosis.

    PubMed

    LeGuern, E; Ravise, N; Gouider, R; Gugenheim, M; Lopes, J; Bouche, P; Agid, Y; Brice, A

    1996-01-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant peripheral neuropathy characterized by recurrent episodes of nerve palsies. We have analyzed 11 microsatellite markers from chromosome 17p12 --> p11 in nine French families with HNPP. The three microsatellites D17S839 (afm200yb12), D17S955 (afm317ygl), and D17S921 (afm191xh12) were localized in the deleted region. In allele segregation analyses, the microsatellite D17S793 (afm165zd4) detected two chromosome 17-linked loci, one of which was deleted in HNPP patients. Using these STR markers, we found that the deletion coincided with the CMT1A/HNPP monomer unit in eight of the nine families. In the remaining pedigree, the deletion lay between the centromeric microsatellite D17S805 (afm234tal) and the telomeric marker D17S922 (afm197xh6), which flank the CMT1A monomer unit. Comparison of these data with the available genetic and physical maps of 17p12 --> p11 shows that this region, which is frequently subject to rearrangement-inducing diseases, such as Smith-Magenis syndrome, Charcot-Marie-Tooth type 1A, and HNPP, presents recombination hot spots. Finally, this study demonstrates the usefulness of the D17S122 (RM11GT) and D17S921 (afm191xh12) microsatellites as tools for the molecular diagnosis of HNPP.

  18. Missense mutations in the TP53 DNA-binding domain predict outcomes in patients with advanced oral cavity squamous cell carcinoma

    PubMed Central

    Lee, Li-Yu; Lin, Chien-Yu; Wang, Hung-Ming; Ng, Shu-Hang; Chen, Shu-Jen; Yen, Tzu-Chen

    2016-01-01

    TP53 mutations have been linked to reduced survival in patients with oral cavity squamous cell carcinoma (OSCC). However, the impact of different types of TP53 mutations remains unclear. Here, we demonstrate that the carriage of missense mutations in the TP53 DNA binding domain (DBD missense mutations) is associated with decreased disease-specific survival (DSS) compared with wild-type TP53 (P=0.002) in a cohort of 345 OSCC patients. In contrast, DSS of patients bearing all of the remaining TP53 mutations did not differ from that observed in wild-type TP53 patients (P=0.955). Our classification method for TP53 mutations was superior to previously reported approaches (disruptive, truncating, Evolutionary Action score, mutations in L2/L3/LSH) for distinguishing between low- and high-risk patients. When analyzed in combination with traditional clinicopathological factors, TP53 DBD missense mutations were an independent prognostic factor for shorter DSS (P=0.014) alongside with advanced AJCC T- and N-classifications and the presence of extracapsular spread. A scoring system that included the four independent prognostic factors allowed a reliable patient stratification into distinct risk groups (high-risk patients, 16.2%). Our results demonstrate the usefulness of TP53 DBD missense mutations combined with clinicopathological factors for improving the prognostic stratification of OSCC patients. PMID:27283772

  19. Damage-inducible intragenic demethylation of the human TP53 tumor suppressor gene is associated with transcription from an alternative intronic promoter.

    PubMed

    Blackburn, James; Roden, Daniel L; Ng, Robert; Wu, Jianmin; Bosman, Alexis; Epstein, Richard J

    2016-12-01

    Wild-type TP53 exons 5-8 contain CpG dinucleotides that are prone to methylation-dependent mutation during carcinogenesis, but the regulatory effects of methylation affecting these CpG sites are unclear. To clarify this, we first assessed site-specific TP53 CpG methylation in normal and transformed cells. Both DNA damage and cell ageing were associated with site-specific CpG demethylation in exon 5 accompanied by induction of a truncated TP53 isoform regulated by an adjacent intronic promoter (P2). We then synthesized novel synonymous TP53 alleles with divergent CpG content but stable encodement of the wild-type polypeptide. Expression of CpG-enriched TP53 constructs selectively reduced production of the full-length transcript (P1), consistent with a causal relationship between intragenic demethylation and transcription. 450K methylation comparison of normal (TP53-wildtype) and cancerous (TP53-mutant) human cells and tissues revealed focal cancer-associated declines in CpG methylation near the P1 transcription start site, accompanied by rises near the alternate exon 5 start site. These data confirm that site-specific changes of intragenic TP53 CpG methylation are extrinsically inducible, and suggest that human cancer progression is mediated in part by dysregulation of damage-inducible intragenic CpG demethylation that alters TP53 P1/P2 isoform expression. © 2015 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.

  20. Missense mutations in the TP53 DNA-binding domain predict outcomes in patients with advanced oral cavity squamous cell carcinoma.

    PubMed

    Lapke, Nina; Lu, Yen-Jung; Liao, Chun-Ta; Lee, Li-Yu; Lin, Chien-Yu; Wang, Hung-Ming; Ng, Shu-Hang; Chen, Shu-Jen; Yen, Tzu-Chen

    2016-07-12

    TP53 mutations have been linked to reduced survival in patients with oral cavity squamous cell carcinoma (OSCC). However, the impact of different types of TP53 mutations remains unclear. Here, we demonstrate that the carriage of missense mutations in the TP53 DNA binding domain (DBD missense mutations) is associated with decreased disease-specific survival (DSS) compared with wild-type TP53 (P=0.002) in a cohort of 345 OSCC patients. In contrast, DSS of patients bearing all of the remaining TP53 mutations did not differ from that observed in wild-type TP53 patients (P=0.955). Our classification method for TP53 mutations was superior to previously reported approaches (disruptive, truncating, Evolutionary Action score, mutations in L2/L3/LSH) for distinguishing between low- and high-risk patients. When analyzed in combination with traditional clinicopathological factors, TP53 DBD missense mutations were an independent prognostic factor for shorter DSS (P=0.014) alongside with advanced AJCC T- and N-classifications and the presence of extracapsular spread. A scoring system that included the four independent prognostic factors allowed a reliable patient stratification into distinct risk groups (high-risk patients, 16.2%). Our results demonstrate the usefulness of TP53 DBD missense mutations combined with clinicopathological factors for improving the prognostic stratification of OSCC patients.

  1. LUNG TUMOR KRAS AND TP53 MUTATIONS IN NONSMOKERS REFLECT EXPOSURE TO PAH-RICH COAL COMBUSTION EMISSIONS

    EPA Science Inventory

    Lung Tumor KRAS and TP53 Mutations in Nonsmokers Reflect Exposure to PAH-Rich
    Coal Combustion Emissions

    Use of smoky coal in unvented homes in Xuan Wei County, Yunnan Province, China, is associated with lung cancer among nonsmoking females. Such women have the highest...

  2. LUNG TUMOR KRAS AND TP53 MUTATIONS IN NON-SMOKERS REFLECT EXPOSURE TO PAH-RICH COAL COMBUSTION EMISSIONS

    EPA Science Inventory


    Abstract

    We determined the TP53 and codon 12 KRAS mutations in lung tumors from 24 nonsmokers whose tumors were associated with exposure to smoky coal. Among any tumors studied previously, these showed the highest percentage of mutations that (a) were G -+ T transver...

  3. Neovascularization and functional recovery after intracerebral hemorrhage is conditioned by the Tp53 Arg72Pro single-nucleotide polymorphism

    PubMed Central

    Rodríguez, Cristina; Sobrino, Tomás; Agulla, Jesús; Bobo-Jiménez, Verónica; Ramos-Araque, María E; Duarte, Juan J; Gómez-Sánchez, José C; Bolaños, Juan P; Castillo, José; Almeida, Ángeles

    2017-01-01

    Intracerebral hemorrhage (ICH) is a devastating subtype of stroke that lacks effective therapy and reliable prognosis. Neovascularization following ICH is an essential compensatory response that mediates brain repair and modulates the clinical outcome of stroke patients. However, the mechanism that dictates this process is unknown. Bone marrow-derived endothelial progenitor cells (EPCs) promote endothelial repair and contribute to ischemia-induced neovascularization. The human Tp53 gene harbors a common single-nucleotide polymorphism (SNP) at codon 72, which yields an arginine-to-proline amino-acidic substitution (Arg72Pro) that modulates the apoptotic activity of the p53 protein. Previously, we found that this SNP controls neuronal susceptibility to ischemia-induced apoptosis in vitro. Here, we evaluated the impact of the Tp53 Arg72Pro SNP on vascular repair and functional recovery after ICH. We first analyzed EPC mobilization and functional outcome based on the modified Rankin scale scores in a hospital-based cohort of 78 patients with non-traumatic ICH. Patients harboring the Pro allele of the Tp53 Arg72Pro SNP showed higher levels of circulating EPC-containing CD34+ cells, EPC-mobilizing cytokines – vascular endothelial growth factor and stromal cell-derived factor-1α – and good functional outcome following ICH, when compared with the homozygous Arg allele patients, which is compatible with increased neovascularization. To assess directly whether Tp53 Arg72Pro SNP regulated neovascularization after ICH, we used the humanized Tp53 Arg72Pro knock-in mice, which were subjected to the collagenase-induced ICH. The brain endothelial cells of the Pro allele-carrying mice were highly resistant to ICH-mediated apoptosis, which facilitated cytokine-mediated EPC mobilization, cerebrovascular repair and functional recovery. However, these processes were not observed in the Arg allele-carrying mice. These results reveal that the Tp53 Arg72Pro SNP determines

  4. Sp1 regulates Raf/MEK/ERK-induced p21(CIP1) transcription in TP53-mutated cancer cells.

    PubMed

    Karkhanis, Mansi; Park, Jong-In

    2015-03-01

    We previously reported that the upregulation of mortalin, an Hsp70 family chaperone, is important for B-Raf(V600E) tumor cells to bypass p21(CIP1) expression, which is activated as a tumor-suppressive mechanism in response to aberrant MEK/ERK activation (Wu et al., 2013). Interestingly, mortalin depletion induced p21(CIP1) transcription not only in wild-type TP53 but also in TP53-mutated B-Raf(V600E) cancer cells, suggesting the presence of an additional mechanism for p21(CIP1) regulation. In the present study, using luciferase reporter truncation analysis in a TP53-mutated B-Raf(V600E) cancer cell line, SK-MEL28, we identified a proximal p21(CIP1) promoter region responsive to mortalin depletion. Interestingly, when Sp1-like cis-elements in this promoter region were mutagenized, the p21(CIP1) promoter luciferase reporter was no longer responsive to mortalin depletion. Consistent with this, our ChIP analysis revealed that mortalin knockdown could induce Sp1 binding to p21(CIP1) promoter in a MEK/ERK-dependent manner. Moreover, RNA interference of Sp1 substantially attenuated p21(CIP1) expression induced by mortalin depletion in SK-MEL28 cells. Consistent with this observation in SK-MEL28 cells, Sp1 was necessary for the tamoxifen-regulated ∆Raf-1:ER to induce p21(CIP1) transcription in U251 cells, in which TP53 is mutated. However, in contrast, Sp1 was not necessary for ∆Raf-1:ER to induce p21(CIP1) transcription in LNCaP cells, in which TP53 is wild type. These data suggest that Sp1 may address TP53-independent p21(CIP1) transcription in Raf/MEK/ERK-activated cancer cells and that its requirement in Raf/MEK/ERK-induced p21(CIP1) transcription is subject to TP53 status.

  5. Neovascularization and functional recovery after intracerebral hemorrhage is conditioned by the Tp53 Arg72Pro single-nucleotide polymorphism.

    PubMed

    Rodríguez, Cristina; Sobrino, Tomás; Agulla, Jesús; Bobo-Jiménez, Verónica; Ramos-Araque, María E; Duarte, Juan J; Gómez-Sánchez, José C; Bolaños, Juan P; Castillo, José; Almeida, Ángeles

    2017-01-01

    Intracerebral hemorrhage (ICH) is a devastating subtype of stroke that lacks effective therapy and reliable prognosis. Neovascularization following ICH is an essential compensatory response that mediates brain repair and modulates the clinical outcome of stroke patients. However, the mechanism that dictates this process is unknown. Bone marrow-derived endothelial progenitor cells (EPCs) promote endothelial repair and contribute to ischemia-induced neovascularization. The human Tp53 gene harbors a common single-nucleotide polymorphism (SNP) at codon 72, which yields an arginine-to-proline amino-acidic substitution (Arg72Pro) that modulates the apoptotic activity of the p53 protein. Previously, we found that this SNP controls neuronal susceptibility to ischemia-induced apoptosis in vitro. Here, we evaluated the impact of the Tp53 Arg72Pro SNP on vascular repair and functional recovery after ICH. We first analyzed EPC mobilization and functional outcome based on the modified Rankin scale scores in a hospital-based cohort of 78 patients with non-traumatic ICH. Patients harboring the Pro allele of the Tp53 Arg72Pro SNP showed higher levels of circulating EPC-containing CD34(+) cells, EPC-mobilizing cytokines - vascular endothelial growth factor and stromal cell-derived factor-1α - and good functional outcome following ICH, when compared with the homozygous Arg allele patients, which is compatible with increased neovascularization. To assess directly whether Tp53 Arg72Pro SNP regulated neovascularization after ICH, we used the humanized Tp53 Arg72Pro knock-in mice, which were subjected to the collagenase-induced ICH. The brain endothelial cells of the Pro allele-carrying mice were highly resistant to ICH-mediated apoptosis, which facilitated cytokine-mediated EPC mobilization, cerebrovascular repair and functional recovery. However, these processes were not observed in the Arg allele-carrying mice. These results reveal that the Tp53 Arg72Pro SNP determines

  6. Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis.

    PubMed

    Yemelyanova, Anna; Vang, Russell; Kshirsagar, Malti; Lu, Dan; Marks, Morgan A; Shih, Ie Ming; Kurman, Robert J

    2011-09-01

    Immunohistochemical staining for p53 is used as a surrogate for mutational analysis in the diagnostic workup of carcinomas of multiple sites including ovarian cancers. Strong and diffuse immunoexpression of p53 is generally interpreted as likely indicating a TP53 gene mutation. The immunoprofile that correlates with wild-type TP53, however, is not as clear. In particular, the significance of completely negative immunostaining is controversial. The aim of this study was to clarify the relationship of the immunohistochemical expression of p53 with the mutational status of the TP53 gene in ovarian cancer. A total of 57 ovarian carcinomas (43 high-grade serous ovarian/peritoneal carcinomas, 2 malignant mesodermal mixed tumors (carcinosarcomas), 2 low-grade serous carcinomas, 4 clear cell carcinomas, 1 well-differentiated endometrioid carcinoma, and 5 carcinomas with mixed epithelial differentiation) were analyzed for TP53 mutations by nucleotide sequencing (exons 4-9), and subjected to immunohistochemical analysis of p53 expression. Thirty six tumors contained functional mutations and 13 had wild type TP53. Five tumors were found to harbor known TP53 polymorphism and changes in the intron region were detected in three. Tumors with wild-type TP53 displayed a wide range of immunolabeling patterns, with the most common pattern showing ≤10% of positive cells in 6 cases (46%). Mutant TP53 was associated with 60-100% positive cells in 23 cases (64% of cases). This pattern of staining was also seen in three cases with wild-type TP53. Tumors that were completely negative (0% cells staining) had a mutation of TP53 in 65% of cases and wild-type TP53 in 11%. Combining two immunohistochemical labeling patterns associated with TP53 mutations (0% and 60-100% positive cells), correctly identified a mutation in 94% of cases (P<0.001). Immunohistochemical analysis can be used as a robust method for inferring the presence of a TP53 mutation in ovarian carcinomas. In addition to a

  7. Molecular analysis of the Ink4a/Rb1-Arf/Tp53 pathways in radon-induced rat lung tumors.

    PubMed

    Bastide, Kristell; Guilly, Marie-Noëlle; Bernaudin, Jean-François; Joubert, Christophe; Lectard, Bruno; Levalois, Céline; Malfoy, Bernard; Chevillard, Sylvie

    2009-03-01

    Inhalation of radon is closely associated with an increased risk of lung cancers. While the involvement of Ink4a in lung tumor development has been widely described, the tumor suppressor gene has not been studied in radon-induced lung tumors. In this study, loss of heterozygosity (LOH) analysis of the Cdkn2a locus, common to the Ink4a and Arf genes, was performed on 33 radon-induced rat lung tumors and showed a DNA loss in 50% of cases. The analysis of p16(Ink4a) protein expression by immunohistochemistry revealed that 50% of the tumors were negative for this protein. Looking for the origin of this lack of expression, we observed a low frequency of homozygous deletion (6%), a lack of mutation, an absence of correlation between promoter methylation and Ink4a mRNA expression and no correlation between LOH and protein expression. However, a tendency for an inverse correlation between p16(Ink4a) and pRb protein expression was observed. The expressions of p19Arf, Mmd2 and Mdm4 were not deregulated and only 14% of the tumors were mutated for Tp53. These results indicated that Ink4a/Cdk4/Rb1 pathway deregulation, more than Arf/Mdm2/Tp53 pathway, has a major role in the development of these tumors through p16(Ink4a) deregulation. However, all known mechanisms of inactivation of the pathway do not play a recurrent role in these tumors and the actual origin of the lack of p16(Ink4a) protein expression remains to be established.

  8. Rational Manual and Automated Scoring Thresholds for the Immunohistochemical Detection of TP53 Missense Mutations in Human Breast Carcinomas.

    PubMed

    Taylor, Nicholas J; Nikolaishvili-Feinberg, Nana; Midkiff, Bentley R; Conway, Kathleen; Millikan, Robert C; Geradts, Joseph

    2016-07-01

    Missense mutations in TP53 are common in human breast cancer, have been associated with worse prognosis, and may predict therapy effect. TP53 missense mutations are associated with aberrant accumulation of p53 protein in tumor cell nuclei. Previous studies have used relatively arbitrary cutoffs to characterize breast tumors as positive for p53 staining by immunohistochemical assays. This study aimed to objectively determine optimal thresholds for p53 positivity by manual and automated scoring methods using whole tissue sections from the Carolina Breast Cancer Study. p53-immunostained slides were available for 564 breast tumors previously assayed for TP53 mutations. Average nuclear p53 staining intensity was manually scored as negative, borderline, weak, moderate, or strong and percentage of positive tumor cells was estimated. Automated p53 signal intensity was measured using the Aperio nuclear v9 algorithm combined with the Genie histology pattern recognition tool and tuned to achieve optimal nuclear segmentation. Receiver operating characteristic curve analysis was performed to determine optimal cutoffs for average staining intensity and percent cells positive to distinguish between tumors with and without a missense mutation. Receiver operating characteristic curve analysis demonstrated a threshold of moderate average nuclear staining intensity as a good surrogate for TP53 missense mutations in both manual (area under the curve=0.87) and automated (area under the curve=0.84) scoring systems. Both manual and automated immunohistochemical scoring methods predicted missense mutations in breast carcinomas with high accuracy. Validation of the automated intensity scoring threshold suggests a role for such algorithms in detecting TP53 missense mutations in high throughput studies.

  9. Oropharyngeal Squamous Cell Carcinoma Treated With Radiotherapy or Radiochemotherapy: Prognostic Role of TP53 and HPV Status

    SciTech Connect

    Fallai, Carlo; Perrone, Federica; Licitra, Lisa; Pilotti, Silvana; Locati, Laura; Bossi, Paolo; Orlandi, Ester; Palazzi, Mauro; Olmi, Patrizia

    2009-11-15

    Purpose: To study the prognostic value of the TP53 mutation and human papilloma virus (HPV) status in oropharyngeal squamous cell carcinoma (OPSCC). Methods and materials: The TP53 mutation and HPV status were analyzed in 78 cases of locoregionally advanced OPSCC. The possible correlation of these factors with locoregiownal control, relapse-free survival, disease-specific survival, and overall survival (OS) was also investigated. Results: Of these 78 cases, 22 had disruptive and 22 had non-disruptive (silent) TP53 mutations; the remaining 34 cases had wild-type (WT) TP53. HPV 16 DNA was found in 9 cases (11%), but all HPV-positive (HPV+) cases carried a functional p53 protein, except for 1 case that had a silent mutation. HPV+ patients fared better than HPV-negative (HPV-) patients in terms of all survival parameters, with highly statistically significant differences between the groups. Specifically, no distant metastases were observed in the HPV+ patients, whereas they occurred in 17% of the HPV- patients. However, no difference was observed between the WT TP53 and mutation group, even when this was analyzed in terms of disruptive and non-disruptive mutations. Regardless, treatment with chemotherapy nearly doubled the 5-year OS rates, both in the mutation (42% vs. 22%) and WT (30 vs. 16%) group, but only the mutation group showed improvement in all survival parameters. In addition, the second tumor-free 5-year survival rate was 72% in HPV- cases, but no second tumors were observed in HPV+ and WT p53 cases. Conclusions: Patients with HPV+ OPSCC have an excellent prognosis after radiochemotherapy, but cisplatin-based chemotherapy may not confer a satisfactory outcome, especially in WT cases, thereby justifying the additional or alternative use of taxanes and epidermal growth factor receptors inhibitors. Uncommon distant metastases and second tumors in the HPV+ group may be cause for clinicians to review the follow-up policies in these patients.

  10. TP53 and RET may serve as biomarkers of prognostic evaluation and targeted therapy in hepatocellular carcinoma.

    PubMed

    Ye, Song; Zhao, Xin-Yi; Hu, Xiao-Ge; Li, Tang; Xu, Qiu-Ran; Yang, Huan-Ming; Huang, Dong-Sheng; Yang, Liu

    2017-03-08

    Hepatocellular carcinoma (HCC) is the most common malignancy of the liver. Genomic analysis is conducted to identify genetic alterations in driver genes which are all druggable targets for cancer therapy. In the present study, we performed an exome sequencing of 45 driver genes in 100 paired samples from HCC patients including tumors and matched adjacent normal tissues using Illumina HiSeq 2000 platform. Non-synonymous mutations were ascertained using the iPLEX MassARRAY system and Sanger sequencing. Clinicopathological relevance with genetic variations was assessed using SPSS software. The prognostic analyses of patients with gene mutation status were summarized using Kaplan-Meier curves. Sixty-one non-synonymous somatic mutations were identified in 43% of the HCC patients. The most frequent mutations were: TP53 (20%), RET (6%), PLCE1 (5%), PTEN (4%) and VEGFR2 (3%). Patients with mutations in TP53 had a lower overall survival (OS) (P=0.002) than those without mutations. Recurrent mutations in the Ret proto‑oncogene (RET) were associated with poor outcomes for both disease‑free survival (DFS) (P=0.028) and OS (P=0.001) in HCC patients. The mutational status of sorafenib-targeted genes were associated with decreased DFS (P=0.039), and decreased OS (P=0.15) without statistical significance. Mutual exclusion of TP53 and RET mutations were observed in the present study. In conclusion, patients with TP53 mutations, RET mutations and sorafenib-targeted gene mutations were demonstrated to be associated with poor HCC prognosis, which suggests that both TP53 and RET may serve as biomarkers of prognostic evaluation and targeted therapy in HCC.

  11. Molecular analysis of two patients with a duplicated 17p11.2 indicates that this entity may be the reciprocal of the deletion seen in Smith-Magenis syndrome

    SciTech Connect

    Brown, A.; Schwartz, C.; Rogers, R.C.

    1994-09-01

    J.M. and H.G. are two unrelated patients that presented at an early age with developmental delay and failure to thrive. Clinical features specific to J.M. include unusual facies, global developmental delay, and clinodactyly of the fifth toe. A cytogenetic analysis of H.G. was performed on amniocytes obtained due to a low MSAFP conducted as part of a routine screening. In both J.M. and H.G., a duplication of chromosome 17p11.2 was discovered. The extent of the duplicated region was determined using single copy DNA probes: cen-D17S58-D17S29-D17S258-D17S71-D17S445-tel. All of the markers were found to be duplicated by dosage analysis except for D17S58. FISH analysis of H.G., using the Smith-Magenis diagnostic probe obtained from ONCOR, also detected a duplication in 17p11.2. The chromosome containing the duplication could be the result of unequal crossing over due to a misalignment of the two chromosomes during meiosis I. It has been shown that the markers deleted in Smith-Magenis syndrome (SMS) patients are the same as those markers duplicated in J.M. and H.G. Therefore, the chromosomal duplication in 17p11.2 observed in these two patients could be the reciprocal of the chromosomal deletion seen in Smith-Magenis syndrome patients. Interestingly, a similar reciprocal duplication/deletion event is observed for CMT1A and HNPP (hereditary neuropathy with liability to pressure palsies) just distal to the SMS region.

  12. The human Tp53 Arg72Pro polymorphism explains different functional prognosis in stroke

    PubMed Central

    Gomez-Sanchez, Jose C.; Delgado-Esteban, Maria; Rodriguez-Hernandez, Irene; Sobrino, Tomas; Perez de la Ossa, Natalia; Reverte, Silvia; Bolaños, Juan P.; Gonzalez-Sarmiento, Rogelio; Castillo, Jose

    2011-01-01

    The functional outcome after stroke is unpredictable; it is not accurately predicted by clinical pictures upon hospital admission. The presence of apoptotic neurons in the ischemic penumbra and perihematoma area may account for poor prognosis, but whether the highly variable stroke outcome reflects differences in genetic susceptibility to apoptosis is elusive. The p53 tumor suppressor protein, an important transcriptional regulator of apoptosis, naturally occurs in humans in two variants with single nucleotide polymorphisms resulting in Arg or Pro at residue 72. We show that poor functional outcome after either ischemic or hemorrhagic stroke was linked to the Arg/Arg genotype. This genotype was also associated with early neurological deterioration in ischemic stroke and with increased residual cavity volume in intracerebral hemorrhage. In primary cultured neurons, Arg72-p53, but not Pro72-p53, interacted directly with mitochondrial Bcl-xL and activated the intrinsic apoptotic pathway, increasing vulnerability to ischemia-induced apoptotic cell death. These results suggest that the Tp53 Arg/Arg genotype governs neuronal vulnerability to apoptosis and can be considered as a genetic marker predicting poor functional outcome after stroke. PMID:21357744

  13. TP53 codon 72 polymorphism may predict early tumour progression in paediatric pilocytic astrocytoma

    PubMed Central

    Mascelli, Samantha; Nozza, Paolo; Jones, David T.W.; Colin, Carole; Pistorio, Angela; Milanaccio, Claudia; Ravegnani, Marcello; Consales, Alessandro; Witt, Olaf; Morana, Giovanni; Cama, Armando; Capra, Valeria; Biassoni, Roberto; Pfister, Stefan M.; Figarella-Branger, Dominique; Garrè, Maria Luisa; Raso, Alessandro

    2016-01-01

    Pilocytic astrocytoma and ganglioglioma may occur in inaccessible or surgically difficult areas. In case of incomplete resection, the availability of biological predictors of tumour progression could be particularly important. To this end, an analysis of p53 codon 72 polymorphism and assessment of its role as prognostic marker were performed. The status of the p53 Arg72Pro polymorphism was evaluated by pyrosequencing method in a multicenter cohort of 170 paediatric patients. Genotype/phenotype associations were investigated either by means of bivariate or multivariate analyses. In the partially resected pilocytic astrocytomas, the Arg/Arg variant predicts early tumour progression (median survival time: 23.1 months) and is associated with poor event-free survival (p value = 0.0009). This finding remains true also in case of adjuvant therapies, with a 5-year event-free survival of 30.6% for cases with Arg/Arg variant vs. 78.7% for those with other genotypes. There is no association between ganglioglioma and the polymorphism. The assessment of Arg/Arg variant could improve the management of pilocytic astrocytoma. TP53 codon 72 analysis could distinguish low-risk cases, in which surgery could be conservative, from high-risk cases needing an aggressive surgery plan. PMID:27374106

  14. Expression of TP53 mutation-associated microRNAs predicts clinical outcome in head and neck squamous cell carcinoma patients

    PubMed Central

    Ganci, F.; Sacconi, A.; Bossel Ben-Moshe, N.; Manciocco, V.; Sperduti, I.; Strigari, L.; Covello, R.; Benevolo, M.; Pescarmona, E.; Domany, E.; Muti, P.; Strano, S.; Spriano, G.; Fontemaggi, G.; Blandino, G.

    2013-01-01

    Background TP53 mutation is associated with decreased survival rate in head and neck squamous cell carcinoma (HNSCC) patients. We set out to identify microRNAs (miRNAs) whose expression associates with TP53 mutation and survival in HNSCC. Patients and methods We analyzed TP53 status by direct sequencing of exons 2 through 11 of a prospective series of 121 HNSCC samples and assessed its association with outcome in 109 followed-up patients. We carried out miRNA expression profiling on 121 HNSCC samples and 66 normal counterparts. miRNA associations with TP53 mutations and outcome were evaluated. Results A TP53 mutation was present in 58% of the tumors and TP53 mutations were significantly associated with a shorter recurrence-free survival. This association was stronger in the clinical subgroup of patients subjected to adjuvant therapy after surgery. The expression of 49 miRNAs was significantly associated with TP53 status. Among these 49, we identified a group of 12 miRNAs whose expression correlates with recurrence-free survival and a group of 4 miRNAs that correlates with cancer-specific survival. The two groups share three miRNAs. Importantly, miRNAs that correlate with survival are independent prognostic factors either when considered individually or as signatures. Conclusions miRNAs expression associates with TP53 status and with reduced survival after surgical treatment of squamous cell carcinoma of the head and neck. PMID:24107801

  15. The European flounder (Platichthys flesus) TP53 functions as a temperature-sensitive transcription factor which inhibits cell growth in yeast.

    PubMed

    Cachot, J; Flaman, J M; Frébourg, T; Leboulenger, F

    2004-01-07

    Numerous studies focus on biological roles of the TP53 tumor suppressor gene in mammals but little is known about the actual function of TP53 in lower vertebrates. In this study, we used an in vivo functional assay in yeast to address the transactivation capacity of the flounder TP53 protein. We showed that the flounder TP53 acts as a sequence-specific transcription factor which is able to transactivate various human promoters containing a p53-responsive element (RE). This transcriptional activity was completely abrogated in the Val147Glu TP53 mutant previously identified in two flounder hepatic hyperplasia. In addition, we showed that the wild-type (wt) flounder TP53 but not the Val147Glu mutant inhibits cell growth when expressed in yeast. We finally reported that transcription regulation and growth inhibition by the wild-type flounder TP53 is temperature-dependent. The flounder TP53 optimal temperature appeared lower than those reported for the Xenopus and human homologues.

  16. TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants.

    PubMed

    Sulak, Michael; Fong, Lindsey; Mika, Katelyn; Chigurupati, Sravanthi; Yon, Lisa; Mongan, Nigel P; Emes, Richard D; Lynch, Vincent J

    2016-09-19

    A major constraint on the evolution of large body sizes in animals is an increased risk of developing cancer. There is no correlation, however, between body size and cancer risk. This lack of correlation is often referred to as 'Peto's Paradox'. Here, we show that the elephant genome encodes 20 copies of the tumor suppressor gene TP53 and that the increase in TP53 copy number occurred coincident with the evolution of large body sizes, the evolution of extreme sensitivity to genotoxic stress, and a hyperactive TP53 signaling pathway in the elephant (Proboscidean) lineage. Furthermore, we show that several of the TP53 retrogenes (TP53RTGs) are transcribed and likely translated. While TP53RTGs do not appear to directly function as transcription factors, they do contribute to the enhanced sensitivity of elephant cells to DNA damage and the induction of apoptosis by regulating activity of the TP53 signaling pathway. These results suggest that an increase in the copy number of TP53 may have played a direct role in the evolution of very large body sizes and the resolution of Peto's paradox in Proboscideans.

  17. TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants

    PubMed Central

    Sulak, Michael; Fong, Lindsey; Mika, Katelyn; Chigurupati, Sravanthi; Yon, Lisa; Mongan, Nigel P; Emes, Richard D; Lynch, Vincent J

    2016-01-01

    A major constraint on the evolution of large body sizes in animals is an increased risk of developing cancer. There is no correlation, however, between body size and cancer risk. This lack of correlation is often referred to as 'Peto's Paradox'. Here, we show that the elephant genome encodes 20 copies of the tumor suppressor gene TP53 and that the increase in TP53 copy number occurred coincident with the evolution of large body sizes, the evolution of extreme sensitivity to genotoxic stress, and a hyperactive TP53 signaling pathway in the elephant (Proboscidean) lineage. Furthermore, we show that several of the TP53 retrogenes (TP53RTGs) are transcribed and likely translated. While TP53RTGs do not appear to directly function as transcription factors, they do contribute to the enhanced sensitivity of elephant cells to DNA damage and the induction of apoptosis by regulating activity of the TP53 signaling pathway. These results suggest that an increase in the copy number of TP53 may have played a direct role in the evolution of very large body sizes and the resolution of Peto's paradox in Proboscideans. DOI: http://dx.doi.org/10.7554/eLife.11994.001 PMID:27642012

  18. Assessing the TP53 marker type in patients treated with or without neoadjuvant chemotherapy for resectable colorectal liver metastases: a p53 Research Group study.

    PubMed

    Pilat, N; Grünberger, T; Längle, F; Mittlböck, M; Perisanidis, B; Kappel, S; Wolf, B; Starlinger, P; Kührer, I; Mühlbacher, F; Kandioler, D

    2015-05-01

    The type of a biomarker - whether it is prognostic or predictive - is frequently not known, although such information is crucial for assessing the clinical value of a marker. In order to evaluate the type of marker TP53 is, we identified a cohort of 76 patients with colorectal liver metastases (CLM), homogeneously staged as resectable, who had been treated either with or without fluorouracil-based neoadjuvant chemotherapy. The TP53 genotype was assessed retrospectively from paraffin-embedded, diagnostic tumour biopsies using a standardised, p53 gene-specific sequencing protocol (mark53(®) kit). The overall median survival was 44.2 months, and the overall TP53 mutation frequency was 55%. A significant interaction was observed between chemotherapy and TP53 status (P = 0.045). To illustrate this effect, the 51 patients with and the 25 patients without neoadjuvant chemotherapy were described separately. In patients with neoadjuvant chemotherapy, mutated TP53 was significantly associated with poor survival (P = 0.0025), resulting in five-year survival rates of 22%, compared to 60% in patients with normal TP53. The hazard ratio was 3.12 (95% confidence intervals (CI): 1.46-6.95) to the disadvantage of TP53-mutated patients and 5.49 (P = 0.0001; 95% CI: 2.28-13.24) after adjustment for known prognostic factors. In patients treated with surgery alone, a mutated TP53 did not have a negative effect on survival (P = 0.54). A mutated TP53 status independently predicted survival disadvantage in CLM patients in the presence, but not in the absence, of neoadjuvant chemotherapy. Our data suggest that TP53 might be a pure predictive marker.

  19. TP53 Polymorphisms and Colorectal Cancer Risk in Patients with Lynch Syndrome in Taiwan: A Retrospective Cohort Study

    PubMed Central

    Kamiza, Abram Bunya; Hsieh, Ling-Ling; Tang, Reiping; Chien, Huei-Tzu; Lai, Chih-Hsiung; Chiu, Li-Ling; Lo, Tsai-Ping; Hung, Kuan-Yi; You, Jeng-Fu; Wang, Wen-Chang; Hsiung, Chao A.; Yeh, Chih-Ching

    2016-01-01

    Background and Aim TP53 encodes p53, which has a crucial role in modulating genes that regulate defense against cancer development. This study investigated whether TP53 polymorphisms are associated with colorectal cancer (CRC) in patients with Lynch syndrome and whether TP53 interacts with lifestyle factors to modify CRC risk. Methods We identified 260 MLH1 and MSH2 germline mutation carriers from the Taiwan Hereditary Nonpolyposis Colorectal Cancer Consortium. A weighted Cox proportional hazard model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to determine the association of TP53 polymorphisms with CRC development. Results The carriers of the variant C allele of rs1042522 were associated with a decreased CRC risk (GC genotype: HR = 0.35, 95% CI = 0.14–0.86; CC genotype: HR = 0.28, 95% CI = 0.13–0.57). In addition, the dominant model of rs1042522 was associated with a decreased CRC risk (HR = 0.32, 95% CI = 0.15–0.67). The CRC risk was decreased in carriers with the CT and TT genotypes of rs12947788 (HR = 0.20, 95% CI = 0.08–0.46 and HR = 0.25, 95% CI = 0.09–0.65, respectively). Moreover, the dominant model of rs12947788 was significantly associated with a decreased CRC risk (HR = 0.21, 95% CI = 0.09–0.46). A haplotype analysis indicated that compared with the most common GC haplotype, the CT haplotype was associated with a decreased CRC risk (HR = 0.26, 95% CI = 0.11–0.59). However, no significant interaction was observed between TP53 polymorphisms and lifestyle factors. Conclusion The study results revealed that the rs1042522 genotype with the C allele and the rs12947788 genotype with the T allele in TP53 were associated with a decreased CRC risk in patients with Lynch syndrome in Taiwan. PMID:27907203

  20. TP53-induced glycolysis and apoptosis regulator promotes proliferation and invasiveness of nasopharyngeal carcinoma cells

    PubMed Central

    WONG, ELAINE YUE LING; WONG, SZE-CHUEN CESAR; CHAN, CHARLES MING LOK; LAM, EMILY KAI YEE; HO, LOUISA YEUNG; LAU, CECILIA PIK YUK; AU, THOMAS CHI CHUEN; CHAN, AMANDA KIT CHING; TSANG, CHI MAN; TSAO, SAI WAH; LUI, VIVIAN WAI YAN; CHAN, ANTHONY TAK CHEUNG

    2015-01-01

    The TP53-induced glycolysis and apoptosis regulator (TIGAR) is the protein product of the p53 target gene, C12orf5. TIGAR blocks glycolysis and promotes cellular metabolism via the pentose phosphate pathway; it promotes the production of cellular nicotinamide adenine dinucleotide phosphate (NADPH), which leads to enhanced scavenging of intracellular reactive oxygen species, and inhibition of oxidative stress-induced apoptosis in normal cells. Our previous study identified a novel nucleoside analog that inhibited cellular growth and induced apoptosis in nasopharyngeal carcinoma (NPC) cell lines via downregulation of TIGAR expression. Furthermore, the growth inhibitory effects of c-Met tyrosine kinase inhibitors were ameliorated by the overexpression of TIGAR in the NPC cell lines. These results indicate a significant role for TIGAR expression in the survival of NPCs. The present study aimed to further define the function of TIGAR expression in NPC cells. In total, 36 formalin-fixed, paraffin-embedded NPC tissue samples were obtained for the immunohistochemical determination of TIGAR expression. The effects of TIGAR expression on cell proliferation, NADPH production and cellular invasiveness were also assessed in NPC cell lines. Overall, TIGAR was overexpressed in 27/36 (75%) of the NPC tissues compared with the adjacent non-cancer epithelial cells. Similarly, TIGAR overexpression was also observed in a panel of six NPC cell lines compared with normal NP460 hTert and Het1A cell lines. TIGAR overexpression led to increased cellular growth, NADPH production and invasiveness of the NPC cell lines, whereas a knockdown of TIGAR expression resulted in significant inhibition of cellular growth and invasiveness. The expression of the two mesenchymal markers, fibronectin and vimentin, was increased by TIGAR overexpression, but reduced following TIGAR-knockdown. The present study revealed that TIGAR overexpression led to increased cellular growth, NADPH production and

  1. A mutation spectrum that includes GNAS, KRAS and TP53 may be shared by mucinous neoplasms of the appendix.

    PubMed

    Hara, Kieko; Saito, Tsuyoshi; Hayashi, Takuo; Yimit, Alkam; Takahashi, Michiko; Mitani, Keiko; Takahashi, Makoto; Yao, Takashi

    2015-09-01

    Appendiceal mucinous tumors (AMTs) are classified as low-grade appendiceal mucinous neoplasms (LAMNs) or mucinous adenocarcinomas (MACs), although their carcinogenesis is not well understood. As somatic activating mutations of GNAS are considered to be characteristic of LAMNs while TP53 mutations have been shown to be specific to MACs, MACs are unlikely to result from transformation of LAMNs. However, emerging evidence also shows the presence of GNAS mutations in MACs. We examined 16 AMTs (11 LAMNs and 5 MACs) for genetic alterations of GNAS, KRAS, BRAF, TP53, CTNNB1, and TERT promoter in order to elucidate the possibility of a shared genetic background in the two tumor types. Extensive histological examination revealed the presence of a low-grade component in all cases of MAC. GNAS mutations were detected in two LAMNs and in one MAC, although the GNAS mutation in this MAC was a nonsense mutation (Q227X) expected not to be activating mutation. TP53 mutations were detected in three LAMNs; they were frequently detected in MACs. KRAS mutations were detected in three LAMNs and three MACs, and CTNNB1 mutations were detected in two LAMNs. KRAS mutation and activating mutation of GNAS occurred exclusively in AMTs. BRAF and TERT mutations were not detected. Overexpression of p53 was observed in only two MACs, and p53 immunostaining clearly discriminated the high-grade lesion from a low-grade component in one. These findings suggest that p53 overexpression plays an important role in the carcinogenesis of AMTs and that, in addition to mutations of GNAS, KRAS and TP53 alterations might be shared by AMTs, thus providing evidence for the possible progression of LAMNs to MAC.

  2. Preclinical efficacy of the MDM2 inhibitor RG7112 in MDM2 amplified and TP53 wild-type glioblastomas

    PubMed Central

    Verreault, Maite; Schmitt, Charlotte; Goldwirt, Lauriane; Pelton, Kristine; Haidar, Samer; Levasseur, Camille; Guehennec, Jeremy; Knoff, David; Labussiere, Marianne; Marie, Yannick; Ligon, Azra H.; Mokhtari, Karima; Hoang-Xuan, Khe; Sanson, Marc; Alexander, Brian M; Wen, Patrick Y.; Delattre, Jean-Yves; Ligon, Keith L.; Idbaih, Ahmed

    2016-01-01

    Rationale p53 pathway alterations are key molecular events in glioblastoma (GBM). MDM2 inhibitors increase expression and stability of p53 and are presumed to be most efficacious in patients with TP53 wild-type and MDM2-amplified cancers. However, this biomarker hypothesis has not been tested in patients or patient-derived models for GBM. Methods We performed a preclinical evaluation of RG7112 MDM2 inhibitor, across a panel of 36 patient-derived GBM cell lines (PDCLs), each genetically characterized according to their P53 pathway status. We then performed a pharmacokinetic (PK) profiling of RG7112 distribution in mice and evaluated the therapeutic activity of RG7112 in orthotopic and subcutaneous GBM models. Results MDM2-amplified PDCLs were 44 times more sensitive than TP53 mutated lines that showed complete resistance at therapeutically attainable concentrations (avg. IC50 of 0.52 μM vs 21.9 μM). MDM4 amplified PDCLs were highly sensitive but showed intermediate response (avg. IC50 of 1.2 μM), whereas response was heterogeneous in TP53 wild-type PDCLs with normal MDM2/4 levels (avg. IC50 of 7.7 μM). In MDM2-amplified lines, RG7112 restored p53 activity inducing robust p21 expression and apoptosis. PK profiling of RG7112-treated PDCL intracranial xenografts demonstrated that the compound significantly crosses the blood-brain and the blood-tumor barriers. Most importantly, treatment of MDM2-amplified/TP53 wild-type PDCL-derived model (subcutaneous and orthotopic) reduced tumor growth, was cytotoxic, and significantly increased survival. Conclusion These data strongly support development of MDM2 inhibitors for clinical testing in MDM2-amplified GBM patients. Moreover, significant efficacy in a subset of non-MDM2 amplified models suggests that additional markers of response to MDM2 inhibitors must be identified. PMID:26482041

  3. Polymorphism in exon 4 of TP53 gene associated to HPV 16 and 18 in Mexican women with cervical cancer.

    PubMed

    Piña-Sánchez, Patricia; Hernández-Hernández, Dulce María; Taja-Chayeb, Lucia; Cerda-Flores, Ricardo M; González-Herrera, Ana Lilia; Rodea-Avila, Carlos; Apresa-García, Teresa; Ostrosky-Wegman, Patricia; Vázquez-Ortíz, Guelaguetza; Mendoza-Lorenzo, Patricia; Dueñas-González, Alfonso; Salcedo, Mauricio

    2011-12-01

    Cervical cancer (CC) is the second most common cancer in Mexican women. Human papillomavirus (HPV) infection is necessary but not sufficient for CC development. Furthermore, genetic factors as polymorphisms could be important susceptibility factors. Controversial results regarding TP53 polymorphisms specifically in codon 72 of CC have been reported. In the present work, the exon 4 sequence of TP53 gene in CC and healthy Mexican-mestizo women were analyzed. A group of 111 women with CC and 126 healthy women (control) were included. Peripheral blood cells for polymorphism analysis and cervical scrape for HPV detection were used. PCR of exon 4 of TP53 were subjected to denaturing high-performance liquid chromatography (DHPLC) analysis and sequencing. HPV detection was subjected to PCR and sequencing. The statistical analysis was carried out using the Arlequin software. Codon 72 Arg/Arg was the most common SNP detected, and Hardy-Weinberg analysis showed equilibrium in control and CC samples (P>0.05). Wild type sequence of TP53 exon 4 was detected in 66 and 57% in control and CC samples, respectively. For codon 72 Arg/Arg, differences between control and CC women were found (P=0.043). An association between HPV 16/18 infection and 72 Arg/Arg in woman with CC was found (P=0.026). Haplotype GC (codon 36 and 72) was statistically significantly associated with CC (P=0.011). HPV 16 was the most common viral type. Codon 72 Arg/Arg is the most common polymorphism in the Mexican population and could be associated to HPV 16 and/or HPV 18 infection in CC.

  4. TP53 mutation predicts the poor prognosis of non-Hodgkin lymphomas: Evidence from a meta-analysis

    PubMed Central

    Ouyang, Jian; Chen, Bing

    2017-01-01

    Non-Hodgkin lymphoma (NHL) is a group of malignant hematologic disorders with high heterogeneity. The diagnosis, clinical manifestations, classification, and prognosis of this condition differ among numerous NHL subgroups. The prognostic significance of the mutation of TP53, a tumor suppressor gene involved in cell cycle regulation, should be confirmed in NHL. In this study, our searching strategy and inclusion criteria were implemented, and the pooled hazard ratios (HRs) of the included studies were calculated directly or indirectly. A total of 1,851 patients were enrolled in 22 studies. A meta-analysis was then performed using STATA version 12.0 to confirm the correlation between the status of TP53 mutation and the survival time of patients with NHL. Statistical heterogeneity was assessed with a chi-square-based Q statistical test and Inconsistency index (I2) statistic. Sensitivity analysis and publication bias were also evaluated. A total of 22 studies were included in our meta-analysis. The pooled HR of the overall survival from 20 studies was 2.30 (95% CI: 1.92–2.76, p = 0.001) with heterogeneity (I2 30.2% p = 0.099). The pooled HR of the progression free survival provided in 5 articles was 2.28 (95% CI: 1.78–2.93, p = 0.001) with heterogeneity (I2 39.8% p = 0.156). No publication bias was found among the included studies, and sensitivity analysis suggested that the combined HRs were stable after any of the studies was excluded from our meta-analysis. This study identified the prognostic significance of TP53 mutation that varied in different NHL subgroups. The group with a mutated TP53 was significantly associated with poor prognosis in patients with NHL. This parameter is a valuable basis for accurate individual therapeutic regimens. PMID:28369138

  5. Genetic Variations in the TP53 Pathway in Native Americans Strongly Suggest Adaptation to the High Altitudes of the Andes

    PubMed Central

    Peréz, Orlando; de Azevedo, Soledad; Macedo, Gabriel Souza; Sandoval, José Raul; Salazar-Granara, Alberto; Villena, Mercedes; Dugoujon, Jean-Michel; Bisso-Machado, Rafael; Petzl-Erler, Maria Luiza; Salzano, Francisco Mauro; Ashton-Prolla, Patricia; Ramallo, Virginia; Bortolini, Maria Cátira

    2015-01-01

    The diversity of the five single nucleotide polymorphisms located in genes of the TP53 pathway (TP53, rs1042522; MDM2, rs2279744; MDM4, rs1563828; USP7, rs1529916; and LIF, rs929271) were studied in a total of 282 individuals belonging to Quechua, Aymara, Chivay, Cabanaconde, Yanke, Taquile, Amantani, Anapia, Uros, Guarani Ñandeva, and Guarani Kaiowá populations, characterized as Native American or as having a high level (> 90%) of Native American ancestry. In addition, published data pertaining to 100 persons from five other Native American populations (Surui, Karitiana, Maya, Pima, and Piapoco) were analyzed. The populations were classified as living in high altitude (≥ 2,500 m) or in lowlands (< 2,500 m). Our analyses revealed that alleles USP7-G, LIF-T, and MDM2-T showed significant evidence that they were selected for in relation to harsh environmental variables related to high altitudes. Our results show for the first time that alleles of classical TP53 network genes have been evolutionary co-opted for the successful human colonization of the Andes. PMID:26382048

  6. TP53 codon 72 polymorphism and susceptibility to cervical cancer in the Chinese population: an update meta-analysis

    PubMed Central

    Li, Bing; Wang, Xin; Chen, Hong; Shang, Li-Xin; Wu, Nan

    2015-01-01

    Background: Although many epidemiologic studies investigated the TP53 codon 72 polymorphism and its association with cervical cancer (CC), definite conclusions cannot be drawn. Aim of the study: To evaluate the association between TP53 codon 72 polymorphism and risk of cervical cancer in the Chinese population. Methods: A computerized literature search was carried out in PubMed, Springer Link, Ovid, Chinese Biomedical Database (CBM), Chinese National Knowledge Infrastructure (CNKI), and Chinese Wanfang Database to collect relevant articles. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the strength of association. Results: A total of 16 studies including 1684 CC cases and 1178 controls were involved in this meta-analysis. Overall, significant increased association was found between the Pro/Pro carriers and CC risk when all studies in Chinese population pooled into the meta-analysis (heterozygous model: OR = 1.22, 95% CI: 1.01-1.46). In subgroup analyses stratified by ethnicity and source of controls, the same results were observed in Han and in hospital-based studies. Conclusion: Our results suggest that the TP53 codon 72 polymorphism may be potential biomarkers for CC risk in the Chinese population, especially for Han Chinese, and studies with wider spectrum of population are required for definite conclusions. PMID:26309559

  7. MAPK14/p38α confers irinotecan resistance to TP53-defective cells by inducing survival autophagy.

    PubMed

    Paillas, Salome; Causse, Annick; Marzi, Laetitia; de Medina, Philippe; Poirot, Marc; Denis, Vincent; Vezzio-Vie, Nadia; Espert, Lucile; Arzouk, Hayat; Coquelle, Arnaud; Martineau, Pierre; Del Rio, Maguy; Pattingre, Sophie; Gongora, Céline

    2012-07-01

    Recently we have shown that the mitogen-activated protein kinase (MAPK) MAPK14/p38α is involved in resistance of colon cancer cells to camptothecin-related drugs. Here we further investigated the cellular mechanisms involved in such drug resistance and showed that, in HCT116 human colorectal adenocarcinoma cells in which TP53 was genetically ablated (HCT116-TP53KO), overexpression of constitutively active MAPK14/p38α decreases cell sensitivity to SN-38 (the active metabolite of irinotecan), inhibits cell proliferation and induces survival-autophagy. Since autophagy is known to facilitate cancer cell resistance to chemotherapy and radiation treatment, we then investigated the relationship between MAPK14/p38α, autophagy and resistance to irinotecan. We demonstrated that induction of autophagy by SN38 is dependent on MAPK14/p38α activation. Finally, we showed that inhibition of MAPK14/p38α or autophagy both sensitizes HCT116-TP53KO cells to drug therapy. Our data proved that the two effects are interrelated, since the role of autophagy in drug resistance required the MAPK14/p38α. Our results highlight the existence of a new mechanism of resistance to camptothecin-related drugs: upon SN38 induction, MAPK14/p38α is activated and triggers survival-promoting autophagy to protect tumor cells against the cytotoxic effects of the drug. Colon cancer cells could thus be sensitized to drug therapy by inhibiting either MAPK14/p38 or autophagy.

  8. Genetic Variations in the TP53 Pathway in Native Americans Strongly Suggest Adaptation to the High Altitudes of the Andes.

    PubMed

    Jacovas, Vanessa Cristina; Rovaris, Diego Luiz; Peréz, Orlando; de Azevedo, Soledad; Macedo, Gabriel Souza; Sandoval, José Raul; Salazar-Granara, Alberto; Villena, Mercedes; Dugoujon, Jean-Michel; Bisso-Machado, Rafael; Petzl-Erler, Maria Luiza; Salzano, Francisco Mauro; Ashton-Prolla, Patricia; Ramallo, Virginia; Bortolini, Maria Cátira

    2015-01-01

    The diversity of the five single nucleotide polymorphisms located in genes of the TP53 pathway (TP53, rs1042522; MDM2, rs2279744; MDM4, rs1563828; USP7, rs1529916; and LIF, rs929271) were studied in a total of 282 individuals belonging to Quechua, Aymara, Chivay, Cabanaconde, Yanke, Taquile, Amantani, Anapia, Uros, Guarani Ñandeva, and Guarani Kaiowá populations, characterized as Native American or as having a high level (> 90%) of Native American ancestry. In addition, published data pertaining to 100 persons from five other Native American populations (Surui, Karitiana, Maya, Pima, and Piapoco) were analyzed. The populations were classified as living in high altitude (≥ 2,500 m) or in lowlands (< 2,500 m). Our analyses revealed that alleles USP7-G, LIF-T, and MDM2-T showed significant evidence that they were selected for in relation to harsh environmental variables related to high altitudes. Our results show for the first time that alleles of classical TP53 network genes have been evolutionary co-opted for the successful human colonization of the Andes.

  9. Chk1 inhibition significantly potentiates activity of nucleoside analogs in TP53-mutated B-lymphoid cells

    PubMed Central

    Zemanova, Jana; Hylse, Ondrej; Collakova, Jana; Vesely, Pavel; Oltova, Alexandra; Borsky, Marek; Zaprazna, Kristina; Kasparkova, Marie; Janovska, Pavlina; Verner, Jan; Kohoutek, Jiri; Dzimkova, Marta; Bryja, Vitezslav; Jaskova, Zuzana; Brychtova, Yvona; Paruch, Kamil; Trbusek, Martin

    2016-01-01

    Treatment options for TP53-mutated lymphoid tumors are very limited. In experimental models, TP53-mutated lymphomas were sensitive to direct inhibition of checkpoint kinase 1 (Chk1), a pivotal regulator of replication. We initially tested the potential of the highly specific Chk1 inhibitor SCH900776 to synergize with nucleoside analogs (NAs) fludarabine, cytarabine and gemcitabine in cell lines derived from B-cell malignancies. In p53-proficient NALM-6 cells, SCH900776 added to NAs enhanced signaling towards Chk1 (pSer317/pSer345), effectively blocked Chk1 activation (Ser296 autophosphorylation), increased replication stress (p53 and γ-H2AX accumulation) and temporarily potentiated apoptosis. In p53-defective MEC-1 cell line representing adverse chronic lymphocytic leukemia (CLL), Chk1 inhibition together with NAs led to enhanced and sustained replication stress and significantly potentiated apoptosis. Altogether, among 17 tested cell lines SCH900776 sensitized four of them to all three NAs. Focusing further on MEC-1 and co-treatment of SCH900776 with fludarabine, we disclosed chromosome pulverization in cells undergoing aberrant mitoses. SCH900776 also increased the effect of fludarabine in a proportion of primary CLL samples treated with pro-proliferative stimuli, including those with TP53 disruption. Finally, we observed a fludarabine potentiation by SCH900776 in a T-cell leukemia 1 (TCL1)-driven mouse model of CLL. Collectively, we have substantiated the significant potential of Chk1 inhibition in B-lymphoid cells. PMID:27556692

  10. Damage‐inducible intragenic demethylation of the human TP53 tumor suppressor gene is associated with transcription from an alternative intronic promoter

    PubMed Central

    Blackburn, James; Roden, Daniel L.; Ng, Robert; Wu, Jianmin; Bosman, Alexis

    2015-01-01

    Wild‐type TP53 exons 5–8 contain CpG dinucleotides that are prone to methylation‐dependent mutation during carcinogenesis, but the regulatory effects of methylation affecting these CpG sites are unclear. To clarify this, we first assessed site‐specific TP53 CpG methylation in normal and transformed cells. Both DNA damage and cell ageing were associated with site‐specific CpG demethylation in exon 5 accompanied by induction of a truncated TP53 isoform regulated by an adjacent intronic promoter (P2). We then synthesized novel synonymous TP53 alleles with divergent CpG content but stable encodement of the wild‐type polypeptide. Expression of CpG‐enriched TP53 constructs selectively reduced production of the full‐length transcript (P1), consistent with a causal relationship between intragenic demethylation and transcription. 450K methylation comparison of normal (TP53‐wildtype) and cancerous (TP53‐mutant) human cells and tissues revealed focal cancer‐associated declines in CpG methylation near the P1 transcription start site, accompanied by rises near the alternate exon 5 start site. These data confirm that site‐specific changes of intragenic TP53 CpG methylation are extrinsically inducible, and suggest that human cancer progression is mediated in part by dysregulation of damage‐inducible intragenic CpG demethylation that alters TP53 P1/P2 isoform expression. © 2015 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc. PMID:26676339

  11. Gene expression profiles modulated by the human carcinogen aristolochic acid I in human cancer cells and their dependence on TP53

    SciTech Connect

    Simoes, Maria L.; Hockley, Sarah L.; Schwerdtle, Tanja; Schmeiser, Heinz H.; Phillips, David H.; Arlt, Volker M.

    2008-10-01

    Aristolochic acid (AA) is the causative agent of urothelial tumours associated with aristolochic acid nephropathy. These tumours contain TP53 mutations and over-express TP53. We compared transcriptional and translational responses of two isogenic HCT116 cell lines, one expressing TP53 (p53-WT) and the other with this gene knocked out (p53-null), to treatment with aristolochic acid I (AAI) (50-100 {mu}M) for 6-48 h. Modulation of 118 genes was observed in p53-WT cells and 123 genes in p53-null cells. Some genes, including INSIG1, EGR1, CAV1, LCN2 and CCNG1, were differentially expressed in the two cell lines. CDKN1A was selectively up-regulated in p53-WT cells, leading to accumulation of TP53 and CDKN1A. Apoptotic signalling, measured by caspase-3 and -7 activity, was TP53-dependent. Both cell types accumulated in S phase, suggesting that AAI-DNA adducts interfere with DNA replication, independently of TP53 status. The oncogene MYC, frequently over-expressed in urothelial tumours, was up-regulated by AAI, whereas FOS was down-regulated. Observed modulation of genes involved in endocytosis, e.g. RAB5A, may be relevant to the known inhibition of receptor-mediated endocytosis, an early sign of AA-mediated proximal tubule injury. AAI-DNA adduct formation was significantly greater in p53-WT cells than in p53-null cells. Collectively, phenotypic anchoring of the AAI-induced expression profiles to DNA adduct formation, cell-cycle parameters, TP53 expression and apoptosis identified several genes linked to these biological outcomes, some of which are TP53-dependent. These results strengthen the importance of TP53 in AA-induced cancer, and indicate that other alterations, e.g. to MYC oncogenic pathways, may also contribute.

  12. Involvement of phorbol-12-myristate-13-acetate-induced protein 1 in goniothalamin-induced TP53-dependent and -independent apoptosis in hepatocellular carcinoma-derived cells

    SciTech Connect

    Kuo, Kung-Kai; Chen, Yi-Ling; Chen, Lih-Ren; Li, Chien-Feng; Lan, Yu-Hsuan; Chang, Fang-Rong; Wu, Yang-Chang; Shiue, Yow-Ling

    2011-10-01

    The objective was to investigate the upstream apoptotic mechanisms that were triggered by a styrylpyrone derivative, goniothalamin (GTN), in tumor protein p53 (TP53)-positive and -negative hepatocellular carcinoma (HCC)-derived cells. Effects of GTN were evaluated by the flow cytometry, alkaline comet assay, immunocytochemistry, small-hairpin RNA interference, mitochondria/cytosol fractionation, quantitative reverse transcription-polymerase chain reaction, immunoblotting analysis and caspase 3 activity assays in two HCC-derived cell lines. Results indicated that GTN triggered phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1, also known as NOXA)-mediated apoptosis via TP53-dependent and -independent pathways. In TP53-positive SK-Hep1 cells, GTN furthermore induced TP53 transcription-dependent and -independent apoptosis. After GTN treatment, accumulation of reactive oxygen species, formation of DNA double-strand breaks, transactivation of TP53 and/or PMAIP1 gene, translocation of TP53 and/or PMAIP1 proteins to mitochondria, release of cytochrome c from mitochondria, cleavage of caspases and induction of apoptosis in both cell lines were sustained. GTN might represent a novel class of anticancer drug that induces apoptosis in HCC-derived cells through PMAIP1 transactivation regardless of the status of TP53 gene. - Highlights: > Goniothalamin (GTN) induced apoptosis in hepatocellular carcinomas-derived cells. > The apoptosis induced by GTN is PMAIP1-dependent, regardless of TP53 status. > The apoptosis induced by GTN might be TP53 transcription-dependent or -independent. > GTN-induced apoptosis is mitochondria- and caspases-mediated.

  13. TP53 mutations are associated with higher rates of pathologic complete response to anthracycline/cyclophosphamide-based neoadjuvant chemotherapy in operable primary breast cancer.

    PubMed

    Wang, Yuxia; Xu, Ye; Chen, Jiuan; Ouyang, Tao; Li, Jinfeng; Wang, Tianfeng; Fan, Zhaoqing; Fan, Tie; Lin, Benyao; Xie, Yuntao

    2016-01-15

    The role of TP53 mutations in predicting response to neoadjuvant chemotherapy in breast cancer remains controversial. The aims of this study were to investigate whether TP53 mutations were associated with response and survival in breast cancer patients who received neoadjuvant chemotherapy. Therefore, we identified TP53 mutations in the core-needle biopsy tumor samples obtained before the neoadjuvant chemotherapy from 351 operable primary breast cancer patients who either received anthracycline/cyclophosphamide-based (n = 252) or paclitaxel (n = 99) neoadjuvant chemotherapy. We found that 41.0% (144 of 351) of patients harbored TP53 mutations, and 14.8% of patients achieved a pCR (pathologic complete response) after neoadjuvant chemotherapy. Among patients treated with anthracycline/cyclophosphamide (n = 252), patients with TP53 mutations had a significantly higher pCR rate than those with wild-type (28.6 vs.7.1%; p < 0.001), and TP53 mutation was an independent favorable predictor of pCR [odds ratio (OR) = 3.41; 95% confidence interval (CI) 1.50-7.77; p = 0.003] in this group; moreover, patients with TP53 mutation had a better distant recurrence-free survival (DRFS) than those with wild-type [unadjusted hazard ratio (HR) = 0.43; 95% CI 0.20-0.94; p = 0.030] in this group. Among patients treated with paclitaxel (n = 99), no significant difference in pCR rates was observed between patients with or without TP53 mutations (15.2 vs. 11.3%; p = 0.57). Our results suggested that patients with TP53 mutations are more likely to respond to anthracycline/ cyclophosphamide-based neoadjuvant chemotherapy and have a favorable survival.

  14. [Analysis of associations of polymorphic loci of a tumor suppressor gene TP53 with malignant neoplasms in glass fiber manufacturing workers].

    PubMed

    Mukhammadiyeva, G F; Bakirov, A B; Karimova, L K; Valeyeva, E T

    2014-01-01

    The purpose of the study was to determine the role of TP53 tumor suppressor gene polymorphisms in the occurrence of skin malignant neoplasms in glass fiber manufacturing workers. We carried out a comparative study of polymorphous loci Arg72Pro and dup16bp in TP53 gene in workers with skin cancer and hyperkeratosis (n = 68), occupied in continuous glass fiber manufacture, and in healthy workers (n = 52). The associations of both Pro and dup16 minor alleles of TP53 gene, and Arg/Pro-W/dup16 genotype combination with higher risks for skin oncologic diseases of occupational genesis have been revealed.

  15. Pri-Mir-34b/C and Tp-53 Polymorphisms are Associated With The Susceptibility of Papillary Thyroid Carcinoma

    PubMed Central

    Chen, Peng; Sun, Ruifen; Pu, Yan; Bai, Peng; Yuan, Fang; Liang, Yundan; Zhou, Bin; Wang, Yanyun; Sun, Yinghe; Zhu, Jingqiang; Zhang, Lin; Gao, Linbo

    2015-01-01

    Abstract Tumor suppressor p53 directly regulated the abundance of the miR-34b/c. The interaction might contribute to certain cancer. We hypothesized that rs4938723 in the promoter region of pri-miR-34b/c and TP-53 Arg72Pro may be related to the risk of papillary thyroid carcinoma (PTC). A total of 784 patients with PTC and 1006 healthy controls were recruited to participate in this study. The variants were discriminated using a polymerase chain reaction–restriction fragment length polymorphism method (PCR-RFLP). Additionally, the relative expression levels of miR-34b/c and TP-53 in 44 paired samples were revealed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A significantly increased risk of PTC was observed in the miR-34b/c rs4938723 CT, CC, and CT/CC genotypes compared with the TT genotype (CT vs TT: adjusted odds ratio [OR] = 1.51, 95%confidence interval [CI] = 1.23–1.85; CC vs TT: adjusted OR = 1.89, 95%CI = 1.39–2.63; CT/CC vs TT: adjusted OR = 1.59, 95%CI = 1.30–1.92, respectively). Significantly increased PTC susceptibility was also associated with the TP-53 Arg72Pro CC and CG/CC genotypes compared with the GG genotype (CC vs GG: adjusted OR = 2.04, 95%CI = 1.54–2.70; CG/CC vs GG: adjusted OR = 1.35, 95%CI = 1.11–1.67, respectively). Stratification analysis revealed that patients carrying the TP-53 Arg72Pro C allele and CC genotype had a significantly increased risk for developing N1 (C vs. G: OR = 1.27, 95%CI = 1.03–1.56; CC vs. GG: OR = 1.62, 95%CI = 1.07–2.46, respectively). Combined analysis showed that the genotypes of rs4938723 CT/CC + TP-53CG/CC increased the risk of PTC compared with rs4938723TT + TP-53GG (OR = 2.25, 95%CI = 1.67–3.03). Additionally, level of miR-34b was significantly upregulated in PTC patients. These findings indicate that the miR-34b/c rs4938723 and TP-53 Arg72Pro polymorphisms may contribute to the

  16. L-Leucine improves the anaemia in models of Diamond Blackfan anaemia and the 5q- syndrome in a TP53-independent way.

    PubMed

    Narla, Anupama; Payne, Elspeth M; Abayasekara, Nirmalee; Hurst, Slater N; Raiser, David M; Look, A Thomas; Berliner, Nancy; Ebert, Benjamin L; Khanna-Gupta, Arati

    2014-11-01

    Haploinsufficiency of ribosomal proteins (RPs) and upregulation of the tumour suppressor TP53 have been shown to be the common basis for the anaemia observed in Diamond Blackfan anaemia and 5q- myelodysplastic syndrome. We previously demonstrated that treatment with L-Leucine resulted in a marked improvement in anaemia in disease models. To determine if the L-Leucine effect was Tp53-dependent, we used antisense MOs to rps19 and rps14 in zebrafish; expression of tp53 and its downstream target cdkn1a remained elevated following L-leucine treatment. We confirmed this observation in human CD34+ cells. L-Leucine thus alleviates anaemia in RP-deficient cells in a TP53-independent manner.

  17. Clinical Relevance and Molecular Phenotypes in Gastric Cancer, of TP53 Mutations and Gene Expressions, in Combination With Other Gene Mutations

    PubMed Central

    Park, Sungjin; Lee, Jinhyuk; Kim, Yon Hui; Park, Jaheun; Shin, Jung-Woog; Nam, Seungyoon

    2016-01-01

    While altered TP53 is the most frequent mutation in gastric cancer (GC), its association with molecular or clinical phenotypes (e.g., overall survival, disease-free survival) remains little known. To that end, we can use genome-wide approaches to identify altered genes significantly related to mutated TP53. Here, we identified significant differences in clinical outcomes, as well as in molecular phenotypes, across specific GC tumor subpopulations, when combining TP53 with other signaling networks, including WNT and its related genes NRXN1, CTNNB1, SLITRK5, NCOR2, RYR1, GPR112, MLL3, MTUS2, and MYH6. Moreover, specific GC subpopulations indicated by dual mutation of NRXN1 and TP53 suggest different drug responses, according to the Connectivity Map, a pharmacological drug-gene association tool. Overall, TP53 mutation status in GC is significantly relevant to clinical or molecular categories. Thus, our approach can potentially provide a patient stratification strategy by dissecting previously unknown multiple TP53-mutated patient groups. PMID:27708434

  18. An identical, complex TP53 mutation arising independently in two unrelated families with diverse cancer profiles: the complexity of interpreting cancer risk in carriers

    PubMed Central

    Pinto, E M; Ribeiro, R C; Li, J; Taja-Chayeb, L; Carrasco, L F; de Lourdes Peña-Torres, M; Vidal-Millán, S; Maldonado-Mtz, H; Dueñas-González, A; McGregor, L; Zambetti, G P

    2012-01-01

    Most inherited TP53 mutations have been identified in individuals with a family cancer predisposition syndrome, in which the activity of p53 mutants is severely reduced. However, germline p53 mutants in children with ‘sporadic' adrenocortical or choroid plexus tumors exhibit a wide range of functional activity. Here, we demonstrate the occurrence of a complex germline TP53 mutation in two unrelated families with different cancer phenotypes, neither fulfilling the classic criteria for Li-Fraumeni syndrome. The TP53 mutation consists of a duplication of 7 bp in exon 4, resulting in a frame shift and premature stop signal. Haplotype analysis indicated that the mutation arose independently in the two families. Analysis of the DNA secondary structure predicts the TP53 mutation occurred within a hairpin loop. Additional germline complex mutations occurring within the same region of exon 4 have been identified in the IARC database. Our findings suggest that certain TP53 regions are prone to intrinsic genetic alterations, possibly through defects in DNA replication or repair. Further, carriers of the same TP53 mutation can have diverse cancer profiles, illustrating the complexity of genetic counseling and risk prediction. PMID:23552518

  19. Targeted sequencing reveals TP53 as a potential diagnostic biomarker in the post-treatment surveillance of head and neck cancer.

    PubMed

    van Ginkel, Joost H; de Leng, Wendy W J; de Bree, Remco; van Es, Robert J J; Willems, Stefan M

    2016-09-20

    Head and neck squamous cell carcinomas (HNSCC) form a large heterogeneous group of tumors and have a relatively poor outcome in advanced cases. Revealing the underlying genetic mutations in HNSCC facilitates the development of diagnostic biomarkers, which might lead to improved diagnosis and post treatment surveillance. We retrospectively analyzed mutational hotspots using targeted next-generation sequencing (NGS) of 239 HNSCC tumor samples in order to examine the mutational profile of HNSCC. Furthermore, we assessed prevalence, co-occurrence, and synonymy of gene mutations in (matched) tumor samples. TP53 was found mutated the most frequent with mutation rates of up to 83% in all tumors, compared to mutation rates of between 0 and 21% of CDKN2A, PIK3CA, HRAS, CDK4, FBXW7 and RB1. Mutational co-occurrence predominantly existed between TP53 and PIK3CA, TP53 and CDKN2A, and HRAS and PIK3CA. Mutational synonymy between primary tumor and associated metastasis and recurrence was present in respectively 88% and 89%. TP53 mutations were concordantly mutated in 95% of metastases and in 91% of recurrences. This indicates TP53 mutations to be highly prevalent and concordant in primary tumors and associated locoregional metastases and recurrences. In turn, this provides ground for further investigating the use of TP53 mutations as diagnostic biomarkers in HNSCC patients.

  20. Association between TP53 Arg72Pro polymorphism and leukemia risk: a meta-analysis of 14 case-control studies.

    PubMed

    Tian, Xin; Dai, Shundong; Sun, Jing; Jiang, Shenyi; Jiang, Youhong

    2016-04-07

    The relationship between the TP53 Arg72Pro polymorphism (rs1042522) and the risk of leukemia remains controversial. Consequently, we performed a meta-analysis to accurately evaluate the association between TP53 Arg72Pro polymorphism and leukemia risk. A comprehensive search was conducted to find all eligible studies of TP53 Arg72Pro polymorphism and leukemia risk. Fourteen case-control studies, with 2,506 cases and 4,386 controls, were selected for analysis. The overall data failed to indicate a significant association between TP53 Arg72Pro polymorphism and the risk of leukemia (C vs. G: OR = 1.09, 95% CI = 0.93-1.26; CC vs. GC + GG: OR = 1.23, 95% CI = 0.96-1.57). In a subgroup analysis of clinical types, an increased risk was observed in the acute lymphocytic leukemia (ALL) subgroup (CC vs. GC + GG: OR = 1.73; 95% CI = 1.07-2.81) but not in the acute myeloid leukemia (AML) subgroup. In the subgroup analysis, no significant associations with ethnicity and the source of the controls were observed. In conclusion, the results suggest that there is no association between TP53 Arg72Pro polymorphism and the risk of leukemia, but the CC genotype may increase the risk of ALL TP53 Arg72Pro polymorphism CC genotype may increase the risk of ALL but is not associated with AML. Further large-scale, well-designed studies are needed to confirm our results.

  1. Targeted sequencing reveals TP53 as a potential diagnostic biomarker in the post-treatment surveillance of head and neck cancer

    PubMed Central

    van Ginkel, Joost H.; de Leng, Wendy W.J.; de Bree, Remco; van Es, Robert J.J.; Willems, Stefan M.

    2016-01-01

    Head and neck squamous cell carcinomas (HNSCC) form a large heterogeneous group of tumors and have a relatively poor outcome in advanced cases. Revealing the underlying genetic mutations in HNSCC facilitates the development of diagnostic biomarkers, which might lead to improved diagnosis and post treatment surveillance. We retrospectively analyzed mutational hotspots using targeted next-generation sequencing (NGS) of 239 HNSCC tumor samples in order to examine the mutational profile of HNSCC. Furthermore, we assessed prevalence, co-occurrence, and synonymy of gene mutations in (matched) tumor samples. TP53 was found mutated the most frequent with mutation rates of up to 83% in all tumors, compared to mutation rates of between 0 and 21% of CDKN2A, PIK3CA, HRAS, CDK4, FBXW7 and RB1. Mutational co-occurrence predominantly existed between TP53 and PIK3CA, TP53 and CDKN2A, and HRAS and PIK3CA. Mutational synonymy between primary tumor and associated metastasis and recurrence was present in respectively 88% and 89%. TP53 mutations were concordantly mutated in 95% of metastases and in 91% of recurrences. This indicates TP53 mutations to be highly prevalent and concordant in primary tumors and associated locoregional metastases and recurrences. In turn, this provides ground for further investigating the use of TP53 mutations as diagnostic biomarkers in HNSCC patients. PMID:27528217

  2. Study of polymorphisms in the TP53 and RB1 genes in children with retinoblastoma in northern Mexico

    PubMed Central

    Nares-Cisneros, Jesús; Cárdenas-Hernández, Rubén I.; Jaramillo-Rodríguez, Yolanda; Zambrano-Galván, Graciela

    2017-01-01

    Purpose To determine the frequency and association of polymorphisms in the TP53 and RB1 genes with clinical characteristics in a group of children with retinoblastoma (RB) in northern Mexico. Methods A prospective, longitudinal, and analytical study of 11 patients diagnosed with RB was conducted. Endpoint PCR and high-resolution real-time PCR were performed. Chi-square and Student t tests were used to evaluate associations between variables. Allelic frequencies, as well as genotypic and Hardy–Weinberg equilibriums, were evaluated using Guo and Thompson’s method. Results We found a statistically significant difference between the polymorphism RB1-GG/rs9568036 and tumor chemoresistance (p<0.05). The allelic variants RB1-AA and AG/rs9568036 were determined to be associated with tumor chemosensitivity (p<0.05). A statistically significant relation between the polymorphism RB1-GG/rs9568036 and males (p = 0.0386), rate ratio (RR) = 2.0 (95% confidence interval [CI] = 0.76–5.32), as well as between the allelic variants RB1-AA and AG/rs9568036 and females (p = 0.0027), RR = 8.0 (95% CI = 1.28–50.04), was observed. We also observed a statistically significant association between the rs1042522 polymorphism in the TP53 gene and unilateral presentation of the disease. Conclusions The rs9568036 polymorphism in the RB1 gene and the allelic variants can be associated with type of response to medical therapy and associated with male sex, while the allelic variant rs1042522 polymorphism in the TP53 gene is associated with the unilateral presentation of the disease in a group of Mexican children with RB. PMID:28210099

  3. TP53 mutation at early stage of colorectal cancer progression from two types of laterally spreading tumors.

    PubMed

    Sakai, Eiji; Fukuyo, Masaki; Matsusaka, Keisuke; Ohata, Ken; Doi, Noriteru; Takane, Kiyoko; Matsuhashi, Nobuyuki; Fukushima, Junichi; Nakajima, Atsushi; Kaneda, Atsushi

    2016-06-01

    Although most sporadic colorectal cancers (CRC) are thought to develop from protruded adenomas through the adenoma-carcinoma sequence, some CRC develop through flat lesions, so-called laterally spreading tumors (LST). We previously analyzed epigenetic aberrations in LST and found that LST are clearly classified into two molecular subtypes: intermediate-methylation with KRAS mutation and low-methylation with absence of oncogene mutation. Intermediate-methylation LST were mostly granular type LST (LST-G) and low-methylation LST were mostly non-granular LST (LST-NG). In the present study, we conducted a targeted exon sequencing study including 38 candidate CRC driver genes to gain insight into how these genes modulate the development of LST. We identified a mean of 11.5 suspected nonpolymorphic variants per sample, including indels and non-synonymous mutations, although there was no significant difference in the frequency of total mutations between LST-G and LST-NG. Genes associated with RTK/RAS signaling pathway were mutated more frequently in LST-G than LST-NG (P = 0.004), especially KRAS mutation occurring at 70% (30/43) of LST-G but 26% (13/50) of LST-NG (P < 0.0001). Both LST showed high frequency of APC mutation, even at adenoma stage, suggesting its involvement in the initiation stage of LST, as it is involved at early stage of colorectal carcinogenesis via adenoma-carcinoma sequence. TP53 mutation was never observed in adenomas, but was specifically detected in cancer samples. TP53 mutation occurred during development of intramucosal cancer in LST-NG, but during development of cancer with submucosal invasion in LST-G. It is suggested that TP53 mutation occurs in the early stages of cancer development from adenoma in both LST-G and LST-NG, but is involved at an earlier stage in LST-NG.

  4. MDM2 is a potential therapeutic target and prognostic factor for ovarian clear cell carcinomas with wild type TP53

    PubMed Central

    Makii, Chinami; Oda, Katsutoshi; Ikeda, Yuji; Sone, Kenbun; Hasegawa, Kosei; Uehara, Yuriko; Nishijima, Akira; Asada, Kayo; Koso, Takahiro; Fukuda, Tomohiko; Inaba, Kanako; Oki, Shinya; Machino, Hidenori; Kojima, Machiko; Kashiyama, Tomoko; Mori-Uchino, Mayuyo; Arimoto, Takahide; Wada-Hiraike, Osamu; Kawana, Kei; Yano, Tetsu; Fujiwara, Keiichi; Aburatani, Hiroyuki; Osuga, Yutaka; Fujii, Tomoyuki

    2016-01-01

    MDM2, a ubiquitin ligase, suppresses wild type TP53 via proteasome-mediated degradation. We evaluated the prognostic and therapeutic value of MDM2 in ovarian clear cell carcinoma. MDM2 expression in ovarian cancer tissues was analyzed by microarray and real-time PCR, and its relationship with prognosis was evaluated by Kaplan-Meier method and log-rank test. The anti-tumor activities of MDM2 siRNA and the MDM2 inhibitor RG7112 were assessed by cell viability assay, western blotting, and flow cytometry. The anti-tumor effects of RG7112 in vivo were examined in a mouse xenograft model. MDM2 expression was significantly higher in clear cell carcinoma than in ovarian high-grade serous carcinoma (P = 0.0092) and normal tissues (P = 0.035). High MDM2 expression determined by microarray was significantly associated with poor progression-free survival and poor overall survival (P = 0.0002, and P = 0.0008, respectively). Notably, RG7112 significantly suppressed cell viability in clear cell carcinoma cell lines with wild type TP53. RG7112 also strongly induced apoptosis, increased TP53 phosphorylation, and stimulated expression of the proapoptotic protein PUMA. Similarly, siRNA knockdown of MDM2 induced apoptosis. Finally, RG7112 significantly reduced the tumor volume of xenografted RMG-I clear cell carcinoma cells (P = 0.033), and the density of microvessels (P = 0.011). Our results highlight the prognostic value of MDM2 expression in clear cell carcinoma. Thus, MDM2 inhibitors such as RG7112 may constitute a class of potential therapeutics. PMID:27659536

  5. Clonal Ordering of 17p and 5q Allelic Losses in Barrett Dysplasia and Adenocarcinoma

    NASA Astrophysics Data System (ADS)

    Blount, Patricia L.; Meltzer, Stephen J.; Yin, Jing; Huang, Ying; Krasna, Mark J.; Reid, Brian J.

    1993-04-01

    Both 17p and 5q allelic losses appear to be involved in the pathogenesis or progression of many human solid tumors. In colon carcinogenesis, there is strong evidence that the targets of the 17p and 5q allelic losses are TP53, the gene encoding p53, and APC, respectively. It is widely accepted that 5q allelic losses precede 17p allelic losses in the progression to colonic carcinoma. The data, however, supporting this proposed order are largely based on the prevalence of 17p and 5q allelic losses in adenomas and unrelated adenocarcinomas from different patients. We investigated the order in which 17p and 5q allelic losses developed during neoplastic progression in Barrett esophagus by evaluating multiple aneuploid cell populations from the same patient. Using DNA content flow cytometric cell sorting and polymerase chain reaction, 38 aneuploid cell populations from 14 patients with Barrett esophagus who had high grade dysplasia, cancer or both were evaluated for 17p and 5q allelic losses. 17p allelic losses preceded 5q allelic losses in 7 patients, both 17p and 5q allelic losses were present in all aneuploid populations of 4 patients, and only 17p (without 5q) allelic losses were present in the aneuploid populations of 3 patients. In no patient did we find that a 5q allelic loss preceded a 17p allelic loss. Our data suggest that 17p allelic losses typically occur before 5q allelic losses during neoplastic progression in Barrett esophagus.

  6. Unambiguous Detection of Multiple TP53 Gene Mutations in AAN-Associated Urothelial Cancer in Belgium Using Laser Capture Microdissection

    PubMed Central

    Aydin, Selda; Dekairelle, Anne-France; Ambroise, Jérôme; Durant, Jean-François; Heusterspreute, Michel; Guiot, Yves

    2014-01-01

    In the Balkan and Taiwan, the relationship between exposure to aristolochic acid and risk of urothelial neoplasms was inferred from the A>T genetic hallmark in TP53 gene from malignant cells. This study aimed to characterize the TP53 mutational spectrum in urothelial cancers consecutive to Aristolochic Acid Nephropathy in Belgium. Serial frozen tumor sections from female patients (n = 5) exposed to aristolochic acid during weight-loss regimen were alternatively used either for p53 immunostaining or laser microdissection. Tissue areas with at least 60% p53-positive nuclei were selected for microdissecting sections according to p53-positive matching areas. All areas appeared to be carcinoma in situ. After DNA extraction, mutations in the TP53 hot spot region (exons 5–8) were identified using nested-PCR and sequencing. False-negative controls consisted in microdissecting fresh-frozen tumor tissues both from a patient with a Li-Fraumeni syndrome who carried a p53 constitutional mutation, and from KRas mutated adenocarcinomas. To rule out false-positive results potentially generated by microdissection and nested-PCR, a phenacetin-associated urothelial carcinoma and normal fresh ureteral tissues (n = 4) were processed with high laser power. No unexpected results being identified, molecular analysis was pursued on malignant tissues, showing at least one mutation in all (six different mutations in two) patients, with 13/16 exonic (nonsense, 2; missense, 11) and 3/16 intronic (one splice site) mutations. They were distributed as transitions (n = 7) or transversions (n = 9), with an equal prevalence of A>T and G>T (3/16 each). While current results are in line with A>T prevalence previously reported in Balkan and Taiwan studies, they also demonstrate that multiple mutations in the TP53 hot spot region and a high frequency of G>T transversion appear as a complementary signature reflecting the toxicity of a cumulative dose of aristolochic acid ingested over a

  7. The Evolution of TP53 Mutations: From Loss-of-Function to Separation-of-Function Mutants

    PubMed Central

    Miller, Madison; Shirole, Nitin; Tian, Ruxiao; Pal, Debjani; Sordella, Raffaella

    2017-01-01

    As the most mutated gene in cancer, it is no surprise that TP53 has been the center of cancer biology discourse since its discovery in the late 1970s. Although early demonstrations of p53’s role in the modulation of cell proliferation and survival solidified its classification as a tumor suppressor and transcription factor, our conceptualization of p53 is ever-evolving. Here, we present novel evidence of the role of alternative splicing isoforms, truncating/separation-of-function mutations, and hotspot silent mutations in the regulation of p53’s activities. PMID:28191499

  8. Autophagy Induction Is a Tor- and Tp53-Independent Cell Survival Response in a Zebrafish Model of Disrupted Ribosome Biogenesis

    PubMed Central

    Boglev, Yeliz; Badrock, Andrew P.; Trotter, Andrew J.; Du, Qian; Richardson, Elsbeth J.; Parslow, Adam C.; Markmiller, Sebastian J.; Hall, Nathan E.; de Jong-Curtain, Tanya A.; Ng, Annie Y.; Verkade, Heather; Ober, Elke A.; Field, Holly A.; Shin, Donghun; Shin, Chong H.; Hannan, Katherine M.; Hannan, Ross D.; Pearson, Richard B.; Kim, Seok-Hyung; Ess, Kevin C.; Lieschke, Graham J.; Stainier, Didier Y. R.; Heath, Joan K.

    2013-01-01

    Ribosome biogenesis underpins cell growth and division. Disruptions in ribosome biogenesis and translation initiation are deleterious to development and underlie a spectrum of diseases known collectively as ribosomopathies. Here, we describe a novel zebrafish mutant, titania (ttis450), which harbours a recessive lethal mutation in pwp2h, a gene encoding a protein component of the small subunit processome. The biochemical impacts of this lesion are decreased production of mature 18S rRNA molecules, activation of Tp53, and impaired ribosome biogenesis. In ttis450, the growth of the endodermal organs, eyes, brain, and craniofacial structures is severely arrested and autophagy is up-regulated, allowing intestinal epithelial cells to evade cell death. Inhibiting autophagy in ttis450 larvae markedly reduces their lifespan. Somewhat surprisingly, autophagy induction in ttis450 larvae is independent of the state of the Tor pathway and proceeds unabated in Tp53-mutant larvae. These data demonstrate that autophagy is a survival mechanism invoked in response to ribosomal stress. This response may be of relevance to therapeutic strategies aimed at killing cancer cells by targeting ribosome biogenesis. In certain contexts, these treatments may promote autophagy and contribute to cancer cells evading cell death. PMID:23408911

  9. TP53 and MDM2 single nucleotide polymorphisms influence survival in non-del(5q) myelodysplastic syndromes

    PubMed Central

    Sallman, David A.; Basiorka, Ashley A.; Irvine, Brittany A.; Zhang, Ling; Epling-Burnette, P.K.; Rollison, Dana E.; Mallo, Mar; Sokol, Lubomir; Solé, Francesc; Maciejewski, Jaroslaw; List, Alan F.

    2015-01-01

    P53 is a key regulator of many cellular processes and is negatively regulated by the human homolog of murine double minute-2 (MDM2) E3 ubiquitin ligase. Single nucleotide polymorphisms (SNPs) of either gene alone, and in combination, are linked to cancer susceptibility, disease progression, and therapy response. We analyzed the interaction of TP53 R72P and MDM2 SNP309 SNPs in relationship to outcome in patients with myelodysplastic syndromes (MDS). Sanger sequencing was performed on DNA isolated from 208 MDS cases. Utilizing a novel functional SNP scoring system ranging from +2 to −2 based on predicted p53 activity, we found statistically significant differences in overall survival (OS) (p = 0.02) and progression-free survival (PFS) (p = 0.02) in non-del(5q) MDS patients with low functional scores. In univariate analysis, only IPSS and the functional SNP score predicted OS and PFS in non-del(5q) patients. In multivariate analysis, the functional SNP score was independent of IPSS for OS and PFS. These data underscore the importance of TP53 R72P and MDM2 SNP309 SNPs in MDS, and provide a novel scoring system independent of IPSS that is predictive for disease outcome. PMID:26416416

  10. TP53 and ATM mRNA expression in skin and skeletal muscle after low-level laser exposure.

    PubMed

    Guedes de Almeida, Luciana; Silva Sergio, Luiz Philippe da; de Paoli, Flavia; Mencalha, Andre Luiz; da Fonseca, Adenilson de Souza

    2017-02-16

    Low-level lasers are widespread in regenerative medicine, but the molecular mechanisms involved in their biological effects are not fully understood, particularly those on DNA stability. Therefore, this study aimed to investigate mRNA expression of genes related to DNA genomic stability in skin and skeletal muscle tissue from Wistar rats exposed to low-level red and infrared lasers. For this, TP53 (Tumor Protein 53) and ATM (Ataxia Telangiectasia Mutated gene) mRNA expressions were evaluated by real-time quantitative PCR (RT-qPCR) technique 24 hours after low-level red and infrared laser exposure. Our data showed that relative TP53 mRNA expression was not significantly altered in both tissues exposed to lasers. For ATM, relative mRNA expression in skin tissue was not significantly altered, but in muscle tissue, laser exposure increased relative ATM mRNA expression. Low-level red and infrared laser radiations alter ATM mRNA expression related to DNA stability in skeletal muscle tissue.

  11. Basic fibroblast growth factor suppresses radiation-induced apoptosis and TP53 pathway in rat small intestine.

    PubMed

    Matsuu-Matsuyama, Mutsumi; Nakashima, Masahiro; Shichijo, Kazuko; Okaichi, Kumio; Nakayama, Toshiyuki; Sekine, Ichiro

    2010-07-01

    The effect of basic fibroblast growth factor (bFGF) was studied in radiation-induced apoptosis in rat jejunal crypt cells. Six-week-old male Wistar rats were administered 4 mg/kg bFGF intraperitoneally 25 h before receiving 8 Gy whole-body X rays. The jejunum was removed for analysis from time 0 to 120 h after irradiation. Villus length in control rats declined steadily until 72 h, while in bFGF-treated rats the villi were longer than in the controls until 48 h. Crypt lengths were similar to villi. bFGF treatment increased Ki-67-positive cells in the jejunal crypt at 0, 24 and 48 h. The treatment with bFGF reduced the number of apoptotic cells per jejunal crypt to 23% and 10% of the control values at 3 and 6 h, respectively, and increased numbers of mitotic cells significantly at 48 and 72 h. bFGF decreased the levels of TP53, CDKN1A, Puma and Cleaved caspase 3 at 3 h as detected by Western blot analyses. Our results suggest that bFGF protected against acute radiation-induced injury by suppressing the crypt apoptotic cells including the stem cells and promoted crypt cell proliferation. The inhibition of apoptosis thus might be related to suppression of the TP53 pathway.

  12. Prevalence of an inherited cancer predisposition syndrome associated with the germ line TP53 R337H mutation in Paraguay.

    PubMed

    Legal, Edith Falcon-de; Ascurra, Marta; Custódio, Gislaine; Ayala, Horacio Legal; Monteiro, Magna; Vega, Celeste; Fernández-Nestosa, María José; Vega, Sonia; Sade, Elis R; Coelho, Izabel M M; Ribeiro, Enilze M S F; Cavalli, Iglenir J; Figueiredo, Bonald C

    2015-04-01

    The tumor suppressor gene TP53 is the most frequently mutated gene in human cancer, and the germline TP53 R337H mutation is the most common mutation reported to date. However, this mutation is associated with a lower cumulative lifetime cancer risk than other mutations in the p53 DNA-binding domain. A detailed statistical analysis of 171,500 DNA tests in Brazilian neonates found that 0.27% of the general population is positive for this mutation, and some of the estimated 200,000 Brazilian R337H carriers in southern and southeastern Brazil have already developed cancer. The present study was designed to estimate R337H prevalence in neighboring Paraguay. To address this question, 10,000 dried blood samples stored in Guthrie cards since 2008 were randomly selected from the Paraguayan municipalities located at the border with Brazil. These samples were tested for R337H mutation using the PCR-restriction fragment length polymorphism assay. This germline mutation was detected in five samples (5/10,000), indicating that the total number of R337H carriers in Paraguay may be as high as 3500. Previous studies have shown that other countries (i.e., Portugal, Spain, and Germany) presented one family with this mutation, leading us to conclude that, besides Brazil and Paraguay, other countries may have multiple families carrying this mutation, which is an inherited syndrome that is difficult to control.

  13. A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma

    PubMed Central

    Chen, Kenneth S.; Kwon, Woo Sun; Kim, Jiwoong; Heo, Su Jin; Kim, Hyo Song; Kim, Hyo Ki; Kim, Soo Hee; Lee, Won Suk; Chung, Hyun Cheol; Rha, Sun Young; Hwang, Tae Hyun

    2016-01-01

    Osteosarcoma is the most common primary bone cancer. It can be cured by aggressive surgery and chemotherapy, but outcomes for metastatic or chemoresistant disease remain dismal. Cancer sequencing studies have shown that the p53 pathway is dysregulated in nearly every case, often by translocation; however, no studies of osteosarcoma evolution or intratumor heterogeneity have been done to date. We studied a patient with chemoresistant, metastatic disease over the course of 3 years. We performed exome sequencing on germline DNA and DNA collected from tumor at three separate time points. We compared variant calls and variant allele frequencies between different samples. We identified subclonal mutations in several different genes in the primary tumor sample and found that one particular subclone dominated subsequent tumor samples at relapse. This clone was marked by a novel TP53-KPNA3 translocation and loss of the opposite-strand wild-type TP53 allele. Future research must focus on the functional significance of such clones and strategies to eliminate them. PMID:27626065

  14. TP53 mutated glioblastoma stem-like cell cultures are sensitive to dual mTORC1/2 inhibition while resistance in TP53 wild type cultures can be overcome by combined inhibition of mTORC1/2 and Bcl-2

    PubMed Central

    Venkatesan, Subramanian; Hoogstraat, Marlous; Caljouw, Ester; Pierson, Tessa; Spoor, Jochem K.H.; Zeneyedpour, Lona; Dubbink, Hendrikus J.; Dekker, Lennard J.; van der Kaaij, Mariëlle; Kloezeman, Jenneke; Berghauser Pont, Lotte M.E.; Besselink, Nicolle J.M.; Luider, Theo M.; Joore, Jos; Martens, John W.; Lamfers, Martine L.M.; Sleijfer, Stefan; Leenstra, Sieger

    2016-01-01

    Background Glioblastoma is the most malignant tumor of the central nervous system and still lacks effective treatment. This study explores mutational biomarkers of 11 drugs targeting either the RTK/Ras/PI3K, the p53 or the Rb pathway using 25 patient-derived glioblastoma stem-like cell cultures (GSCs). Results We found that TP53 mutated GSCs were approximately 3.5 fold more sensitive to dual inhibition of mammalian target of rapamycin complex 1 and 2 (mTORC1/2) compared to wild type GSCs. We identified that Bcl-2(Thr56/Ser70) phosphorylation contributed to the resistance of TP53 wild type GSCs against dual mTORC1/2 inhibition. The Bcl-2 inhibitor ABT-263 (navitoclax) increased sensitivity to the mTORC1/2 inhibitor AZD8055 in TP53 wild type GSCs, while sensitivity to AZD8055 in TP53 mutated GSCs remained unchanged. Conclusion Our data suggest that Bcl-2 confers resistance to mTORC1/2 inhibitors in TP53 wild type GSCs and that combined inhibition of both mTORC1/2 and Bcl-2 is worthwhile to explore further in TP53 wild type glioblastomas, whereas in TP53 mutated glioblastomas dual mTORC1/2 inhibitors should be explored. PMID:27533080

  15. MEK plus PI3K/mTORC1/2 therapeutic efficacy is impacted by TP53 mutation in preclinical models of colorectal cancer

    PubMed Central

    Ibrahim, Yasir H.; Calvo, María Teresa; Gris-Oliver, Albert; Rodríguez, Olga; Grueso, Judit; Antón, Pilar; Guzmán, Marta; Aura, Claudia; Nuciforo, Paolo; Jessen, Katti; Argilés, Guillem; Dienstmann, Rodrigo; Bertotti, Andrea; Trusolino, Livio; Matito, Judit; Vivancos, Ana; Chicote, Irene; Palmer, Héctor G.; Tabernero, Josep; Scaltriti, Maurizio; Baselga, José; Serra, Violeta

    2016-01-01

    Purpose PI3K-pathway activation occurs in concomitance with RAS/BRAF mutations in colorectal cancer (CRC) limiting the sensitivity to targeted therapies. Several clinical studies are being conducted to test the tolerability and clinical activity of dual MEK and PI3K-pathway blockade in solid tumors. Experimental design In the present study we explored the efficacy of dual pathway blockade in CRC preclinical models harboring concomitant activation of the ERK- and PI3K-pathways. Moreover, we investigated if TP53 mutation impacts the response to this therapy. Results Dual MEK and mTORC1/2 blockade resulted in synergistic antiproliferative effects in cell lines bearing alterations in KRAS/BRAF and PIK3CA/PTEN. Although the on-treatment cell cycle effects were not impacted by the TP53 status, a marked proapoptotic response to therapy was observed exclusively in wild-type TP53 CRC models. We further interrogated two independent panels of KRAS/BRAF- and PIK3CA/PTEN-altered cell line- and patient-derived tumor xenografts for the antitumor response towards this combination of agents. A combination-response that resulted in substantial antitumor activity was exclusively observed among the wild-type TP53-models (two out of five, 40%), while there was no such response across the eight mutant TP53 models (0%). Interestingly, within a cohort of fourteen CRC patients treated with these agents for their metastatic disease, two patients with long-lasting responses (32 weeks) had TP53 wild-type tumors. Conclusions Our data supports that in wild-type TP53-CRC cells with ERK- and PI3K-pathway alterations MEK-blockade results in potent p21-induction preventing apoptosis to occur. In turn, mTORC1/2 inhibition blocks MEK-inhibitor-mediated p21-induction, unleashing apoptosis. PMID:26272063

  16. Reversion of apoptotic resistance of TP53-mutated Burkitt lymphoma B-cells to spindle poisons by exogenous activation of JNK and p38 MAP kinases

    PubMed Central

    Farhat, M; Poissonnier, A; Hamze, A; Ouk-Martin, C; Brion, J-D; Alami, M; Feuillard, J; Jayat-Vignoles, C

    2014-01-01

    Defects in apoptosis are frequently the cause of cancer emergence, as well as cellular resistance to chemotherapy. These phenotypes may be due to mutations of the tumor suppressor TP53 gene. In this study, we examined the effect of various mitotic spindle poisons, including the new isocombretastatin derivative isoNH2CA-4 (a tubulin-destabilizing molecule, considered to bind to the colchicine site by analogy with combretastatin A-4), on BL (Burkitt lymphoma) cells. We found that resistance to spindle poison-induced apoptosis could be reverted in tumor protein p53 (TP53)-mutated cells by EBV (Epstein Barr virus) infection. This reversion was due to restoration of the intrinsic apoptotic pathway, as assessed by relocation of the pro-apoptotic molecule Bax to mitochondria, loss of mitochondrial integrity and activation of the caspase cascade with PARP (poly ADP ribose polymerase) cleavage. EBV sensitized TP53-mutated BL cells to all spindle poisons tested, including vincristine and taxol, an effect that was systematically downmodulated by pretreatment of cells with inhibitors of p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases. Exogenous activation of p38 and JNK pathways by dihydrosphingosine reverted resistance of TP53-mutated BL cells to spindle poisons. Dihydrosphingosine treatment of TP53-deficient Jurkat and K562 cell lines was also able to induce cell death. We conclude that activation of p38 and JNK pathways may revert resistance of TP53-mutated cells to spindle poisons. This opens new perspectives for developing alternative therapeutic strategies when the TP53 gene is inactivated. PMID:24787013

  17. MIR517C inhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

    PubMed Central

    Lu, Yuntao; Xiao, Limin; Liu, Yawei; Wang, Hai; Li, Hong; Zhou, Qiang; Pan, Jun; Lei, Bingxi; Huang, Annie; Qi, Songtao

    2015-01-01

    The epithelial-to-mesenchymal (-like) transition (EMT), a crucial embryonic development program, has been linked to the regulation of glioblastoma (GBM) progression and invasion. Here, we investigated the role of MIR517C/miR-517c, which belongs to the C19MC microRNA cluster identified in our preliminary studies, in the pathogenesis of GBM. We found that MIR517C was associated with improved prognosis in patients with GBM. Furthermore, following treatment with the autophagy inducer temozolomide (TMZ) and low glucose (LG), MIR517C degraded KPNA2 (karyopherin alpha 2 [RAG cohort 1, importin alpha 1]) and subsequently disturbed the nuclear translocation of TP53 in the GBM cell line U87 in vitro. Interestingly, this microRNA could inhibit autophagy and reduce cell migration and infiltration in U87 cells harboring wild-type (WT) TP53, but not in U251 cells harboring mutant (MU) TP53. Moreover, the expression of epithelial markers (i.e., CDH13/T-cadherin and CLDN1 [claudin 1]) increased, while the expression of mesenchymal markers (i.e., CDH2/N-cadherin, SNAI1/Snail, and VIM [vimentin]) decreased, indicating that the EMT status was blocked by MIR517C in U87 cells. Compared with MIR517C overexpression, MIR517C knockdown promoted infiltration of U87 cells to the surrounding structures in nude mice in vivo. The above phenotypic changes were also observed in TP53+/+ and TP53-/- HCT116 colon cancer cells. In summary, our study provided support for a link between autophagy and EMT status in WT TP53 GBM cells and provided evidence for the signaling pathway (MIR517C-KPNA2-cytoplasmic TP53) involved in attenuating autophagy and eliminating the increased migration and invasion during the EMT. PMID:26553592

  18. FGFR3 and Tp53 mutations in T1G3 transitional bladder carcinomas: independent distribution and lack of association with prognosis.

    PubMed

    Hernández, Silvia; López-Knowles, Elena; Lloreta, Josep; Kogevinas, Manolis; Jaramillo, Roberto; Amorós, Alex; Tardón, Adonina; García-Closas, Reina; Serra, Consol; Carrato, Alfredo; Malats, Núria; Real, Francisco X

    2005-08-01

    FGFR3 and Tp53 mutations have been proposed as defining two alternative pathways in the pathogenesis of transitional bladder cancer. FGFR3 mutations are associated with low-grade tumors and a favorable prognosis. Tp53 alterations are associated with advanced tumors and, possibly, with a poor prognosis. We focus here on the subgroup of T1G3 superficial tumors because they are a major clinical challenge. Patients (n = 119) were identified from a prospective study of 1,356 cases. Mutations in FGFR3 (exons 7, 10, and 15) and Tp53 (exons 4-9) were analyzed using PCR and direct sequencing. All cases were followed for recurrence and death. Survival was analyzed using Kaplan-Meier curves and multivariable Cox regression. FGFR3 mutations were detected in 20 (16.8%) tumors; 100 mutations in Tp53 were found in tumors from 78 (65.5%) cases. Multiple alterations in Tp53 were present in 19 tumors (16%). Inactivating mutations were present in 58% of tumors. The combined mutation distribution (FGFR3/Tp53) was: wt/wt (34.5%), mut/wt (7.6%), wt/mut (48.7%), and mut/mut (9.2%), indicating that the presence of either mutation did not depend on the other (P value = 0.767). FGFR3 and Tp53 mutations were not associated with clinicopathologic characteristics of patients and did not predict, alone or in combination, recurrence or survival. Taking the risk of the wt/wt group as reference, the mutation-associated risks of cancer-specific mortality were: mut/wt 1.42 (0.15-13.75), wt/mut 0.67 (0.19-2.31), mut/mut 1.62 (0.27-9.59). These molecular features support the notion that T1G3 tumors are at the crossroads of the two main molecular pathways proposed for bladder cancer development and progression.

  19. Differential Gene Expression of BRCA1,ERBB2 and TP53 biomarkers between Human Breast Tissue and Peripheral Blood Samples of Breast Cancer.

    PubMed

    Zghair, Abdulrazzaq Neamah; Sinha, Deepak Kumar; Kassim, Arkan; Alfaham, Mohmmad; Sharma, Anil K

    2016-01-01

    Breast cancer is a most common malignancy especially in Iraqi women accounting for high morbidity and mortality. Mutations in BRCA1 gene is one of the important genetic predisposing factors inbreast cancer. Similarly ERBB2 and TP53 are also key prognostic markers in breast cancer treatment.We were interested to explore the gene expression profiles of BRCA1, ERBB2 and TP53 in breast cancer women patients from Iraq so as to assess the potential of such markers in breast cancer treatment. The mRNA levels were significantly over-expressed in tumor tissues in comparison to normal ones with p values (p<0.005) observed between malignant BRCA1 and control tissue samples. Similarly significant difference (p<0.001) was observed between malignant ERBB2 in comparison to control, and malignant TP53 and benign tissue samples as well. However in blood samples, no considerable expression of these markers was observed. Out of three selected genes, ERBB2 expression was significantly expressed in comparison to BRCA1 and TP53 in cancer tissue. Mutation analysis of BRCA1, ERBB2 and TP53 has been made to find out the region most susceptible to mutations in these genes The BRCA1 exon 11, ERBB2 16 and TP53 exon 5 displayed increased chances of having mutations. We can conclude from the study that differential gene expression of BRCA1, ERBB2 and TP53 at mRNA levels may act as a diagnostic marker of circulating tumor cells having important prognostic value in breast cancer patients.

  20. Baseline results from the UK SIGNIFY study: a whole-body MRI screening study in TP53 mutation carriers and matched controls.

    PubMed

    Saya, Sibel; Killick, Emma; Thomas, Sarah; Taylor, Natalie; Bancroft, Elizabeth K; Rothwell, Jeanette; Benafif, Sarah; Dias, Alexander; Mikropoulos, Christos; Pope, Jenny; Chamberlain, Anthony; Gunapala, Ranga; Izatt, Louise; Side, Lucy; Walker, Lisa; Tomkins, Susan; Cook, Jackie; Barwell, Julian; Wiles, Vicki; Limb, Lauren; Eccles, Diana; Leach, Martin O; Shanley, Susan; Gilbert, Fiona J; Hanson, Helen; Gallagher, David; Rajashanker, Bala; Whitehouse, Richard W; Koh, Dow-Mu; Sohaib, S Aslam; Evans, D Gareth; Eeles, Rosalind A

    2017-01-16

    In the United Kingdom, current screening guidelines for TP53 germline mutation carriers solely recommends annual breast MRI, despite the wide spectrum of malignancies typically seen in this group. This study sought to investigate the role of one-off non-contrast whole-body MRI (WB MRI) in the screening of asymptomatic TP53 mutation carriers. 44 TP53 mutation carriers and 44 population controls were recruited. Scans were read by radiologists blinded to participant carrier status. The incidence of malignancies diagnosed in TP53 mutation carriers against general population controls was calculated. The incidences of non-malignant relevant disease and irrelevant disease were measured, as well as the number of investigations required to determine relevance of findings. In TP53 mutation carriers, 6 of 44 (13.6, 95% CI 5.2-27.4%) participants were diagnosed with cancer during the study, all of which would be considered life threatening if untreated. Two were found to have two primary cancers. Two participants with cancer had abnormalities on the MRI which were initially thought to be benign (a pericardial cyst and a uterine fibroid) but transpired to be sarcomas. No controls were diagnosed with cancer. Fifteen carriers (34.1, 95% CI 20.5-49.9%) and seven controls (15.9, 95% CI 6.7-30.1%) underwent further investigations following the WB MRI for abnormalities that transpired to be benign (p = 0.049). The cancer detection rate in this group justifies a minimum baseline non-contrast WB MRI in germline TP53 mutation carriers. This should be adopted into national guidelines for management of adult TP53 mutation carriers in addition to the current practice of contrast enhanced breast MRI imaging.

  1. MIR517C inhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation.

    PubMed

    Lu, Yuntao; Xiao, Limin; Liu, Yawei; Wang, Hai; Li, Hong; Zhou, Qiang; Pan, Jun; Lei, Bingxi; Huang, Annie; Qi, Songtao

    2015-01-01

    The epithelial-to-mesenchymal (-like) transition (EMT), a crucial embryonic development program, has been linked to the regulation of glioblastoma (GBM) progression and invasion. Here, we investigated the role of MIR517C/miR-517c, which belongs to the C19MC microRNA cluster identified in our preliminary studies, in the pathogenesis of GBM. We found that MIR517C was associated with improved prognosis in patients with GBM. Furthermore, following treatment with the autophagy inducer temozolomide (TMZ) and low glucose (LG), MIR517C degraded KPNA2 (karyopherin alpha 2 [RAG cohort 1, importin alpha 1]) and subsequently disturbed the nuclear translocation of TP53 in the GBM cell line U87 in vitro. Interestingly, this microRNA could inhibit autophagy and reduce cell migration and infiltration in U87 cells harboring wild-type (WT) TP53, but not in U251 cells harboring mutant (MU) TP53. Moreover, the expression of epithelial markers (i.e., CDH13/T-cadherin and CLDN1 [claudin 1]) increased, while the expression of mesenchymal markers (i.e., CDH2/N-cadherin, SNAI1/Snail, and VIM [vimentin]) decreased, indicating that the EMT status was blocked by MIR517C in U87 cells. Compared with MIR517C overexpression, MIR517C knockdown promoted infiltration of U87 cells to the surrounding structures in nude mice in vivo. The above phenotypic changes were also observed in TP53(+/+) and TP53(-/-) HCT116 colon cancer cells. In summary, our study provided support for a link between autophagy and EMT status in WT TP53 GBM cells and provided evidence for the signaling pathway (MIR517C-KPNA2-cytoplasmic TP53) involved in attenuating autophagy and eliminating the increased migration and invasion during the EMT.

  2. Effects of TP53 and PIK3CA mutations in early breast cancer: a matter of co-mutation and tumor-infiltrating lymphocytes.

    PubMed

    Kotoula, Vassiliki; Karavasilis, Vasilios; Zagouri, Flora; Kouvatseas, George; Giannoulatou, Eleni; Gogas, Helen; Lakis, Sotiris; Pentheroudakis, George; Bobos, Mattheos; Papadopoulou, Kyriaki; Tsolaki, Eleftheria; Pectasides, Dimitrios; Lazaridis, Georgios; Koutras, Angelos; Aravantinos, Gerasimos; Christodoulou, Christos; Papakostas, Pavlos; Markopoulos, Christos; Zografos, George; Papandreou, Christos; Fountzilas, George

    2016-07-01

    The purpose of this study is to investigate whether the outcome of breast cancer (BC) patients treated with adjuvant chemotherapy is affected by co-mutated TP53 and PIK3CA according to stromal tumor-infiltrating lymphocytes (TILs). Paraffin tumors of all clinical subtypes from 1661 patients with operable breast cancer who were treated within 4 adjuvant trials with anthracycline-taxanes chemotherapy were informative for TP53 and PIK3CA mutation status (semiconductor sequencing genotyping) and for stromal TILs density. Disease-free survival (DFS) was examined. TP53 mutations were associated with higher (p < 0.001) and PIK3CA with lower (p = 0.004) TILs in an ER /PgR-specific manner (p < 0.001). Mutations did not affect the favorable DFS of patients with lymphocyte-predominant (LP) BC. Within non-LPBC, PIK3CA-only mutations conferred best, while TP53-PIK3CA co-mutations (6 % of all tumors) conferred worst DFS (HR 0.59; 95 % CI 0.44-0.79; p = 0.001 for PIK3CA-only). TP53-only mutations were unfavorable in patients with lower TILs, while patients with lower TILs performed worse if their tumors carried TP53-only mutations (interaction p = 0.046). Multivariate analysis revealed favorable PIK3CA-only mutations in non-LPBC (HR 0.64; 95 % CI 0.47-0.88; p = 0.007), and unfavorable TP53 mutations in ER/PgRpos/HER2neg (HR 1.55; 95 % CI 1.07-2.24; p = 0.021). Mutations did not interact with TILs in non-LP triple-negative and HER2-positive patients. TP53 and PIK3CA mutations appear to have diverse effects on the outcome of early BC patients, according to whether these genes are co-mutated or not, and for TP53 according to TILs density and ER/PgR-status. These findings need to be considered when evaluating the effect of these two most frequently mutated genes in the context of large clinical trials.

  3. Base damage, local sequence context and TP53 mutation hotspots: a molecular dynamics study of benzo[a]pyrene induced DNA distortion and mutability

    PubMed Central

    Menzies, Georgina E.; Reed, Simon H.; Brancale, Andrea; Lewis, Paul D.

    2015-01-01

    The mutational pattern for the TP53 tumour suppressor gene in lung tumours differs to other cancer types by having a higher frequency of G:C>T:A transversions. The aetiology of this differing mutation pattern is still unknown. Benzo[a]pyrene,diol epoxide (BPDE) is a potent cigarette smoke carcinogen that forms guanine adducts at TP53 CpG mutation hotspot sites including codons 157, 158, 245, 248 and 273. We performed molecular modelling of BPDE-adducted TP53 duplex sequences to determine the degree of local distortion caused by adducts which could influence the ability of nucleotide excision repair. We show that BPDE adducted codon 157 has greater structural distortion than other TP53 G:C>T:A hotspot sites and that sequence context more distal to adjacent bases must influence local distortion. Using TP53 trinucleotide mutation signatures for lung cancer in smokers and non-smokers we further show that codons 157 and 273 have the highest mutation probability in smokers. Combining this information with adduct structural data we predict that G:C>T:A mutations at codon 157 in lung tumours of smokers are predominantly caused by BPDE. Our results provide insight into how different DNA sequence contexts show variability in DNA distortion at mutagen adduct sites that could compromise DNA repair at well characterized cancer related mutation hotspots. PMID:26400171

  4. An ultra-deep sequencing strategy to detect sub-clonal TP53 mutations in presentation chronic lymphocytic leukaemia cases using multiple polymerases.

    PubMed

    Worrillow, L; Baskaran, P; Care, M A; Varghese, A; Munir, T; Evans, P A; O'Connor, S J; Rawstron, A; Hazelwood, L; Tooze, R M; Hillmen, P; Newton, D J

    2016-10-06

    Chronic lymphocytic leukaemia (CLL) is the most common clonal B-cell disorder characterized by clonal diversity, a relapsing and remitting course, and in its aggressive forms remains largely incurable. Current front-line regimes include agents such as fludarabine, which act primarily via the DNA damage response pathway. Key to this is the transcription factor p53. Mutations in the TP53 gene, altering p53 functionality, are associated with genetic instability, and are present in aggressive CLL. Furthermore, the emergence of clonal TP53 mutations in relapsed CLL, refractory to DNA-damaging therapy, suggests that accurate detection of sub-clonal TP53 mutations prior to and during treatment may be indicative of early relapse. In this study, we describe a novel deep sequencing workflow using multiple polymerases to generate sequencing libraries (MuPol-Seq), facilitating accurate detection of TP53 mutations at a frequency as low as 0.3%, in presentation CLL cases tested. As these mutations were mostly clustered within the regions of TP53 encoding DNA-binding domains, essential for DNA contact and structural architecture, they are likely to be of prognostic relevance in disease progression. The workflow described here has the potential to be implemented routinely to identify rare mutations across a range of diseases.

  5. TP53 supports basal-like differentiation of mammary epithelial cells by preventing translocation of deltaNp63 into nucleoli

    NASA Astrophysics Data System (ADS)

    Munne, Pauliina M.; Gu, Yuexi; Tumiati, Manuela; Gao, Ping; Koopal, Sonja; Uusivirta, Sanna; Sawicki, Janet; Wei, Gong-Hong; Kuznetsov, Sergey G.

    2014-04-01

    Multiple observations suggest a cell type-specific role for TP53 in mammary epithelia. We developed an in vitro assay, in which primary mouse mammary epithelial cells (mMECs) progressed from lumenal to basal-like phenotypes based on expression of Krt18 or ΔNp63, respectively. Such transition was markedly delayed in Trp53-/- mMECs suggesting that Trp53 is required for specification of the basal, but not lumenal cells. Evidence from human basal-like cell lines suggests that TP53 may support the activity of ΔNp63 by preventing its translocation from nucleoplasm into nucleoli. In human lumenal cells, activation of TP53 by inhibiting MDM2 or BRCA1 restored the nucleoplasmic expression of ΔNp63. Trp53-/- mMECs eventually lost epithelial features resulting in upregulation of MDM2 and translocation of ΔNp63 into nucleoli. We propose that TP63 may contribute to TP53-mediated oncogenic transformation of epithelial cells and shed light on tissue- and cell type-specific biases observed for TP53-related cancers.

  6. A radiation-induced acute apoptosis involving TP53 and BAX precedes the delayed apoptosis and neoplastic transformation of CGL1 human hybrid cells.

    PubMed

    Mendonca, Marc S; Mayhugh, Brendan M; McDowell, Berry; Chin-Sinex, Helen; Smith, Martin L; Dynlacht, Joseph R; Spandau, Dan F; Lewis, Davina A

    2005-06-01

    Exposing CGL1 (HeLa x fibroblast) hybrid cells to 7 Gy of X rays results in the onset of a delayed apoptosis in the progeny of the cells 10 to 12 cell divisions postirradiation that correlates with the emergence of neoplastically transformed foci. The delayed apoptosis begins around day 8 postirradiation and lasts for 11 days. We now demonstrate that the delayed apoptosis is also characterized by the appearance of approximately 50-kb apoptotic DNA fragments and caspase 3 activation postirradiation. In addition, we confirm that stabilization of TP53 and transactivation of pro-apoptosis BAX also occurs during the delayed apoptosis and show that anti-apoptosis BCL-X(L) is down-regulated. To test whether the delayed apoptosis was due to a nonfunctional acute TP53 damage response in CGL1 cells, studies of acute apoptosis were completed. After irradiation, CGL1 cells underwent an acute wave of apoptosis that involves TP53 stabilization, transactivation of BAX gene expression, and a rapid caspase activation that ends by 96 h postirradiation. In addition, the acute onset of apoptosis correlates with transactivation of a standard wild-type TP53-responsive reporter (pG13-CAT) in CGL1 cells after radiation exposure. We propose that the onset of the delayed apoptosis is not the result of a nonfunctional acute TP53 damage response pathway but rather is a consequence of X-ray-induced genomic instability arising in the distant progeny of the irradiated cells.

  7. Breast cancer risk in relation to TP53 codon 72 and CDH1 gene polymorphisms in the Bangladeshi women.

    PubMed

    Shabnaz, Samia; Ahmed, Maizbha Uddin; Islam, Md Siddiqul; Islam, Md Reazul; Al-Mamun, Mir Md Abdullah; Islam, Mohammad Safiqul; Hasnat, Abul

    2016-06-01

    Pharmacogenomic studies play a significant role in understanding the risk of breast cancer where genetic abnormalities are implicated as the etiology of cancer. Various polymorphisms of tumor suppressor gene TP53 and E-cadherin (CDH1) have been found to be associated with increased breast cancer risk worldwide. This study aimed to analyze the contribution of TP53 and CDH1 gene anomalies in breast cancer risk in the Bangladeshi breast cancer patients. For risk determination, 310 patients with breast cancer and 250 controls from Bangladeshi women were recruited who are matched up with age and use of contraceptives with patients. Genetic polymorphisms were detected by using polymerase chain reaction restriction fragment length polymorphism. A significant association was found between TP53Arg72Pro (rs1042522) and CDH1 -160 C/A (rs16260) polymorphisms and breast cancer risk. In case of P53rs1042522 polymorphism, Arg/Pro (P = 0.0053, odds ratio (OR) = 1.69) and Pro/Pro (P = 0.018, OR = 1.83) genotypes were associated with increased risk of breast cancer in comparison to the Arg/Arg genotype. Arg/Pro + Pro/Pro genotype and Pro allele also increased the risk of breast cancer (P = 0.002, OR = 1.73; P = 0.004, OR = 1.43, respectively). In case of CDH1rs16260 polymorphism, C/A heterozygote and combined C/A + A/A genotypes were found to be strongly associated (P = 0.005, OR = 1.67; P = 0.0037, OR = 1.68) with increased risk of breast cancer. The variant A allele also increased the breast cancer risk (P = 0.0058, OR = 1.52). The present study demonstrates that P53Arg72Pro and CDH1rs16260 polymorphisms are associated with elevated breast cancer risk in the Bangladeshi population.

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

    PubMed Central

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

    1994-01-01

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

  9. Exploratory Analysis of TP53 Mutations in Circulating Tumour DNA as Biomarkers of Treatment Response for Patients with Relapsed High-Grade Serous Ovarian Carcinoma: A Retrospective Study

    PubMed Central

    Piskorz, Anna M.; Biggs, Heather; Addley, Helen; Freeman, Sue; Moyle, Penelope; Sala, Evis; Sayal, Karen; Hosking, Karen; Gounaris, Ioannis; Earl, Helena M.; Rosenfeld, Nitzan; Brenton, James D.

    2016-01-01

    Background Circulating tumour DNA (ctDNA) carrying tumour-specific sequence alterations may provide a minimally invasive means to dynamically assess tumour burden and response to treatment in cancer patients. Somatic TP53 mutations are a defining feature of high-grade serous ovarian carcinoma (HGSOC). We tested whether these mutations could be used as personalised markers to monitor tumour burden and early changes as a predictor of response and time to progression (TTP). Methods and Findings We performed a retrospective analysis of serial plasma samples collected during routine clinical visits from 40 patients with HGSOC undergoing heterogeneous standard of care treatment. Patient-specific TP53 assays were developed for 31 unique mutations identified in formalin-fixed paraffin-embedded tumour DNA from these patients. These assays were used to quantify ctDNA in 318 plasma samples using microfluidic digital PCR. The TP53 mutant allele fraction (TP53MAF) was compared to serum CA-125, the current gold-standard response marker for HGSOC in blood, as well as to disease volume on computed tomography scans by volumetric analysis. Changes after one cycle of treatment were compared with TTP. The median TP53MAF prior to treatment in 51 relapsed treatment courses was 8% (interquartile range [IQR] 1.2%–22%) compared to 0.7% (IQR 0.3%–2.0%) for seven untreated newly diagnosed stage IIIC/IV patients. TP53MAF correlated with volumetric measurements (Pearson r = 0.59, p < 0.001), and this correlation improved when patients with ascites were excluded (r = 0.82). The ratio of TP53MAF to volume of disease was higher in relapsed patients (0.04% per cm3) than in untreated patients (0.0008% per cm3, p = 0.004). In nearly all relapsed patients with disease volume > 32 cm3, ctDNA was detected at ≥20 amplifiable copies per millilitre of plasma. In 49 treatment courses for relapsed disease, pre-treatment TP53MAF concentration, but not CA-125, was associated with TTP. Response to

  10. Identification of a Novel TP53 Germline Mutation E285V in a Rare Case of Pediatric Adrenocortical Carcinoma and Choroid Plexus Carcinoma

    PubMed Central

    Russell-Swetek, Aubrey; West, Alina N.; Mintern, Jane E.; Jenkins, Jesse; Rodriguez-Galindo, Carlos; Ribeiro, Raul; Zambetti, Gerard P.

    2012-01-01

    Pediatric choroid plexus carcinomas (CPC) and adrenocortical carcinomas (ACC) are exceedingly rare tumors, each occurring at an annual rate of 0.3 cases per million children or less. Although both tumor types are associated with Li-Fraumeni Syndrome (LFS), the penetrance of germline TP53 mutations in CPC remains to be established. We report here a young boy without a family history of cancer who presented with CPC and subsequently ACC. Genetic testing revealed a novel de novo germline TP53 mutation (E285V). Neither tumor underwent loss of heterozygosity. Consistent with this observation, functional analyses demonstrated that E285V acts as a dominant-negative mutant that is defective in regulating target gene expression, growth suppression and apoptosis. These results further strengthen the association between germline TP53 mutations and childhood CPC, even when occurring in the absence of familial tumor susceptibility. PMID:18762572

  11. Transitions at CpG Dinucleotides, Geographic Clustering of TP53 Mutations and Food Availability Patterns in Colorectal Cancer

    PubMed Central

    Verginelli, Fabio; Bishehsari, Faraz; Napolitano, Francesco; Mahdavinia, Mahboobeh; Cama, Alessandro; Malekzadeh, Reza; Miele, Gennaro; Raiconi, Giancarlo; Tagliaferri, Roberto; Mariani-Costantini, Renato

    2009-01-01

    Background Colorectal cancer is mainly attributed to diet, but the role exerted by foods remains unclear because involved factors are extremely complex. Geography substantially impacts on foods. Correlations between international variation in colorectal cancer-associated mutation patterns and food availabilities could highlight the influence of foods on colorectal mutagenesis. Methodology To test such hypothesis, we applied techniques based on hierarchical clustering, feature extraction and selection, and statistical pattern recognition to the analysis of 2,572 colorectal cancer-associated TP53 mutations from 12 countries/geographic areas. For food availabilities, we relied on data extracted from the Food Balance Sheets of the Food and Agriculture Organization of the United Nations. Dendrograms for mutation sites, mutation types and food patterns were constructed through Ward's hierarchical clustering algorithm and their stability was assessed evaluating silhouette values. Feature selection used entropy-based measures for similarity between clusterings, combined with principal component analysis by exhaustive and heuristic approaches. Conclusion/Significance Mutations clustered in two major geographic groups, one including only Western countries, the other Asia and parts of Europe. This was determined by variation in the frequency of transitions at CpGs, the most common mutation type. Higher frequencies of transitions at CpGs in the cluster that included only Western countries mainly reflected higher frequencies of mutations at CpG codons 175, 248 and 273, the three major TP53 hotspots. Pearson's correlation scores, computed between the principal components of the datamatrices for mutation types, food availability and mutation sites, demonstrated statistically significant correlations between transitions at CpGs and both mutation sites and availabilities of meat, milk, sweeteners and animal fats, the energy-dense foods at the basis of “Western” diets. This is

  12. TP53INP2/DOR, a mediator of cell autophagy, promotes rDNA transcription via facilitating the assembly of the POLR1/RNA polymerase I preinitiation complex at rDNA promoters.

    PubMed

    Xu, Yinfeng; Wan, Wei; Shou, Xin; Huang, Rui; You, Zhiyuan; Shou, Yanhong; Wang, Lingling; Zhou, Tianhua; Liu, Wei

    2016-07-02

    Cells control their metabolism through modulating the anabolic and catabolic pathways. TP53INP2/DOR (tumor protein p53 inducible nuclear protein 2), participates in cell catabolism by serving as a promoter of autophagy. Here we uncover a novel function of TP53INP2 in protein synthesis, a major biosynthetic and energy-consuming anabolic process. TP53INP2 localizes to the nucleolus through its nucleolar localization signal (NoLS) located at the C-terminal domain. Chromatin immunoprecipitation (ChIP) assays detected an association of TP53INP2 with the ribosomal DNA (rDNA), when exclusion of TP53INP2 from the nucleolus repressed rDNA promoter activity and the production of ribosomal RNA (rRNA) and proteins. The removal of TP53INP2 also impaired the association of the POLR1/RNA polymerase I preinitiation complex (PIC) with rDNA. Further, TP53INP2 interacts directly with POLR1 PIC, and is required for the assembly of the complex. These data indicate that TP53INP2 promotes ribosome biogenesis through facilitating rRNA synthesis at the nucleolus, suggesting a dual role of TP53INP2 in cell metabolism, assisting anabolism on the nucleolus, and stimulating catabolism off the nucleolus.

  13. The association between the TP53 Arg72Pro polymorphism and colorectal cancer: An updated meta-analysis based on 32 studies

    PubMed Central

    Tian, Xin; Dai, Shundong; Sun, Jing; Jiang, Shenyi; Jiang, Youhong

    2017-01-01

    Several previous studies evaluated the association between the Arg72Pro (rs1042522) polymorphism in the TP53 tumor suppressor gene and colorectal cancer (CRC). However, the results are conflicting. This meta-analysis aimed to shed new light on the precise association between TP53 variants and CRC. We analyzed 32 published case-control studies involving 8,586 cases and 10,275 controls using crude odd ratios (ORs) with 95% confidence intervals (CIs). The meta-analysis was performed using a fixed-effect or random-effects model, as appropriate. We found that the TP53 Arg72Pro polymorphism was not significantly associated with CRC risk in the overall population. However, subgroup analysis based on ethnicity revealed an increased risk of CRC among Asians (CC vs. GC+GG: OR=1.22, 95% CI: 1.02-1.45), and similar results were found for rectal cancer (CC vs. GC+GG: OR=1.34, 95% CI: 1.120-1.62). These results suggest that the TP53 Arg72Pro polymorphism CC genotype may contribute to an increased risk of CRC, especially for rectal cancer and among Asians. PMID:27901479

  14. MUTATION SPECTRA OF SMOKY COAL COMBUSTION EMMISSIONS IN SALMONELLA REFLECTS THE TP53 AND KRAS MUTATIONS IN LUNG TUMORS FROM SMOKY COAL EXPOSED INDIVIDUALS

    EPA Science Inventory


    Mutation Spectra of Smoky Coal Combustion Emissions in Salmonella Reflect the TP53
    and KRAS Mutations in Lung Tumors from Smoky Coal-Exposed Individuals

    Abstract
    Nonsmoking women in Xuan Wei County, Yunnan Province, China who use smoky coal for cooking and h...

  15. The role of HPV RNA transcription, immune response-related gene expression and disruptive TP53 mutations in diagnostic and prognostic profiling of head and neck cancer.

    PubMed

    Wichmann, Gunnar; Rosolowski, Maciej; Krohn, Knut; Kreuz, Markus; Boehm, Andreas; Reiche, Anett; Scharrer, Ulrike; Halama, Dirk; Bertolini, Julia; Bauer, Ulrike; Holzinger, Dana; Pawlita, Michael; Hess, Jochen; Engel, Christoph; Hasenclever, Dirk; Scholz, Markus; Ahnert, Peter; Kirsten, Holger; Hemprich, Alexander; Wittekind, Christian; Herbarth, Olf; Horn, Friedemann; Dietz, Andreas; Loeffler, Markus

    2015-12-15

    Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA+ RNA-) are similar to HPV-negative (DNA-) tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively). We also find that an immune response-related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status and that disruptive TP53 mutations are associated with lymph node metastasis in HPV16 DNA- tumors. We validate each of these associations in another large data set. Four gene expression clusters which we identify differ moderately but significantly in overall survival. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) and TP53-mutation status for patient stratification and identify associations of an immune response-related gene expression cluster and TP53 mutations with lymph node metastasis in HNSCC.

  16. 17β-estradiol up-regulates miR-155 expression and reduces TP53INP1 expression in MCF-7 breast cancer cells.

    PubMed

    Zhang, Chunmei; Zhao, Jing; Deng, Huayu

    2013-07-01

    In estrogen responsive breast cancer cells, estradiol (E2) is a key regulator of cell proliferation and survival. MiR-155 has emerged as an "oncomiR", which is the most significantly up-regulated miRNA in breast cancer. Moreover, miR-155 is higher in ERα (+) breast tumors than ERα (-), but no one has examined whether E2 regulates miR-155 expression in MCF-7 cells. In this study, the aim was to explore whether miR-155 involved in E2 regulated expression of estrogen responsive genes. We evaluated miR-155 expression in human breast cancer cells by real-time PCR, finding out miR-155 was overexpressed in MCF-7 cells compared with MDA-MB-231 cells. Treatment with E2 in MCF-7 cells increased miR-155 expression, promoting proliferation and decreasing apoptosis, similarly, transfection of miR-155m to MCF-7 cells gave the similar results. In contrast, inhibited miR-155 expression by transfection with miR-155 inhibitors reduced proliferation and promoted apoptosis of MCF-7 cells. Moreover, TP53INP1 is one of the targets of miR-155. E2 negatively regulated TP53INP1 mRNA expression and the protein expression of TP53INP1, cleaved-caspase-3, -8, -9, and p21, whereas transfection with miR-155 inhibitors increased TP53INP1, cleaved-caspase-3, -8, -9, and p21 protein level. These results demonstrated that E2 promoted breast cancer development and progression possibly through increasing the expression of miR-155, which was overexpressed in MCF-7 cells, contributes to proliferation of MCF-7 cells possibly through down-regulating TP53INP1.

  17. Transcriptomes and shRNA Suppressors in a TP53 Allele-specific Model of Early-onset Colon Cancer in African Americans

    PubMed Central

    Weige, Charles C.; Birtwistle, Marc R.; Mallick, Himel; Yi, Nengjun; Berrong, Zuzana; Cloessner, Emily; Duff, Keely; Tidwell, Josephine; Clendenning, Megan; Wilkerson, Brent; Farrell, Christopher; Bunz, Fred; Ji, Hao; Shtutman, Michael; Creek, Kim E.; Banister, Carolyn E.; Buckhaults, Phillip J.

    2014-01-01

    African Americans are disproportionately affected by early-onset, high-grade malignancies. A fraction of this cancer health disparity can be explained by genetic differences between individuals of African or European descent. Here the wild-type Pro/Pro genotype at the TP53Pro72Arg (P72R) polymorphism (SNP: rs1042522) is more frequent in African Americans with cancer than in African Americans without cancer (51% vs 37%), and is associated with a significant increase in the rates of cancer diagnosis in African Americans. To test the hypothesis that p53 allele-specific gene expression may contribute to African American cancer disparities, p53 hemizygous knockout variants were generated and characterized in the RKO colon carcinoma cell line, which is wild-type for p53 and heterozygous at the TP53Pro72Arg locus. Transcriptome profiling, using RNAseq, in response to the DNA-damaging agent etoposide revealed a large number of p53-regulated transcripts, but also a subset of transcripts that were TP53Pro72Arg allele specific. In addition, a shRNA-library suppressor screen for p53 allele-specific escape from p53-induced arrest was performed. Several novel RNAi suppressors of p53 were identified, one of which, PRDM1β (BLIMP-1), was confirmed to be an Arg-specific transcript. PRDM1β silences target genes by recruiting H3K9 trimethyl (H3K9me3) repressive chromatin marks, and is necessary for stem cell differentiation. These results reveal a novel model for African American cancer disparity, in which the TP53 codon 72 allele influences lifetime cancer risk by driving damaged cells to differentiation through an epigenetic mechanism involving gene silencing. Implications TP53 P72R polymorphism significantly contributes to increased African American cancer disparity. PMID:24743655

  18. An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model.

    PubMed

    Jennis, Matthew; Kung, Che-Pei; Basu, Subhasree; Budina-Kolomets, Anna; Leu, Julia I-Ju; Khaku, Sakina; Scott, Jeremy P; Cai, Kathy Q; Campbell, Michelle R; Porter, Devin K; Wang, Xuting; Bell, Douglas A; Li, Xiaoxian; Garlick, David S; Liu, Qin; Hollstein, Monica; George, Donna L; Murphy, Maureen E

    2016-04-15

    A nonsynonymous single-nucleotide polymorphism at codon 47 in TP53 exists in African-descent populations (P47S, rs1800371; referred to here as S47). Here we report that, in human cell lines and a mouse model, the S47 variant exhibits a modest decrease in apoptosis in response to most genotoxic stresses compared with wild-type p53 but exhibits a significant defect in cell death induced by cisplatin. We show that, compared with wild-type p53, S47 has nearly indistinguishable transcriptional function but shows impaired ability to transactivate a subset of p53 target genes, including two involved in metabolism:Gls2(glutaminase 2) and Sco2 We also show that human and mouse cells expressing the S47 variant are markedly resistant to cell death by agents that induce ferroptosis (iron-mediated nonapoptotic cell death). We show that mice expressing S47 in homozygous or heterozygous form are susceptible to spontaneous cancers of diverse histological types. Our data suggest that the S47 variant may contribute to increased cancer risk in individuals of African descent, and our findings highlight the need to assess the contribution of this variant to cancer risk in these populations. These data also confirm the potential relevance of metabolism and ferroptosis to tumor suppression by p53.

  19. The influence of TP53 mutations on the prognosis of patients with early stage non-small cell lung cancer may depend on the intratumor heterogeneity of the mutations.

    PubMed

    Lee, Shin Yup; Jeon, Hyo-Sung; Hwangbo, Yup; Jeong, Ji Yun; Park, Ji Young; Lee, Eun Jin; Jin, Guang; Shin, Kyung Min; Yoo, Seung Soo; Lee, Jaehee; Lee, Eung Bae; Cha, Seung Ick; Kim, Chang Ho; Park, Jae Yong

    2015-02-01

    A large number of studies have evaluated the impact of TP53 mutations on the prognosis of patients with non-small cell lung cancer (NSCLC); however, the results of these studies are still controversial. Recently, considerable intratumor heterogeneity for genetic alterations has been demonstrated in various human cancers, including lung cancer. In the present study, we evaluated TP53 mutations in NSCLCs by direct sequencing and observed remarkable variation in the values of relative intensity (RI, the height of the peak of mutated allele/the height of the peak of non-mutated allele) of the mutations. We also examined whether the RI values were associated with intratumor heterogeneity of TP53 mutations. In addition, we evaluated the relationship between TP53 mutations and survival outcome. The patients with a TP53 mutation did not have significantly worse survival compared to those without the mutation. However, when tumors with a TP53 mutation were categorized into two groups, those with a low and those with a high RI, the latter group had significantly worse survival compared to those with wild-type TP53 (adjusted hazard ratio = 2.58, 95% confidence interval = 1.21-5.48, P = 0.01), whereas the former group did not. These results suggest that intratumor genetic heterogeneity may be an important factor in determining the role of TP53 mutations on the prognosis of NSCLC patients.

  20. Association study between the TP53 Rs1042522G/C polymorphism and susceptibility to systemic lupus erythematosus in a Chinese Han population.

    PubMed

    Yang, Jie; Zhu, Ji-Min; Wu, Song; Li, Jing; Wang, Ming-Rui; Wang, Ting-Ting; Lu, Yu-Wei

    2017-04-01

    Tumour suppressor protein 53 (p53) plays a central role in apoptosis, cell proliferation and death. Previously studies found contribution of functional p53 Arg72Pro polymorphism (TP53 rs1042522G/C polymorphism) in the development of systemic lupus erythematosus (SLE) remains controversial. In this study, for the first time, we evaluated its association with SLE in a Chinese Han population. This case-control study enrolled 1470 SLE patients and 2283 healthy controls. The genotyping of TP53 rs1042522 polymorphism was determined by Sequenom Mass ARRAY technology. Statistical analysis was conducted by Chi-square test (χ (2) test). Odds ratio (OR) with 95% confidence interval (CI) was calculated using unconditional logistic regression with adjusting age and sex. Allele and genotype frequencies of TP53 rs1042522G/C polymorphism showed statistically significant difference between the SLE patients and the normal controls (C vs. G: OR = 0.89, 95% CI 0.89-0.97, p = 0.01; (GC + CC) vs. GG using recessive model: OR = 0.84, 95% CI 0.73-0.96, p = 0.01; GC vs. GG using co-dominant model: OR = 0.86, 95% CI 0.74-0.99, p = 0.04; CC vs. GG using co-dominant model: OR = 0.80, 95% CI 0.66-0.96, p = 0.02; GC vs. GG using co-dominant model: OR = 0.86, 95% CI 0.74-0.99, p = 0.02). In addition, there was weak association between discoid rash and distribution of TP53 rs1042522G/C polymorphism in SLE patients (C vs. G: OR = 1.25, 95% CI 1.00-1.55, p = 0.04; CC vs. GG using co-dominant model: OR = 1.54, 95% CI 1.10-2.36, p = 0.04). Our finding suggests a significant relationship between the TP53 rs1042522G/C polymorphism and SLE. TP53 rs1042522G/C polymorphism would be promising as an indicator of SLE as well as the therapeutic target if its functions and mechanisms could be further investigated.

  1. Altered PTEN, ATRX, CHGA, CHGB & TP53 Expression are Associated with Aggressive VHL-Associated Pancreatic Neuroendocrine Tumors

    PubMed Central

    Weisbrod, Allison B.; Zhang, Lisa; Jain, Meenu; Barak, Stephanie; Quezado, Martha M.; Kebebew, Electron

    2013-01-01

    Von Hippel-Lindau (VHL) syndrome is an inherited cancer syndrome in which 8-17% of germline mutation carriers develop pancreatic neuroendocrine tumors (PNETs). There is limited data on prognostic markers for PNETs other than Ki-67, which is included in the World Health Organization classification system. Recently, specific genes and pathways have been identified by whole exome sequencing which may be involved in the tumorigenesis of PNETs and may be markers of disease aggressiveness. The objective of this study was to identify molecular markers of aggressive disease in VHL-associated PNETs. The protein expression of 8 genes (PTEN, CHGA, CHGB, ATRX, DAXX, CC-3, VEGF, TP53) was analyzed in PNETs by immunohistochemistry and compared to clinical data, VHL genotype, functional imaging results, and pathologic findings. Subcellular distribution of PTEN, CHGA and ATRX were significantly different by WHO classifications (p<0.05). There was decreased PTEN nuclear to cytoplasmic ratio (p<0.01) and decreased CHGA nuclear expression (p=0.03) in malignant samples as compared to benign. Lower cytoplasmic CHGB expression (p=0.03) was associated with malignant tumors and metastasis. Higher nuclear expression of PTEN was associated with VHL mutations in exon 3 (p=0.04). Higher PTEN and CHGB expression was associated with higher FDG-PET avidity (p<0.05). Cytoplasmic expression of CC-3 was associated with higher serum Chromogranin A levels (σ=0.72, p= 0.02). Lastly, greater cytoplasmic expression of p53 was associated with metastasis. Our findings suggest that altered PTEN, ATRX, CHGA and CHGB expression are associated with aggressive PNET phenotype in VHL and may serve as useful adjunct prognostic markers to Ki-67 in PNETs. PMID:23361940

  2. Potential Therapeutic Targets for Oral Cancer: ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF, CD70

    PubMed Central

    Bundela, Saurabh; Sharma, Anjana; Bisen, Prakash S.

    2014-01-01

    In India, oral cancer has consistently ranked among top three causes of cancer-related deaths, and it has emerged as a top cause for the cancer-related deaths among men. Lack of effective therapeutic options is one of the main challenges in clinical management of oral cancer patients. We interrogated large pool of samples from oral cancer gene expression studies to identify potential therapeutic targets that are involved in multiple cancer hallmark events. Therapeutic strategies directed towards such targets can be expected to effectively control cancer cells. Datasets from different gene expression studies were integrated by removing batch-effects and was used for downstream analyses, including differential expression analysis. Dependency network analysis was done to identify genes that undergo marked topological changes in oral cancer samples when compared with control samples. Causal reasoning analysis was carried out to identify significant hypotheses, which can explain gene expression profiles observed in oral cancer samples. Text-mining based approach was used to detect cancer hallmarks associated with genes significantly expressed in oral cancer. In all, 2365 genes were detected to be differentially expressed genes, which includes some of the highly differentially expressed genes like matrix metalloproteinases (MMP-1/3/10/13), chemokine (C-X-C motif) ligands (IL8, CXCL-10/-11), PTHLH, SERPINE1, NELL2, S100A7A, MAL, CRNN, TGM3, CLCA4, keratins (KRT-3/4/13/76/78), SERPINB11 and serine peptidase inhibitors (SPINK-5/7). XIST, TCEAL2, NRAS and FGFR2 are some of the important genes detected by dependency and causal network analysis. Literature mining analysis annotated 1014 genes, out of which 841 genes were statistically significantly annotated. The integration of output of various analyses, resulted in the list of potential therapeutic targets for oral cancer, which included targets such as ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF and CD70. PMID:25029526

  3. The effect of epigenetic silencing and TP53 mutation on the expression of DLL4 in human cancer stem disorder

    PubMed Central

    Yao, Zhixing; Sherif, Zaki A.

    2016-01-01

    The Li-Fraumeni Syndrome (LFS), a genetically rare heterogeneous cancer syndrome, is characterized primarily by a germline p53 (TP53) gene mutation. We recently discovered a balanced reciprocal chromosomal translocation t(11;15)(q23;q15) in the non-cancerous skin fibroblasts of a bilateral breast cancer patient in LFS family. This prompted us to investigate the breakpoint region of the translocation, which uncovered a gene that encodes a Notch ligand, DLL4, (locus at 15q15.1), a key target in tumor vasculature. We analyzed DLL4 gene expression and protein level in LFS non-cancerous skin fibroblast cell lines and non-LFS cancer cell lines. DLL4 is abrogated in all the LFS cells and drastically down-regulated in breast (MCF7) and brain (IMR32) cancer cells and tumor tissue samples. However, DNA methylation studies revealed that DLL4 promoter is silenced only in MCF7 but not in LFS cells. We further investigated the regulation of DLL4 gene expression by ChIP assays, which demonstrated that p53 binds to DLL4 promoter through its association with CTCF, a chromosomal networking protein CCCTC binding factor. This implies a possible karyotype-phenotype correlation with respect to DLL4 in LFS and breast cancer initiation and progression. The drastic reduction or absence in the expression of DLL4 in LFS as well as breast and brain cancer cells is significant and supports the concept that this ligand may also play a role in cancer immune-surveillance; and its resuscitation in the tumor microenvironment may stimulate T-cell immunity and suppress tumor growth. Therefore, DLL4 may provide a strong platform as an immuno-therapeutic target in LFS and cancer patients. PMID:27542210

  4. The TP53 codon 72 Pro/Pro genotype may be associated with an increased lung cancer risk in North China: an updated meta-analysis

    PubMed Central

    Wang, Xin; Hao, Li-Ran; Yue, Kai

    2015-01-01

    Background: The polymorphism of TP53 codon 72, a transversion of G to C (Arg to Pro), has been demonstrated to be associated with the risk for lung cancer. However, individual studies conducted in Chinese have provided conflicting and inconclusive findings. Thus, we performed a meta-analysis by pooling all currently available case-control studies to estimate the effect of TP53 codon 72 Arg/Pro polymorphism on the development of lung cancer in the Chinese population. Material/Methods: Related studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) till 10 October 2014. Pooled ORs and 95% CIs were used to assess the strength of the associations. Results: A total of 12 case-control studies including 3681 lung cancer cases and 4358 controls were involved in this meta-analysis. Overall, no significant association was found between TP53 codon 72 variation and lung cancer risk when all studies in the Chinese population pooled into this meta-analysis. However, in the subgroup analysis by geographical locations, significantly increased risk was found in the population from North China under all genetic models (Allele model, OR=1.22, 95% CI: 1.04-1.43; Dominant model, OR=1.13, 95% CI: 1.01-1.25; Recessive model, OR=1.41, 95% CI: 1.07-1.87; Homozygous model, OR=1.47, 95% CI: 1.09-1.99; Heterozygous model, OR=1.40, 95% CI: 1.04-1.89). Conclusions: This meta-analysis provides the evidence that TP53 codon 72 polymorphism may contribute to the lung cancer development in North China and studies with large sample size and gene-gene (gene-environment) interactions are warranted to verify this finding. PMID:26064201

  5. Methylation levels of P16 and TP53 that are involved in DNA strand breakage of 16HBE cells treated by hexavalent chromium.

    PubMed

    Hu, Guiping; Li, Ping; Li, Yang; Wang, Tiancheng; Gao, Xin; Zhang, Wenxiao; Jia, Guang

    2016-05-13

    The correlations between methylation levels of p16 and TP53 with DNA strand breakage treated by hexavalent chromium [Cr(VI)] remain unknown. In this research, Human bronchial epithelial cells (16HBE cells) in vitro and bioinformatics analysis were used to analyze the epigenetic role in DNA damage and potential biomarkers. CCK-8 and single cell gel electrophoresis assay were chosen to detect the cellular biological damage. MALDI-TOF-MS was used to detect the methylation levels of p16 and TP53. qRT-PCR was used to measure their expression levels in different Cr(VI) treatment groups. The transcription factors with target sequences of p16 and TP53 were predicted using various bioinformatics software. The findings showed that the cellular toxicity and DNA strand damage were Cr(VI) concentration dependent. The hypermethylation of CpG1, CpG31 and CpG32 of p16 was observed in Cr(VI) treated groups. There was significant positive correlation between the CpG1 methylation level of p16 and cell damage. In Cr(VI) treated groups, the expression level of p16 was lower than that in control group. The expression level of TP53 increased when the Cr(VI)concentration above 5μM. About p16, there was significant negative correlation between the CpG1 methylation levels with its expression level. A lot of binding sites for transcription factors existed in our focused CpG islands of p16. All the results suggested that the CpG1 methylation level of p16 could be used as a biomarker of epigenetic effect caused by Cr(VI) treatment, which can enhance cell damage by regulating its expression or affecting some transcription factors to combine with their DNA strand sites.

  6. The rate of recurrent BRCA1, BRCA2, and TP53 mutations in the general population, and unselected ovarian cancer cases, in Belo Horizonte, Brazil.

    PubMed

    Schayek, Hagit; De Marco, Luiz; Starinsky-Elbaz, Sigal; Rossette, Mariana; Laitman, Yael; Bastos-Rodrigues, Luciana; da Silva Filho, Agnaldo Lopes; Friedman, Eitan

    2016-01-01

    In Brazil, several recurring mutations in BRCA1 and BRCA2 and a TP53 mutation (R337H) have been reported in high risk breast cancer cases. We hypothesized that these recurring mutations may also be detected in the general population and ovarian cancer cases in the state of Minas Gerais. To test this notion, participants were recruited from the outpatient and the Gynecological clinic in the UFMG Medical Center in Belo Horizonte, Minas Gerais, Brazil. BRCA1 (c.68_69delAG, c.5266dupC, c.181T>G, c.4034delA, c.5123C>A), BRCA2 (c.5946delT, c.8537_8538delAG, 4936_4939delGAAA), the c.156_157insAlu* BRCA2 and the c.1010G>A *TP53 mutation were genotyped using validated techniques. Overall, 513 cancer free participants (273 men) (mean age 47.7 ± 15.1 years) and 103 ovarian cancer cases (mean age at diagnosis 58.7 ± 9.6 years) were studied. None of the participants were found to carry any of the genotyped mutations. We conclude that the recurring mutations in BRCA1, BRCA2 and TP53 cannot be detected in the general population or consecutive ovarian cancer cases in this geographical region in Brazil.

  7. CXCL12 and TP53 genetic polymorphisms as markers of susceptibility in a Brazilian children population with acute lymphoblastic leukemia (ALL).

    PubMed

    de Lourdes Perim, Aparecida; Guembarovski, Roberta Losi; Oda, Julie Massayo Maeda; Lopes, Leandra Fiori; Ariza, Carolina Batista; Amarante, Marla Karine; Fungaro, Maria Helena Pelegrinelli; de Oliveira, Karen Brajão; Watanabe, Maria Angelica Ehara

    2013-07-01

    Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Genetic polymorphisms in the 3'UTR region of the CXCL12 (rs1801157) and TP53 codon 72 (rs1042522) genes may contribute to susceptibility to childhood ALL because they affect some important processes, such as metastasis regulation and tumor suppression. Thus the objective of the present study was to detect the frequency of two genetic polymorphisms in ALL patients and controls and to add information their impact on genetic susceptibility and prognosis. The CXCL12 and TP53 polymorphisms were tested in 54 ALL child patients and in 58 controls by restriction fragment length polymerase chain reaction and allelic specific chain reaction techniques, respectively. The frequencies of both allelic variants were higher in ALL patients than in the controls and indicated a positive association: OR = 2.44; 95 % CI 1.05-5.64 for CXCL12 and OR = 2.20; 95 % CI 1.03-4.70 for TP53. Furthermore, when the two genetic variants were analyzed together, they increased significantly more than fivefold the risk of this neoplasia development (OR = 5.24; 95 % CI 1.39-19.75), indicating their potential as susceptibility markers for ALL disease and the relevance of the allelic variant combination to increased risk of developing malignant tumors. Future studies may indicate a larger panel of genes involved in susceptibility of childhood ALL and other hematological neoplasias.

  8. Influence of TP53 Codon 72 Polymorphism Alone or in Combination with HDM2 SNP309 on Human Infertility and IVF Outcome

    PubMed Central

    Chan, Ying; Zhu, Baosheng; Jiang, Hongguo; Zhang, Jinman; Luo, Ying; Tang, Wenru

    2016-01-01

    To evaluate the association of the TP53 codon 72 (rs 1042522) alone or in combination with HDM2 SNP309 (rs 2279744) polymorphisms with human infertility and IVF outcome, we collected 1450 infertility women undergoing their first controlled ovarian stimulation for IVF treatment and 250 fertile controls in the case-control study. Frequencies, distribution, interaction of genes, and correlation with infertility and IVF outcome of clinical pregnancy were analyzed. We found a statistically significant association between TP53 codon 72 polymorphism and IVF outcome (52.10% vs. 47.40%, OR = 0.83, 95%CI:0.71–0.96, p = 0.01). No significant difference was shown between TP53 codon 72, HDM2 SNP309 polymorphisms, human infertility, and between the combination of two genes polymorphisms and the clinical pregnancy outcome of IVF. The data support C allele as a protective factor for IVF pregnancy outcome. Further researches should be focused on the mechanism of these associations. PMID:27898708

  9. Human Papillomavirus 16 Infection and TP53 Mutation: Two Distinct Pathogeneses for Oropharyngeal Squamous Cell Carcinoma in an Eastern Chinese Population

    PubMed Central

    Ye, Dong-Xia; Li, Jiang

    2016-01-01

    Objectives To investigate the clinicopathological characteristics, human papillomavirus (HPV) infection, p53 expression, and TP53 mutations in oropharyngeal squamous cell carcinoma (OPSCC) and determine their utility as prognostic predictors in a primarily eastern Chinese population. Methods The HPV infection status was tested via p16INK4A immunohistochemistry and validated using PCR, reverse blot hybridization and in situ hybridization (ISH) in 188 OPSCC samples. p53 expression levels and TP53 gene mutations were assessed through immunohistochemistry and sequencing, respectively. Clinicopathological characteristics and follow-up information were collected. Overall survival was estimated using the Log-rank test. Results Overall, 22 of the 188 OPSCC samples were associated with HPV infection. HPV16 was identified in all 22 samples, whereas no samples were positive for HPV18. All 22 HPV-associated OPSCC samples were p53 negative and lacked TP53 mutations. HPV16 positivity, female patients, non-smokers, and patients with histological grade I and stage N0 diseases showed better overall survival (p = 0.009, 0.003, 0.048, 0.009, and 0.004, respectively). No significant differences in overall survival between smoking and non-smoking patients were observed in the HPV-associated OPSCC group. Patients without mutations in TP53 exons 5–8 had better prognoses (p = 0.031) among the 43 sequenced specimens. Multivariate analysis indicated that HPV16 infection status (p = 0.011), histological grade (p = 0.017), and N stage (p = 0.019) were independent prognostic factors for patients with OPSCC. Conclusions Distinct from the situation in Europe and America, for the patients with OPSCC in this study, HPV16 infection was relatively low, although it was still the most important independent prognostic predictor for the disease. In addition to the high smoking and drinking rate in this population, HPV16 infection and TP53 dysfunction appear to be two distinct pathogens for OPSCC

  10. Combined analysis of pri-miR-34b/c rs4938723 and TP53 Arg72Pro with cervical cancer risk.

    PubMed

    Yuan, Fang; Sun, Ruifen; Chen, Peng; Liang, Yundan; Ni, Shanshan; Quan, Yi; Huang, Juan; Zhang, Lin; Gao, Linbo

    2016-05-01

    miR-34 family members can form a p53-miR-34 positive feedback loop and induce apoptosis, DNA repair, angiogenesis, and cell cycle arrest. We conducted a case-control study to examine whether two polymorphisms (i.e., rs4938723 in the promoter of pri-miR-34b/c and TP53 Arg72Pro) were linked to the carcinogenesis of cervical cancer among Chinese Han women. Genotypes of the two polymorphisms in 328 cervical cancer patients and 568 control subjects were determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. We found a significantly increased cervical cancer risk in the pri-miR-34b/c rs4938723 under dominant and overdominant model (CT/CC vs. TT: adjusted OR = 1.34, 95 % CI = 1.01-1.77; CT vs. TT/CC: adjusted OR = 1.37, 95 % CI = 1.05-1.80, respectively). Increased cervical cancer risks were also found in the TP53 Arg72Pro under a heterozygous comparison and overdominant model (CG vs. GG: adjusted OR = 1.44, 95 % CI = 1.06-1.95; CG vs. GG/CC: adjusted OR = 1.47, 95 % CI = 1.12-1.94, respectively). Stratification analysis showed that patients carrying the pri-miR-34b/c rs4938723 CT genotype had a significantly increased risk for developing poorly differential status and clinical stage I. Moreover, increased cancer risks were observed for the TP53 Arg72Pro polymorphism in patients with poorly differential status, clinical stage II, and without lymph node metastasis. Combined analysis revealed that the genotypes of rs4938723 CT/CC and TP53 Arg72Pro CG/CC had an increased cervical cancer risk (OR = 2.21, 95 % CI = 1.38-3.53). These findings suggest that the pri-miR-34b/c rs4938723 and TP53 Arg72Pro polymorphisms may contribute to the genesis of cervical cancer.

  11. Roles for microRNAs, miR-93 and miR-130b, and TP53INP1 tumor suppressor in cell growth dysregulation by HTLV-1

    PubMed Central

    Yeung, Man Lung; Yasunaga, Jun-ichirou; Bennasser, Yamina; Dusetti, Nelson; Harris, David; Ahmad, Nafees; Matsuoka, Masao; Jeang, Kuan-Teh

    2008-01-01

    A role for miRNAs in human T-cell leukemia virus-1, HTLV-1, mediated cellular transformation has not been described. Here, we profiled miRNA expression in HTLV-1 transformed human T cell lines and primary peripheral blood mononuclear cells (PBMCs) from Adult-T cell leukemia (ATL) patients. Analyses of eleven different profiles revealed six miRNAs which were consistently up-regulated. Two of the up-regulated miRNAs (miR-93 and miR-130b) target the 3′ untranslated region (3′UTR) of the mRNA for a tumor suppressor protein, Tumor Protein 53-Induced Nuclear Protein 1 (TP53INP1). A low expression level of TP53INP1 protein was found in HTLV-1 transformed cells. Additionally, when antagomirs were used to knock down miR-93 and miR-130b in these cells, the expression of TP53INP1 was increased suggesting that the latter is regulated inside cells by the former. A role for TP53INP1 in regulating cell growth was established by experiments which showed that enhanced TP53INP1 expression increased apoptosis. Collectively, the findings implicate a miR-93/miR-130b – TP53INP1 axis that impacts the proliferation and survival of HTLV-1 infected / transformed cells. PMID:18974142

  12. The association between exposure to aflatoxin, mutation in TP53, infection with hepatitis B virus, and occurrence of liver disease in a selected population in Hyderabad, India.

    PubMed

    Anitha, S; Raghunadharao, D; Waliyar, F; Sudini, H; Parveen, M; Rao, Ratna; Kumar, P Lava

    2014-05-15

    Aflatoxin B1 is a carcinogen produced by Aspergillus flavus and a few related fungi that are often present in many food substances. It interacts synergistically with Hepatitis B or C virus (HBV, HBC) infection, thereby increasing the risk of hepatocellular carcinoma (HCC). The G to T transversion at the third position of codon 249 (AGG) of the TP53 gene, substituting arginine to serine, is the most common aflatoxin-induced mutation linked to HCC. This study examined mutations in TP53 by PCR-RFLP analysis and by measurement of an aflatoxin-albumin adduct as a biomarker for human exposure of aflatoxin B1 by indirect-competitive ELISA, in samples collected from healthy controls as well as patients with hepatitis in Hyderabad, Andhra Pradesh, India. A total of 238 blood samples were analyzed the presence of the G to T mutation. Eighteen of these samples were from HBV-positive subjects, 112 of these were from subjects who had HBV-induced liver cirrhosis, and 108 samples were taken from subjects without HBV infection or liver cirrhosis (control group). The G to T mutation was detected in 10 samples, 8 of which were from subjects positive to both HBV and aflatoxin-albumin adduct in blood (p=0.07); whilst two were from individuals who were HBV-negative, but positive for the aflatoxin-albumin adduct (p=0.14). The aflatoxin-albumin adduct was detected in 37 of 238 samples, 29 samples were from HBV-positive subjects and eight were from individuals who were positive for both HBV and the TP53 mutation (p=0.07). The concentration of aflatoxin-albumin adduct ranged from 2.5 to 667pg/mg albumin. Despite low incidence of the G to T mutation, its detection in subjects positive to aflatoxin-adducts is indicative of a strong association between the mutation and aflatoxin exposure in India.

  13. Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia

    PubMed Central

    Nadeu, Ferran; Delgado, Julio; Royo, Cristina; Baumann, Tycho; Stankovic, Tatjana; Pinyol, Magda; Jares, Pedro; Navarro, Alba; Martín-García, David; Beà, Sílvia; Salaverria, Itziar; Oldreive, Ceri; Aymerich, Marta; Suárez-Cisneros, Helena; Rozman, Maria; Villamor, Neus; Colomer, Dolors; López-Guillermo, Armando; González, Marcos; Alcoceba, Miguel; Terol, Maria José; Colado, Enrique; Puente, Xose S.; López-Otín, Carlos; Enjuanes, Anna

    2016-01-01

    Genomic studies have revealed the complex clonal heterogeneity of chronic lymphocytic leukemia (CLL). The acquisition and selection of genomic aberrations may be critical to understanding the progression of this disease. In this study, we have extensively characterized the mutational status of TP53, SF3B1, BIRC3, NOTCH1, and ATM in 406 untreated CLL cases by ultra-deep next-generation sequencing, which detected subclonal mutations down to 0.3% allele frequency. Clonal dynamics were examined in longitudinal samples of 48 CLL patients. We identified a high proportion of subclonal mutations, isolated or associated with clonal aberrations. TP53 mutations were present in 10.6% of patients (6.4% clonal, 4.2% subclonal), ATM mutations in 11.1% (7.8% clonal, 1.3% subclonal, 2% germ line mutations considered pathogenic), SF3B1 mutations in 12.6% (7.4% clonal, 5.2% subclonal), NOTCH1 mutations in 21.8% (14.2% clonal, 7.6% subclonal), and BIRC3 mutations in 4.2% (2% clonal, 2.2% subclonal). ATM mutations, clonal SF3B1, and both clonal and subclonal NOTCH1 mutations predicted for shorter time to first treatment irrespective of the immunoglobulin heavy-chain variable-region gene (IGHV) mutational status. Clonal and subclonal TP53 and clonal NOTCH1 mutations predicted for shorter overall survival together with the IGHV mutational status. Clonal evolution in longitudinal samples mainly occurred in cases with mutations in the initial samples and was observed not only after chemotherapy but also in untreated patients. These findings suggest that the characterization of the subclonal architecture and its dynamics in the evolution of the disease may be relevant for the management of CLL patients. PMID:26837699

  14. [TP53 codon 72 polymorphism and gastric cancer risk: a case-control study in individuals from the central-western region of Venezuela].

    PubMed

    Cañas, Miryan; Morán, Yeinmy; Camargo, María Eugenia; Rivero, María Belén; Bohórquez, Adolfo; Villegas, Venus; Ramírez, Eddy; Rendón, Yanet; Suárez, Alfredo; Morales, Luis; Useche, Emerson; Salazar, Sandra; Zambrano, Amado; Ramírez, Alvaro; Valderrama, Elvis; Briceño, Zuly; Chiurillo, Miguel Angel

    2009-06-01

    Codon 72 polymorphism of the tumor suppressor gene TP53 has been associated with a higher risk in the development of several types of cancer. The polymorphism results in a variant protein with either an arginine (CGC) or a proline residue (CCC). The aim of this study was to analyze the association of the TP53 codon 72 polymorphism with the risk of developing gastric cancer in a high-risk population from the central-western region of Venezuela. DNA was extracted from paraffin-embedded gastric adenocarcinoma biopsies (n=65) and endoscopic biopsies from chronic gastritis patients (n=87). TP53 codon 72 polymorphism was determined by PCR-RFLP from all samples. Patients with gastric cancer had a significantly higher frequency (P = 0.037) of the Arg allele than those with chronic gastritis. A logistic regression analysis suggested that Arg carrier individuals had a 4.6-fold higher risk (95% CI 1.0-21.3) of developing gastric cancer. An increment of the Arg/Arg genotype was observed in poor-differentiated gastric adenocarcinoma (OR: 3.1; 95% CI 1.0-9.2), and of the Arg/Pro genotype in well/moderate-differentiated adenocarcinoma samples (OR: 3.5; 95% CI 1.1-11.0), when comparing within the gastric cancer samples; and the last group also when contrasting it with chronic gastritis patients (OR: 2.4; 95% CI 1.1-5.2). The results of this study suggest that the carriage of the Arg allele could be associated with the development of gastric cancer in this Venezuelan population.

  15. Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: a portrait of early-onset breast cancer in Brazil.

    PubMed

    Carraro, Dirce Maria; Koike Folgueira, Maria Aparecida Azevedo; Garcia Lisboa, Bianca Cristina; Ribeiro Olivieri, Eloisa Helena; Vitorino Krepischi, Ana Cristina; de Carvalho, Alex Fiorini; de Carvalho Mota, Louise Danielle; Puga, Renato David; do Socorro Maciel, Maria; Michelli, Rodrigo Augusto Depieri; de Lyra, Eduardo Carneiro; Grosso, Stana Helena Giorgi; Soares, Fernando Augusto; Achatz, Maria Isabel Alves de Souza Waddington; Brentani, Helena; Moreira-Filho, Carlos Alberto; Brentani, Maria Mitzi

    2013-01-01

    Germline mutations in BRCA1, BRCA2 and TP53 genes have been identified as one of the most important disease-causing issues in young breast cancer patients worldwide. The specific defective biological processes that trigger germline mutation-associated and -negative tumors remain unclear. To delineate an initial portrait of Brazilian early-onset breast cancer, we performed an investigation combining both germline and tumor analysis. Germline screening of the BRCA1, BRCA2, CHEK2 (c.1100delC) and TP53 genes was performed in 54 unrelated patients <35 y; their tumors were investigated with respect to transcriptional and genomic profiles as well as hormonal receptors and HER2 expression/amplification. Germline mutations were detected in 12 out of 54 patients (22%) [7 in BRCA1 (13%), 4 in BRCA2 (7%) and one in TP53 (2%) gene]. A cancer familial history was present in 31.4% of the unrelated patients, from them 43.7% were carriers for germline mutation (37.5% in BRCA1 and in 6.2% in the BRCA2 genes). Fifty percent of the unrelated patients with hormone receptor-negative tumors carried BRCA1 mutations, percentage increasing to 83% in cases with familial history of cancer. Over-representation of DNA damage-, cellular and cell cycle-related processes was detected in the up-regulated genes of BRCA1/2-associated tumors, whereas cell and embryo development-related processes were over-represented in the up-regulated genes of BRCA1/2-negative tumors, suggesting distinct mechanisms driving the tumorigenesis. An initial portrait of the early-onset breast cancer patients in Brazil was generated pointing out that hormone receptor-negative tumors and positive familial history are two major risk factors for detection of a BRCA1 germline mutation. Additionally, the data revealed molecular factors that potentially trigger the tumor development in young patients.

  16. Molecular spectrum of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC somatic gene mutations in Arab patients with colorectal cancer: determination of frequency and distribution pattern

    PubMed Central

    Al-Shamsi, Humaid O.; Jones, Jeremy; Fahmawi, Yazan; Dahbour, Ibrahim; Tabash, Aziz; Abdel-Wahab, Reham; Abousamra, Ahmed O. S.; Shaw, Kenna R.; Xiao, Lianchun; Hassan, Manal M.; Kipp, Benjamin R.; Kopetz, Scott; Soliman, Amr S.; McWilliams, Robert R.; Wolff, Robert A.

    2016-01-01

    Background The frequency rates of mutations such as KRAS, NRAS, BRAF, and PIK3CA in colorectal cancer (CRC) differ among populations. The aim of this study was to assess mutation frequencies in the Arab population and determine their correlations with certain clinicopathological features. Methods Arab patients from the Arab Gulf region and a population of age- and sex-matched Western patients with CRC whose tumors were evaluated with next-generation sequencing (NGS) were identified and retrospectively reviewed. The mutation rates of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC were recorded, along with clinicopathological features. Other somatic mutation and their rates were also identified. Fisher’s exact test was used to determine the association between mutation status and clinical features. Results A total of 198 cases were identified; 99 Arab patients and 99 Western patients. Fifty-two point seven percent of Arab patients had stage IV disease at initial presentation, 74.2% had left-sided tumors. Eighty-nine point two percent had tubular adenocarcinoma and 10.8% had mucinous adenocarcinoma. The prevalence rates of KRAS, NRAS, BRAF, PIK3CA, TP53, APC, SMAD, FBXW7 mutations in Arab population were 44.4%, 4%, 4%, 13.1%, 52.5%, 27.3%, 2% and 3% respectively. Compared to 48.4%, 4%, 4%, 12.1%, 47.5%, 24.2%, 11.1% and 0% respectively in matched Western population. Associations between these mutations and patient clinicopathological features were not statistically significant. Conclusions This is the first study to report comprehensive hotspot mutations using NGS in Arab patients with CRC. The frequency of KRAS, NRAS, BRAF, TP53, APC and PIK3CA mutations were similar to reported frequencies in Western population except SMAD4 that had a lower frequency and higher frequency of FBXW7 mutation. PMID:28078112

  17. EZH2-mediated repression of GSK-3β and TP53 promotes Wnt/β-catenin signaling-dependent cell expansion in cervical carcinoma.

    PubMed

    Chen, Qian; Zheng, Peng-Sheng; Yang, Wen-Ting

    2016-06-14

    Enhancer of zeste homolog 2 (EZH2), a catalytic core component of the Polycomb repressive complex 2 (PRC2), stimulates the silencing of target genes through histone H3 lysine 27 trimethylation (H3K27me3). Recent findings have indicated EZH2 is involved in the development and progression of various human cancers. However, the exact mechanism of EZH2 in the promotion of cervical cancer is largely unknown. Here, we show that EZH2 expression gradually increases during the progression of cervical cancer. We identified a significant positive correlation between EZH2 expression and cell proliferation in vitro and tumor formation in vivo by the up-regulation or down-regulation of EZH2 using CRISPR-Cas9-mediated gene editing technology and shRNA in HeLa and SiHa cells. Further investigation indicated that EZH2 protein significantly accelerated the cell cycle transition from the G0/G1 to S phase. TOP/FOP-Flash reporter assay revealed that EZH2 significantly activated Wnt/β-catenin signaling and the target genes of Wnt/β-catenin pathway were up-regulated, including β-catenin, cyclin D1, and c-myc. Moreover, dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays confirmed that EZH2 inhibited the expression of glycogen synthase kinase-3β (GSK-3β) and TP53 through physically interacting with motifs in the promoters of the GSK-3β and TP53 genes. Additionally, blockage of the Wnt/β-catenin pathway resulted in significant inhibition of cell proliferation, and activation of the Wnt/β-catenin pathway resulted in significant enhancement of cell proliferation, as induced by EZH2. Taken together, our data demonstrate that EZH2 promotes cell proliferation and tumor formation in cervical cancer through activating the Wnt/β-catenin pathway by epigenetic silencing via GSK-3β and TP53.

  18. ET-62HIGHLY SELECTIVE ACTIVITY OF MDM2 INHIBITOR RG7112 AGAINST MDM2-AMPLIFIED/TP53 WILD-TYPE GLIOBLASTOMAS

    PubMed Central

    Verreault, Maite; Levasseur, Camille; Schmitt, Charlotte; Guehennec, Jeremy; Labussiere, Marianne; Marie, Yannick; Haidar, Sam; Mokhtari, Karima; Hoang-Xuan, Khe; Sanson, Marc; Ligon, Keith; Delattre, Jean-Yves; Idbaih, Ahmed

    2014-01-01

    Alteration of P53 pathway is one of the key molecular events involved in glioblastoma (GBM) biology. Genetic alterations which reduce TP53 function in GBM include MDM2 amplification (14% of patients), MDM4 amplification (7%), and TP53 gene mutations (35%), each of which is generally thought to be mutually exclusive. The study presented here aims to test the therapeutic activity of RG7112, a member of cis-imidazoline MDM2 inhibitors (Nutlins), in GBM cells according to their functional P53 pathway status. The effect of RG7112 was assessed in a panel of eleven GBM patient-derived cell lines (PDCLs) genetically selected to assess the drug response of the different alterations of P53 pathway. RG7112 was found to be able to induce cell death in all cell lines tested, with the highest cytotoxic efficacy against MDM2/MDM4-amplified GBM PDCL. Indeed, GBM cell lines carrying MDM2 or MDM4 gene amplification were 10 to 20 times more sensitive to the inhibitor than the other lines. TP53 mutant lines were the least sensitive lines. RG7112 treatment restored P53 and P21 protein levels in MDM2-amplified GBM cells. Most importantly, treatment of MDM2-amplified GBM orthotopic patient derived xenograft (PDX) bearing mice with 100 mg/kg RG7112 (Q5Dx3) reduced tumor growth rate and significantly increased survival duration compared to vehicle-treated mice. This data supports the research towards the development of RG7112 for clinical testing in MDM2/4-amplified glioblastoma patients. Studies assessing the capacity of RG7112 compound to cross the blood-brain barrier in healthy and GBM tumor tissue are currently ongoing.

  19. A common founding clone with TP53 and PTEN mutations gives rise to a concurrent germ cell tumor and acute megakaryoblastic leukemia

    PubMed Central

    Lu, Charles; Riedell, Peter; Miller, Christopher A.; Hagemann, Ian S.; Westervelt, Peter; Ozenberger, Bradley A.; O'Laughlin, Michelle; Magrini, Vincent; Demeter, Ryan T.; Duncavage, Eric J.; Griffith, Malachi; Griffith, Obi L.; Wartman, Lukas D.

    2016-01-01

    We report the findings from a patient who presented with a concurrent mediastinal germ cell tumor (GCT) and acute myeloid leukemia (AML). Bone marrow pathology was consistent with a diagnosis of acute megakaryoblastic leukemia (AML M7), and biopsy of an anterior mediastinal mass was consistent with a nonseminomatous GCT. Prior studies have described associations between hematological malignancies, including AML M7 and nonseminomatous GCTs, and it was recently suggested that a common founding clone initiated both cancers. We performed enhanced exome sequencing on the GCT and the AML M7 from our patient to define the clonal relationship between the two cancers. We found that both samples contained somatic mutations in PTEN (C136R missense) and TP53 (R213 frameshift). The mutations in PTEN and TP53 were present at ∼100% variant allele frequency (VAF) in both tumors. In addition, we detected and validated five other shared somatic mutations. The copy-number analysis of the AML exome data revealed an amplification of Chromosome 12p. We also identified a heterozygous germline variant in FANCA (S858R), which is known to be associated with Fanconi anemia but is of uncertain significance here. In summary, our data not only support a common founding clone for these cancers but also suggest that a specific set of distinct genomic alterations (in PTEN and TP53) underlies the rare association between GCT and AML. This association is likely linked to the treatment resistance and extremely poor outcome of these patients. We cannot resolve the clonal evolution of these tumors given limitations of our data. PMID:27148581

  20. Histologic and Immunohistochemical Analyses of Soft Tissue Sarcomas From brca2-Mutant/ tp53-Mutant Zebrafish Are Consistent With Neural Crest (Schwann Cell) Origin.

    PubMed

    White, L A; Sexton, J M; Shive, H R

    2017-03-01

    The zebrafish ( Danio rerio) provides a powerful model for analyzing genetic contributors to cancer. Multiple zebrafish lines with cancer-associated genetic mutations develop soft tissue sarcomas that are histologically consistent with malignant peripheral nerve sheath tumor (MPNST). The goal of this study was to determine the phenotype of soft tissue sarcomas in a brca2-mutant/ tp53-mutant zebrafish line using immunohistochemical markers that are commonly expressed in mammalian MPNST. We classified 70 soft tissue sarcomas from a brca2-mutant/ tp53-mutant zebrafish cohort as MPNST, undifferentiated sarcoma, or other tumor based on histologic features. The expression of S100, CD57, and glial fibrillary acidic protein (GFAP) was analyzed in nonneoplastic neural tissues and tumor specimens by immunohistochemistry. Each marker was expressed in nonneoplastic neural tissues. In MPNST, S100 and CD57 were widely expressed in neoplastic cells, with greater consistency observed for CD57 expression. In undifferentiated sarcomas, results were variable and correlated to anatomic location. Coelomic undifferentiated sarcomas often exhibited widespread CD57 expression but limited S100 expression. In comparison, ocular undifferentiated sarcomas exhibited limited expression of both CD57 and S100. Overall, CD57 and S100 expression was significantly higher in MPNST than in undifferentiated sarcomas. GFAP was not expressed in any of the tumors. This study identified commercially available antibodies that are useful for analyzing S100, CD57, and GFAP expression in zebrafish. This study further shows a correlation between degree of histologic differentiation and expression of these markers in soft tissue sarcomas from brca2-mutant/ tp53-mutant zebrafish and suggests that these cancers are derived from the neural crest with differentiation toward myelinating Schwann cells.

  1. Dysfunctional p53 deletion mutants in cell lines derived from Hodgkin's lymphoma.

    PubMed

    Feuerborn, Alexander; Möritz, Constanze; Von Bonin, Frederike; Dobbelstein, Matthias; Trümper, Lorenz; Stürzenhofecker, Benjamin; Kube, Dieter

    2006-09-01

    Classical Hodgkin's lymphoma (cHL) is a distinct malignancy of the immune system. Despite the progress made in the understanding of the pathology of cHL, the transforming events remain to be elucidated. It has been proposed that mutations in the TP53 gene in biopsy material as well as cell lines derived from cHL are rare and therefore not notably involved in the pathogenesis of the malignant H&RS cells. Re-evaluating the expression in cHL-derived cell lines, we found that in 3/6 of these cell lines, TP53 transcripts are characterized by deletions within exon 4 (L428 cells) and nearly a complete loss of exons 10 - 11 (L1236) or exons 8 - 11 (HDLM-2), respectively. These changes were found in otherwise rarely mutated regions of TP53. Cell lines L1236 and HDLM-2 harbour fusions with alu-repeats in their TP53 mRNA 3'-ends, resulting in the carboxyterminal truncation and loss of the transcriptional activity of p53. Transcriptional inactivity was also found for p53 in L428 cells. This study characterizes mutations in TP53 transcripts within cHL cell lines with associated functional defects in the resulting p53 proteins and therefore reintroduces the concept that mutations of TP53 might be involved in the pathogenesis of Hodgkin's lymphoma.

  2. A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families.

    PubMed

    Calvete, Oriol; Martinez, Paula; Garcia-Pavia, Pablo; Benitez-Buelga, Carlos; Paumard-Hernández, Beatriz; Fernandez, Victoria; Dominguez, Fernando; Salas, Clara; Romero-Laorden, Nuria; Garcia-Donas, Jesus; Carrillo, Jaime; Perona, Rosario; Triviño, Juan Carlos; Andrés, Raquel; Cano, Juana María; Rivera, Bárbara; Alonso-Pulpon, Luis; Setien, Fernando; Esteller, Manel; Rodriguez-Perales, Sandra; Bougeard, Gaelle; Frebourg, Tierry; Urioste, Miguel; Blasco, Maria A; Benítez, Javier

    2015-09-25

    Cardiac angiosarcoma (CAS) is a rare malignant tumour whose genetic basis is unknown. Here we show, by whole-exome sequencing of a TP53-negative Li-Fraumeni-like (LFL) family including CAS cases, that a missense variant (p.R117C) in POT1 (protection of telomeres 1) gene is responsible for CAS. The same gene alteration is found in two other LFL families with CAS, supporting the causal effect of the identified mutation. We extend the analysis to TP53-negative LFL families with no CAS and find the same mutation in a breast AS family. The mutation is recently found once in 121,324 studied alleles in ExAC server but it is not described in any other database or found in 1,520 Spanish controls. In silico structural analysis suggests how the mutation disrupts POT1 structure. Functional and in vitro studies demonstrate that carriers of the mutation show reduced telomere-bound POT1 levels, abnormally long telomeres and increased telomere fragility.

  3. A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li–Fraumeni-like families

    PubMed Central

    Calvete, Oriol; Martinez, Paula; Garcia-Pavia, Pablo; Benitez-Buelga, Carlos; Paumard-Hernández, Beatriz; Fernandez, Victoria; Dominguez, Fernando; Salas, Clara; Romero-Laorden, Nuria; Garcia-Donas, Jesus; Carrillo, Jaime; Perona, Rosario; Triviño, Juan Carlos; Andrés, Raquel; Cano, Juana María; Rivera, Bárbara; Alonso-Pulpon, Luis; Setien, Fernando; Esteller, Manel; Rodriguez-Perales, Sandra; Bougeard, Gaelle; Frebourg, Tierry; Urioste, Miguel; Blasco, Maria A.; Benítez, Javier

    2015-01-01

    Cardiac angiosarcoma (CAS) is a rare malignant tumour whose genetic basis is unknown. Here we show, by whole-exome sequencing of a TP53-negative Li–Fraumeni-like (LFL) family including CAS cases, that a missense variant (p.R117C) in POT1 (protection of telomeres 1) gene is responsible for CAS. The same gene alteration is found in two other LFL families with CAS, supporting the causal effect of the identified mutation. We extend the analysis to TP53-negative LFL families with no CAS and find the same mutation in a breast AS family. The mutation is recently found once in 121,324 studied alleles in ExAC server but it is not described in any other database or found in 1,520 Spanish controls. In silico structural analysis suggests how the mutation disrupts POT1 structure. Functional and in vitro studies demonstrate that carriers of the mutation show reduced telomere-bound POT1 levels, abnormally long telomeres and increased telomere fragility. PMID:26403419

  4. Constitutive autophagy contributes to resistance to TP53-mediated apoptosis in Epstein-Barr virus-positive latency III B-cell lymphoproliferations.

    PubMed

    Pujals, Anaïs; Favre, Loëtitia; Pioche-Durieu, Catherine; Robert, Aude; Meurice, Guillaume; Le Gentil, Marion; Chelouah, Sonia; Martin-Garcia, Nadine; Le Cam, Eric; Guettier, Catherine; Raphaël, Martine; Vassilev, Lyubomir T; Gaulard, Philippe; Codogno, Patrice; Lipinski, Marc; Wiels, Joëlle

    2015-01-01

    The Epstein-Barr virus (EBV) is associated with various lymphoproliferative disorders and lymphomas. We have previously demonstrated that treating wild-type TP53-expressing B cell lines with the TP53 pathway activator nutlin-3 induced apoptosis in EBV-negative and EBV-positive latency I cells whereas EBV-positive latency III cells remained much more apoptosis-resistant. Here, we report a constitutively high level of autophagy in these resistant cells which express high levels of the proautophagic protein BECN1/Beclin 1 based, at least in part, on the activation of the NFKB signaling pathway by the viral protein LMP1. Following treatment with nutlin-3, several autophagy-stimulating genes were upregulated both in EBV-negative and EBV-positive latency III cells. However the process of autophagy was only triggered in the latter and was associated with an upregulation of SESN1/sestrin 1 and inhibition of MTOR more rapid than in EBV-negative cells. A treatment with chloroquine, an inhibitor of autophagy, potentiated the apoptotic effect of nutlin-3, particularly in those EBV-positive cells which were resistant to apoptosis induced by nutlin-3 alone, thereby showing that autophagy participates in this resistant phenotype. Finally, using immunohistochemical staining, clinical samples from various B cell lymphoproliferations with the EBV-positive latency II or III phenotype were found to harbor a constitutively active autophagy.

  5. Establishment and characterization of a penile cancer cell line, penl1, with a deleterious TP53 mutation as a paradigm of HPV-negative penile carcinogenesis

    PubMed Central

    Li, Zaishang; Deng, Chuangzhong; Wang, Liangjiao; Yu, Xingsu; Liang, Peili; Xie, Qiankun; Chen, Peng; Qin, Zike; Ye, Yunlin; Liu, Zhuowei; Zhou, Fangjian; Zhang, Zhenfeng; Han, Hui

    2016-01-01

    Purpose To establish penile cancer (PeCa) cell lines for the study of molecular mechanisms of carcinogenesis and testing therapeutic reagents. Materials and Methods We successfully established two PeCa cell lines from fresh tumor tissues from 21 cases. One cell line named Penl1 was isolated from a lymph node metastasis (LNM) of penile squamous cell carcinoma (PeSCC), usual type and comprehensively characterized here. Our in-depth characterization analysis of the Penl1 cell line included morphology, tumorigenicity, genetic characteristics, protein expression, biology, and chemosensitivity. Penl1 was authenticated by single tandem repeat (STR) DNA typing. Results Comparative histomorphology, genetic characteristics, and protein expression patterns revealed essential similarities between the cell line and its corresponding LNM. In-depth characterization analysis of Penl1 cell line revealed tumorigenicity in immunodeficient mice, negative human papilloma virus (HPV) and mycoplasma infection, TP53 mutations and sensitivity to cisplatin and epirubicin. STR DNA typing did not match any cell lines within three international cell banks. The limitation of this study is that one patient cannot represent the complete heterogeneity of PeCa, especially primary tumor. Conclusions We established and characterized an HPV-negative and moderately differentiated PeCa cell model with a TP53 missense mutation from a PeSCC, usual type patient. A preliminarily study of carcinogenesis and chemosensitivity suggests that this cell model carries a tumor suppressor gene mutation and is sensitive to chemotherapy drugs. PMID:27351128

  6. Comparison of multiple genotyping methods for the identification of the cancer predisposing founder mutation p.R337H inTP53

    PubMed Central

    Fitarelli-Kiehl, Mariana; Macedo, Gabriel S.; Schlatter, Rosane Paixão; Koehler-Santos, Patricia; Matte, Ursula da Silveira; Ashton-Prolla, Patricia; Giacomazzi, Juliana

    2016-01-01

    Abstract Germline mutations in the TP53 gene are associated with Li-Fraumeni and Li-Fraumeni-Like Syndromes, characterized by increased predisposition to early-onset cancers. In Brazil, the prevalence of the TP53-p.R337H germline mutation is exceedingly high in the general population and in cancer-affected patients, probably as result of a founder effect. Several genotyping methods are used for the molecular diagnosis of LFS/LFL, however Sanger sequencing is still considered the gold standard. We compared performance, cost and turnaround time of Sanger sequencing, PCR-RFLP, TaqMan-PCR and HRM in the p.R337H genotyping. The performance was determined by analysis of 95 genomic DNA samples and results were 100% concordant for all methods. Sequencing was the most expensive method followed by TaqMan-PCR, PCR-RFLP and HRM. The overall cost of HRM increased with the prevalence of positive samples, since confirmatory sequencing must be performed when a sample shows an abnormal melting profile, but remained lower than all other methods when the mutation prevalence was less than 2.5%. Sequencing had the highest throughput and the longest turnaround time, while TaqMan-PCR showed the lowest turnaround and hands-on times. All methodologies studied are suitable for the detection of p.R337H and the choice will depend on the application and clinical scenario. PMID:27275664

  7. High-risk human papilloma virus infection, tumor pathophenotypes, and BRCA1/2 and TP53 status in juvenile breast cancer.

    PubMed

    Aceto, Gitana Maria; Solano, Angela Rosaria; Neuman, Maria Isabel; Veschi, Serena; Morgano, Annalisa; Malatesta, Sara; Chacon, Reinaldo Daniel; Pupareli, Carmen; Lombardi, Mercedes; Battista, Pasquale; Marchetti, Antonio; Mariani-Costantini, Renato; Podestà, Ernesto Jorge

    2010-08-01

    Juvenile breast cancer is rare and poorly known. We studied a series of five breast cancer patients diagnosed within 25 years of age that included two adolescents, 12- and 15-years-old, and 3 young women, 21-, 21-, and 25-years-old, respectively. All cases were scanned for germline mutations along the entire BRCA1/2 coding sequences and TP53 exons 4-10, using protein truncation test, denaturing high performance liquid chromatography and direct sequencing. Paraffin-embedded primary tumors (available for 4/5 cases), and a distant metastasis (from the 15-years-old) were characterized for histological and molecular tumor subtype, human papilloma virus (HPV) types 16/18 E6 sequences and tumor-associated mutations in TP53 exons 5-8. A BRCA2 germline mutation (p.Ile2490Thr), previously reported in breast cancer and, as compound heterozygote, in Fanconi anemia, was identified in the 21-year-old patient diagnosed after pregnancy, negative for cancer family history. The tumor was not available for study. Only germline polymorphisms in BRCA1/2 and/or TP53 were detected in the other cases. The tumors of the 15- and 12-years-old were, respectively, classified as glycogen-rich carcinoma with triple negative subtype and as secretory carcinoma with basal subtype. The tumors of the 25-year-old and of the other 21-year-old were, respectively, diagnosed as infiltrating ductal carcinoma with luminal A subtype and as lobular carcinoma with luminal B subtype. No somatic TP53 mutations were found, but tumor-associated HPV 16 E6 sequences were retrieved from the 12- and 25-year-old, while both HPV 16 and HPV 18 E6 sequences were found in the tumor of the 15-year-old and in its associated metastasis. Blood from the 15- and 25-year-old, diagnosed with high-stage disease, resulted positive for HPV 16 E6. All the HPV-positive cases were homozygous for arginine at TP53 codon 72, a genotype associated with HPV-related cancer risk, and the tumors showed p16(INK4A) immunostaining, a marker of HPV

  8. Combined effects of MDM2 SNP309 and TP53 R72P polymorphisms, and soy isoflavones on breast cancer risk among Chinese women in Singapore

    PubMed Central

    Van Den Berg, David; Jin, Aizhen; Wang, Renwei; Yuan, Jian-Min; Yu, Mimi C.

    2012-01-01

    The MDM2 oncoprotein regulates the p53 pathway and, while functional polymorphisms of the MDM2 and p53 genes have been investigated for association with breast cancer risk, results are largely null or non-conclusive. We have earlier reported that the increased intake of soy isoflavones reduces risk of postmenopausal breast cancer, and experimental studies suggest that dietary isoflavones can down-regulate the expression of the MDM2 oncoprotein. In this study, we investigated the association between the MDM2 SNP309 and TP53 R72P polymorphisms and breast cancer risk using a case–control study of 403 cases and 662 controls nested among 35,303 women in The Singapore Chinese Health Study, a population-based, prospective cohort of middle-aged and elderly men and women who have been continuously followed since 1993. The G allele of the TP53 R72P polymorphism and T allele of the MDM2 SNP309 polymorphism were putative high-risk alleles and exhibited a combined gene–dose-dependent joint effect on breast cancer risk that was more clearly observed in postmenopausal women. Among postmenopausal women, the simultaneous presence of G allele in TP53 and T allele in MDM2 polymorphisms was associated with an odds ratio (OR) of 2.42 [95% confidence interval (CI) 1.06–5.50]. Furthermore, the protective effect of dietary soy isoflavones on postmenopausal breast cancer was mainly confined to women homozygous for the high activity MDM2 allele (GG genotype). In this genetic subgroup, women consuming levels of soy isoflavones above the median level exhibited risk that was half of those with below median intake (OR 0.52; 95% CI 0.28–0.99). Our findings support experimental data implicating combined effects of MDM2 protein and the p53-mediated pathway in breast carcinogenesis, and suggest that soy isoflavones may exert protective effect via down-regulation of the MDM2 protein. PMID:21833626

  9. Microglandular adenosis associated with triple-negative breast cancer is a neoplastic lesion of triple-negative phenotype harbouring TP53 somatic mutations.

    PubMed

    Guerini-Rocco, Elena; Piscuoglio, Salvatore; Ng, Charlotte K Y; Geyer, Felipe C; De Filippo, Maria R; Eberle, Carey A; Akram, Muzaffar; Fusco, Nicola; Ichihara, Shu; Sakr, Rita A; Yatabe, Yasushi; Vincent-Salomon, Anne; Rakha, Emad A; Ellis, Ian O; Wen, Y Hannah; Weigelt, Britta; Schnitt, Stuart J; Reis-Filho, Jorge S

    2016-04-01

    Microglandular adenosis (MGA) is a rare proliferative lesion of the breast composed of small glands lacking myoepithelial cells and lined by S100-positive, oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative epithelial cells. There is evidence to suggest that MGA may constitute a non-obligate precursor of triple-negative breast cancer (TNBC). We sought to define the genomic landscape of pure MGA and of MGA, atypical MGA (AMGA) and associated TNBCs, and to determine whether synchronous MGA, AMGA, and TNBCs would be clonally related. Two pure MGAs and eight cases of MGA and/or AMGA associated with in situ or invasive TNBC were collected, microdissected, and subjected to massively parallel sequencing targeting all coding regions of 236 genes recurrently mutated in breast cancer or related to DNA repair. Pure MGAs lacked clonal non-synonymous somatic mutations and displayed limited copy number alterations (CNAs); conversely, all MGAs (n = 7) and AMGAs (n = 3) associated with TNBC harboured at least one somatic non-synonymous mutation (range 3-14 and 1-10, respectively). In all cases where TNBCs were analyzed, identical TP53 mutations and similar patterns of gene CNAs were found in the MGA and/or AMGA and in the associated TNBC. In the MGA/AMGA associated with TNBC lacking TP53 mutations, somatic mutations affecting PI3K pathway-related genes (eg PTEN, PIK3CA, and INPP4B) and tyrosine kinase receptor signalling-related genes (eg ERBB3 and FGFR2) were identified. At diagnosis, MGAs associated with TNBC were found to display subclonal populations, and clonal shifts in the progression from MGA to AMGA and/or to TNBC were observed. Our results demonstrate the heterogeneity of MGAs, and that MGAs associated with TNBC, but not necessarily pure MGAs, are genetically advanced, clonal, and neoplastic lesions harbouring recurrent mutations in TP53 and/or other cancer genes, supporting the notion that a subset of MGAs and AMGAs may constitute

  10. Renal Cell Carcinomas in Vinylidene Chloride Exposed Male B6C3F1 Mice Are Characterized by Oxidative Stress and TP53 Pathway Dysregulation

    PubMed Central

    Hayes, Schantel A.; Pandiri, Arun R.; Ton, Thai-vu T.; Hong, Hue-Hua L.; Clayton, Natasha P.; Shockley, Keith R.; Peddada, Shyamal D.; Gerrish, Kevin; Wyde, Michael; Sills, Robert C.; Hoenerhoff, Mark J.

    2015-01-01

    Vinylidene Chloride (VDC) has been widely used in the production of plastics and flame retardants. Exposure of B6C3F1 mice to VDC in the 2-year National Toxicology Program carcinogenicity bioassay resulted in a dose-dependent increases in renal cell hyperplasia, adenoma, and carcinoma (RCCs). Among those differentially expressed genes between controls and RCC from VDC-exposed mice, there was an overrepresentation of genes from pathways associated with chronic xenobiotic and oxidative stress, as well as c-Myc overexpression and dysregulation of TP53 cell cycle checkpoint and DNA damage repair pathways in RCC. Trend analysis comparing RCC, VDC-exposed kidney, and chamber control kidney showed a conservation of pathway dysregulation in terms of overrepresentation of xenobiotic and oxidative stress, and DNA damage and cell cycle checkpoint pathways in both VDC-exposed kidney and RCC, suggesting that these mechanisms play a role in the pathogenesis of RCC in VDC-exposed mice. PMID:26682919

  11. Differential allelic expression in leukoblast from patients with acute myeloid leukemia suggests genetic regulation of CDA, DCK, NT5C2, NT5C3, and TP53.

    PubMed

    Jordheim, L P; Nguyen-Dumont, T; Thomas, X; Dumontet, C; Tavtigian, S V

    2008-12-01

    mRNA expression levels of certain genes have shown predictive value for the outcome of cytarabine-treated AML-patients. We hypothesized that genetic variants play a role in the regulation of the transcription of these genes. We studied leukoblasts from 82 patients with acute myeloid leukemia and observed various extent and frequency of differential allelic expression in the CDA, DCK, NT5C2, NT5C3, and TP53 genes. Our attempts to identify the causative regulatory single nucleotide polymorphisms by a bioinformatics approach did not succeed. However, our results indicate that genetic variations are at least in part responsible for the differences in overall expression levels of these genes.

  12. High Relative Biologic Effectiveness of Carbon Ion Radiation on Induction of Rat Mammary Carcinoma and its Lack of H-ras and Tp53 Mutations

    SciTech Connect

    Imaoka, Tatsuhiko Nishimura, Mayumi; Kakinuma, Shizuko; Hatano, Yukiko; Ohmachi, Yasushi; Yoshinaga, Shinji Ph.D.; Kawano, Akihiro; Maekawa, Akihiko; Shimada, Yoshiya

    2007-09-01

    Purpose: The high relative biologic effectiveness (RBE) of high-linear energy transfer (LET) heavy-ion radiation has enabled powerful radiotherapy. The potential risk of later onset of secondary cancers, however, has not been adequately studied. We undertook the present study to clarify the RBE of therapeutic carbon ion radiation and molecular changes that occur in the rat mammary cancer model. Methods and Materials: We observed 7-8-week-old rats (ACI, F344, Wistar, and Sprague-Dawley) until 1 year of age after irradiation (0.05-2 Gy) with either 290 MeV/u carbon ions with a spread out Bragg peak (LET 40-90 keV/{mu}m) generated from the Heavy-Ion Medical Accelerator in Chiba or {sup 137}Cs {gamma}-rays. Results: Carbon ions significantly induced mammary carcinomas in Sprague-Dawley rats but less so in other strains. The dose-effect relationship for carcinoma incidence in the Sprague-Dawley rats was concave downward, providing an RBE of 2 at a typical therapeutic dose per fraction. In contrast, {approx}10 should be considered for radiation protection at low doses. Immunohistochemically, 14 of 18 carcinomas were positive for estrogen receptor {alpha}. All carcinomas examined were free of common H-ras and Tp53 mutations. Importantly, lung metastasis (7%) was characteristic of carbon ion-irradiated rats. Conclusions: We found clear genetic variability in the susceptibility to carbon ion-induced mammary carcinomas. The high RBE for carbon ion radiation further supports the importance of precise dose localization in radiotherapy. Common point mutations in H-ras and Tp53 were not involved in carbon ion induction of rat mammary carcinomas.

  13. Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways.

    PubMed

    Huang, Qichao; Zhan, Lei; Cao, Haiyan; Li, Jibin; Lyu, Yinghua; Guo, Xu; Zhang, Jing; Ji, Lele; Ren, Tingting; An, Jiaze; Liu, Bingrong; Nie, Yongzhan; Xing, Jinliang

    2016-06-02

    Mitochondrial morphology is dynamically remodeled by fusion and fission in cells, and dysregulation of this process is closely implicated in tumorigenesis. However, the mechanism by which mitochondrial dynamics influence cancer cell survival is considerably less clear, especially in hepatocellular carcinoma (HCC). In this study, we systematically investigated the alteration of mitochondrial dynamics and its functional role in the regulation of autophagy and HCC cell survival. Furthermore, the underlying molecular mechanisms and therapeutic application were explored in depth. Mitochondrial fission was frequently upregulated in HCC tissues mainly due to an elevated expression ratio of DNM1L to MFN1, which significantly contributed to poor prognosis of HCC patients. Increased mitochondrial fission by forced expression of DNM1L or knockdown of MFN1 promoted the survival of HCC cells both in vitro and in vivo mainly by facilitating autophagy and inhibiting mitochondria-dependent apoptosis. We further demonstrated that the survival-promoting role of increased mitochondrial fission was mediated via elevated ROS production and subsequent activation of AKT, which facilitated MDM2-mediated TP53 degradation, and NFKBIA- and IKK-mediated transcriptional activity of NFKB in HCC cells. Also, a crosstalk between TP53 and NFKB pathways was involved in the regulation of mitochondrial fission-mediated cell survival. Moreover, treatment with mitochondrial division inhibitor-1 significantly suppressed tumor growth in an in vivo xenograft nude mice model. Our findings demonstrate that increased mitochondrial fission plays a critical role in regulation of HCC cell survival, which provides a strong evidence for this process as drug target in HCC treatment.

  14. Impact of Neonatal Screening and Surveillance for the TP53 R337H Mutation on Early Detection of Childhood Adrenocortical Tumors

    PubMed Central

    Custódio, Gislaine; Parise, Guilherme A.; Kiesel Filho, Nilton; Komechen, Heloisa; Sabbaga, Cesar C.; Rosati, Roberto; Grisa, Leila; Parise, Ivy Z.S.; Pianovski, Mara A.D.; Fiori, Carmem M.C.M.; Ledesma, Jorge A.; Barbosa, José Renato S.; Figueiredo, Francisco R.O.; Sade, Elis R.; Ibañez, Humberto; Arram, Sohaila B.I.; Stinghen, Sérvio T.; Mengarelli, Luciano R.; Figueiredo, Mirna M.O.; Carvalho, Danilo C.; Avilla, Sylvio G.A.; Woiski, Thiago D.; Poncio, Lisiane C.; Lima, Geneci F.R.; Pontarolo, Roberto; Lalli, Enzo; Zhou, Yinmei; Zambetti, Gerard P.; Ribeiro, Raul C.; Figueiredo, Bonald C.

    2013-01-01

    Purpose The incidence of pediatric adrenocortical tumors (ACTs) is remarkably high in southern Brazil, where more than 90% of patients carry the germline TP53 mutation R337H. We assessed the impact of early detection of this mutation and of surveillance of carriers. Patients and Methods Free newborn screening was offered at all hospitals in the state of Paraná. Parents of positive newborns were tested, and relatives in the carrier line were offered screening. Positive newborns and their relatives age < 15 years were offered surveillance (periodic clinical, laboratory, and ultrasound evaluations). ACTs detected by imaging were surgically resected. Results Of 180,000 newborns offered screening, 171,649 were screened, and 461 (0.27%) were carriers. As of April 2012, ACTs had been diagnosed in 11 of these carriers but in only two neonatally screened noncarriers (P < .001); six patient cases were identified among 228 carrier relatives age < 15 years (total, 19 ACTs). Surveillance participants included 347 (49.6%) of 699 carriers. Tumors were smaller in surveillance participants (P < .001) and more advanced in nonparticipants (four with stage III disease; two deaths). Neonatally screened carriers also had neuroblastoma (n = 1), glioblastoma multiforme (n = 1), choroid plexus carcinoma (n = 2), and Burkitt lymphoma (n = 1). Cancer histories and pedigrees were obtained for 353 families that included 1,704 identified carriers. ACTs were the most frequent cancer among carrier children (n = 48). Conclusion These findings establish the prevalence of the TP53 R337H mutation in Paraná state and the penetrance of ACTs among carriers. Importantly, screening and surveillance of heterozygous carriers are effective in detecting ACTs when readily curable. PMID:23733769

  15. The importance of codon context for understanding the Ig-like somatic hypermutation strand-biased patterns in TP53 mutations in breast cancer.

    PubMed

    Lindley, Robyn A

    2013-06-01

    Evidence already exists that the activation-induced deaminase (AID)/APOBEC family constitutes a set of differentially expressed enzymes capable of deaminating cytosines (C to U) in single-stranded DNA (ssDNA) and that they are potentially powerful mutagens. The mutagenic processes involved are believed to be activated in many nonlymphoid tissue types-for example, initiating some cancers and/or leading to further somatic mutagenesis. To investigate the extent that codon context might be important in influencing the likely location of TP53 mutations in breast cancer, the codon-bias patterns resulting from the ssDNA target specificities of cytidine deaminases of the AID/APOBEC family were analyzed. The data indicate that codon context strongly influences the likely location of mutations at motifs for AID/APOBEC1/APOBEC3G, and at WA sites. An unexpected finding is a highly significant preference for transitions of cytosine to occur at the first nucleotide position and for transitions of guanosine to occur at the second nucleotide position in the mutated codon (read 3' to 5'). Thus, the mechanisms involved appear to be sensitive to codon reading frames and to have an intrinsic ability to differentiate between the cytosines on the nontranscribed strand and those on the transcribed strand in the context of an open "transcription bubble."

  16. Lycopene Extracts from Different Tomato-Based Food Products Induce Apoptosis in Cultured Human Primary Prostate Cancer Cells and Regulate TP53, Bax and Bcl-2 Transcript Expression

    PubMed

    Soares, Nathalia da Costa Pereira; Machado, Clara Lima; Trindade, Bruno Boquimpani; Lima, Ingridy Celestino do Canto; Gimba, Etel Rodrigues Pereira; Teodoro, Anderson Junger; Takiya, Christina; Borojevic, Radovan

    2017-02-01

    Carotenoids are the main tomato components, especially lycopene. Lycopene is more bioavailable in tomato processed products than in raw tomatos, since formation of lycopene cis-isomers during food processing and storage may increase its biological activity. In the current study, we evaluated the influence of lycopene extracts (5 mg / mL) from different tomato-based food products (paste, sauce, extract and ketchup) on cell viability and apoptosis on primary human prostate cancer cells (PCa cels) for 96h. Using MTT assay, we observed a significant decrease on primary PCa cell viability upon treatment with lycopene extracted from either 4 tomato-based food products. Flow cytometeric analysis revealed that lycopene from tomato extract and tomato sauce promoted up to fifty-fold increase on the proportion of apoptotic cells, when compared to the control group. Using real time PCR assay, we found that lycopene promoted an upregulation of TP53 and Bax transcript expression and also downregulation of Bcl-2 expression in PCa cells. In conclusion, our data demostrate that cis-lycopene promoted a significant inhibition on primary PCa cell viability, as well as an increase on their apoptotic rates, evidencing that cis-lycopene contained in tomato sauce and extract cain mainly modulate of primary human prostate cancer cell survival.

  17. Establishment and characterization of a novel uterine carcinosarcoma cell line, TU-ECS-1, with mutations of TP53 and KRAS.

    PubMed

    Chiba, Yohei; Sato, Seiya; Itamochi, Hiroaki; Suga, Yasuko; Fukagawa, Tomoyuki; Oumi, Nao; Oishi, Tetsuro; Harada, Tasuku; Sugai, Tamotsu; Sugiyama, Toru

    2017-04-01

    A new human uterine carcinosarcoma (UCS) cell line, TU-ECS-1, was established and characterized. The morphological appearance of the cultured cells was an insular of epithelial-like cells arranged in the form of a jigsaw puzzle and mesenchymal-like cells with a spindle-shaped or fibroblast-like morphology. A relatively high proliferation rate was observed with a doubling time of 18.2 h. The chromosome number ranged from 44 to 49 and had an extra chromosome 12 (trisomy 12). The respective half-maximal inhibitory concentrations of cisplatin, paclitaxel, and doxorubicin were 2.9 µM, 154 nM, and 219 ng/mL, respectively. Mutational analysis revealed that TU-ECS-1 cells have mutations of TP53 in exons 4, 6, and 8 and of KRAS at codon 12 (G12D) in exon 2, which is a mutation hot spot on this gene. Western blot analysis showed that p53 protein was overexpressed in TU-ECS-1 cells. Immunostaining of the cultured cells and in vivo tumors showed that the TU-ECS-1 cells and xenografts were positive for epithelial marker cytokeratin AE1/3 and mesenchymal marker vimentin. These results suggested that TU-ECS-1 cells might have both epithelial and mesenchymal characteristics. This cell line may be useful to study the carcinogenesis of UCS and contribute to the development of novel treatment strategies.

  18. Anaplastic Thyroid Carcinoma: A ceRNA Analysis Pointed to a Crosstalk between SOX2, TP53, and microRNA Biogenesis

    PubMed Central

    Carina, Valeria; Tomasello, Laura; Pitrone, Maria; Baiamonte, Concetta; Amato, Marco Calogero

    2015-01-01

    It has been suggested that cancer stem cells (CSC) may play a central role in oncogenesis, especially in undifferentiated tumours. Anaplastic thyroid carcinoma (ATC) has characteristics suggestive of a tumour enriched in CSC. Previous studies suggested that the stem cell factor SOX2 has a preeminent hierarchical role in determining the characteristics of stem cells in SW1736 ATC cell line. In detail, silencing SOX2 in SW1736 is able to suppress the expression of the stem markers analysed, strongly sensitizing the line to treatment with chemotherapeutic agents. Therefore, in order to further investigate the role of SOX2 in ATC, a competing endogenous RNA (ceRNA) analysis was conducted in order to isolate new functional partners of SOX2. Among the interactors, of particular interest are genes involved in the biogenesis of miRNAs (DICER1, RNASEN, and EIF2C2), in the control cell cycle (TP53, CCND1), and in mitochondrial activity (COX8A). The data suggest that stemness, microRNA biogenesis and functions, p53 regulatory network, cyclin D1, and cell cycle control, together with mitochondrial activity, might be coregulated. PMID:25705224

  19. Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data

    PubMed Central

    Wang, Zhaoming; Rajaraman, Preetha; Melin, Beatrice S.; Chung, Charles C.; Zhang, Weijia; McKean-Cowdin, Roberta; Michaud, Dominique; Yeager, Meredith; Ahlbom, Anders; Albanes, Demetrius; Andersson, Ulrika; Beane Freeman, Laura E.; Buring, Julie E.; Butler, Mary Ann; Carreón, Tania; Feychting, Maria; Gapstur, Susan M.; Gaziano, J. Michael; Giles, Graham G.; Hallmans, Goran; Henriksson, Roger; Hoffman-Bolton, Judith; Inskip, Peter D.; Kitahara, Cari M.; Le Marchand, Loic; Linet, Martha S.; Li, Shengchao; Peters, Ulrike; Purdue, Mark P.; Rothman, Nathaniel; Ruder, Avima M.; Sesso, Howard D.; Severi, Gianluca; Stampfer, Meir; Stevens, Victoria L.; Visvanathan, Kala; Wang, Sophia S.; White, Emily; Zeleniuch-Jacquotte, Anne; Hoover, Robert; Fraumeni, Joseph F.; Chatterjee, Nilanjan; Hartge, Patricia; Chanock, Stephen J.

    2016-01-01

    We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 × 10−11), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls). We subsequently performed integrative analyses on the Cancer Genome Atlas (TCGA) data for GBM (glioblastoma multiforme) and LUAD (lung adenocarcinoma). Based on SNP data, we imputed genotypes for rs78378222 and selected individuals carrying rare risk allele (C). Using RNA sequencing data, we observed aberrant transcripts with ~3 kb longer than normal for those individuals. Using exome sequencing data, we further showed that loss of haplotype carrying common protective allele (A) occurred somatically in GBM but not in LUAD. Our bioinformatic analysis suggests rare risk allele (C) disrupts mRNA termination, and an allelic loss of a genomic region harboring common protective allele (A) occurs during tumor initiation or progression for glioma. PMID:25907361

  20. rs78378222 polymorphism in the 3'-untranslated region of TP53 contributes to development of age-associated cataracts by modifying microRNA-125b-induced apoptosis of lens epithelial cells.

    PubMed

    Zhao, Yang; Li, Xiao; Zhu, Siquan

    2016-09-01

    MicroRNAs (miRNAs) negatively regulate the expression of the target genes by binding to 'seed sequences' in the 3'‑untranslated region (3'‑UTR) mRNA transcripts, and the variants within or nearby 'seed sequences' may compromise or enhance miRNA/mRNA interaction leading to either 'loss‑of‑function' or 'gain‑of‑function' effects. Cataracts are the leading cause of blindness worldwide and are characterized by progressive aggregation and precipitation of lens proteins, and the development of age‑related cataracts is associated with dysregulated cellular activities of lens epithelial cells. Luciferase assays and online miRNA databases were used to validate that tumor protein p53 (TP53) is the target gene of miR‑125b. Furthermore, reverse transcription‑quantitative polymerase chain reaction and western blotting were conducted to detect expression levels of miR‑125b and TP53 in different groups of cells transfected with miR‑125b mimics or inhibitors. In addition, flow cytometry analysis and the MTT assay were conducted to detect the effects of miR‑125b on apoptosis and cell viability. The current study demonstrated that the rs78378222 polymorphism minor allele introduces a novel potential miR‑125b binding site in the TP53 3'‑UTR with a consecutive 8‑bp perfect match, creating a 'gain‑of‑function' variant and affecting the regulation of TP53 expression. A luciferase assay demonstrated that transfection of lens epithelial cells with wild type TP53 3'‑UTR significantly reduced the luciferase activity of the miR‑125b overexpressing cells compared with scramble controls. In addition, the luciferase activity of miR‑125b overexpressing cells transfected with the construct containing the rs78378222 polymorphism minor allele was also reduced compared with cells transfected with the wild type 3'‑UTR. Furthermore, it was demonstrated that the expression level of miR‑125 was comparable in epithelial cells from patients with age

  1. HMGA2 and the p19Arf-TP53-CDKN1A axis: a delicate balance in the growth of uterine leiomyomas.

    PubMed

    Markowski, Dominique Nadine; von Ahsen, Inga; Nezhad, Maliheh Hashemi; Wosniok, Werner; Helmke, Burkhard Maria; Bullerdiek, Jörn

    2010-08-01

    Pathogenetically, uterine leiomyomas (ULs) can be interpreted as the result of a monoclonal abnormal proliferation of myometrial cells. Oncogene-induced senescence (OIS) is a frequent phenomenon in premalignant lesions that leads to a growth arrest mainly by the activation of two potent growth-inhibitory pathways as represented by p16(Ink4a) and p19(Arf). The relevance of OIS for the development of UL has not been addressed, but HMGA2, encoded by a major target gene of recurrent chromosomal abnormalities in UL, has been implicated in the repression of the Ink4a/Arf (CDKN2A) locus. This prompted us to examine if HMGA2 contributes to the growth of leiomyomas by repressing this locus. Contrary to the expectations, we were able to show that generally ULs express significantly higher levels of p19(Arf) mRNA than myometrium and that UL with 12q14 approximately 15 rearrangements showed higher expression levels than UL with other cytogenetic aberrations. Furthermore, the finding of a significant correlation between the expressions of p19(Arf) and CDKN1A shows that p19(Arf) triggers senescence rather than apoptosis in UL. Furthermore, the expression levels of HMGA2, p19(Arf), and CDKN1A were found to be correlated with the size of the tumors, indicating that an enhanced growth potential is counterbalanced by the p19(Arf) pathway. Mechanistically, the UL may thus execute a program already present in their cell of origin, where it is activated to protect the genome, for example, in the case of enhanced proliferation. In summary, the results identify the p19(Arf)-TP53-CDKN1A pathway as a major player in the growth control and genomic stability of uterine fibroids.

  2. Prevalence and coexistence of KRAS, BRAF, PIK3CA, NRAS, TP53, and APC mutations in Indian colorectal cancer patients: Next-generation sequencing-based cohort study.

    PubMed

    Jauhri, Mayank; Bhatnagar, Akanksha; Gupta, Satish; Bp, Manasa; Minhas, Sachin; Shokeen, Yogender; Aggarwal, Shyam

    2017-02-01

    Colorectal cancer incidences are on a rise in India. In this study, we have analyzed the mutation frequencies of six potential biomarkers, their coexistence, association with clinicopathological characteristics, and tumor location in Indian colorectal cancer patients. Next-generation sequencing was performed to identify mutations in the six potential biomarker genes using formalin-fixed paraffin-embedded tissue blocks of 112 colorectal cancer patients. The mutation frequency observed in KRAS, BRAF, PIK3CA, NRAS, TP53, and APC was 35.7%, 7.1%, 16.1%, 6.3%, 39.3%, and 29.5%, respectively. The significant associations of mutations were KRAS with age less than 60 years (p = 0.041), PIK3CA with males (p = 0.032), tumor stage I-II (p = 0.013), lack of metastasis in lymph nodes (p = 0.040), NRAS with rectum (p = 0.002), and APC with T2 stage of tumor growth (p = 0.013). No single patient harbored mutations in these six genes or any five genes simultaneously. Significance was noted in coexistence of KRAS with APC (p = 0.024) and mutual exclusion of KRAS with BRAF (p = 0.029). PIK3CA exon 9 was observed to be more frequently associated with KRAS mutations than PIK3CA exon 20 (p = 0.072). NRAS mutations were mutually exclusive with BRAF and PIK3CA mutations. As per our knowledge, this is the first next-generation sequencing-based biomarker study in Indian colorectal cancer patients. Frequent coexistence of gene mutations in pairs and triplets suggests that synergistic effect of overlapping mutations might further trigger the disease. In addition, infrequent coexistence of multiple gene mutations hints toward different signaling pathways for colorectal cancer tumorigenesis.

  3. Aflatoxin-induced TP53 R249S mutation in hepatocellular carcinoma in Thailand: association with tumors developing in the absence of liver cirrhosis.

    PubMed

    Villar, Stephanie; Ortiz-Cuaran, Sandra; Abedi-Ardekani, Behnoush; Gouas, Doriane; Nogueira da Costa, Andre; Plymoth, Amelie; Khuhaprema, Thiravud; Kalalak, Anant; Sangrajrang, Suleeporn; Friesen, Marlin D; Groopman, John D; Hainaut, Pierre

    2012-01-01

    Primary Liver Cancer (PLC) is the leading cause of death by cancer among males in Thailand and the 3(rd) among females. Most cases are hepatocellular carcinoma (HCC) but cholangiocarcinomas represent between 4 and 80% of liver cancers depending upon geographic area. Most HCC are associated with chronic infection by Hepatitis B Virus while a G → T mutation at codon 249 of the TP53 gene, R249S, specific for exposure to aflatoxin, is detected in tumors for up to 30% of cases. We have used Short Oligonucleotide Mass Analysis (SOMA) to quantify free circulating R249S-mutated DNA in plasma using blood specimens collected in a hospital case:control study. Plasma R249S-mutated DNA was detectable at low concentrations (≥ 67 copies/mL) in 53 to 64% of patients with primary liver cancer or chronic liver disease and in 19% of controls. 44% of patients with HCC and no evidence of cirrhosis had plasma concentrations of R249S-mutated DNA ≥ 150 copies/mL, compared to 21% in patients with both HCC and cirrhosis, 22% in patients with cholangiocarcinoma, 12% in patients with non-cancer chronic liver disease and 3% of subjects in the reference group. Thus, plasma concentrations of R249S-mutated DNA ≥ 150 copies/mL tended to be more common in patients with HCC developing without pre-existing cirrhosis (p = 0.027). Overall, these results support the preferential occurrence of R249S-mutated DNA in HCC developing in the absence of cirrhosis in a context of HBV chronic infection.

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

    PubMed Central

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

    1996-01-01

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

  5. Relationship of Ki67, TP53, MDM-2 and BCL-2 expressions with WHO 1973 and WHO/ISUP grades, tumor category and overall patient survival in urothelial tumors of the bladder.

    PubMed

    Gönül, Ipek Işik; Akyürek, Nalan; Dursun, Ayşe; Küpeli, Bora

    2008-01-01

    Using the 1998 World Health Organization/International Society of Urological Pathology (WHO/ISUP) (2004 WHO), 1999 WHO/ISUP, and 1973 WHO classifications, we examined Ki67, BCL-2, TP53, and MDM-2 expressions in invasive and noninvasive urothelial neoplasias of the bladder of 72 patients, and compared the results regarding tumor category and grade with clinical outcome to determine the clinicopathological relevance of these classifications. Ki67 and TP53 expressions were correlated with tumor grades of the 1973 WHO classification, and they also distinguished "papillary urothelial neoplasm with low malignant potential" from other WHO/ISUP grades (p < 0.05). No difference was observed for Ki67 and TP53 expressions between the other WHO/ISUP grades (p > 0.05). Neither tumor grade nor tumor category correlated with MDM-2 or BCL-2 expressions (p > 0.05). WHO/ISUP classifications are obviously not superior to the 1973 WHO classification for grading urothelial neoplasia of the bladder. However, if the "papillary urothelial neoplasm with low malignant potential" is distinguished from grade 1 tumors of the 1973 WHO classification, more precise prognostic information may be obtained.

  6. Screening for germline BRCA1, BRCA2, TP53 and CHEK2 mutations in families at-risk for hereditary breast cancer identified in a population-based study from Southern Brazil

    PubMed Central

    Palmero, Edenir Inêz; Alemar, Bárbara; Schüler-Faccini, Lavínia; Hainaut, Pierre; Moreira-Filho, Carlos Alberto; Ewald, Ingrid Petroni; dos Santos, Patricia Koehler; Ribeiro, Patricia Lisbôa Izetti; de Oliveira, Cristina Brinkmann; Kelm, Florence Le Calvez; Tavtigian, Sean; Cossio, Silvia Liliana; Giugliani, Roberto; Caleffi, Maira; Ashton-Prolla, Patricia

    2016-01-01

    Abstract In Brazil, breast cancer is a public health care problem due to its high incidence and mortality rates. In this study, we investigated the prevalence of hereditary breast cancer syndromes (HBCS) in a population-based cohort in Brazils southernmost capital, Porto Alegre. All participants answered a questionnaire about family history (FH) of breast, ovarian and colorectal cancer and those with a positive FH were invited for genetic cancer risk assessment (GCRA). If pedigree analysis was suggestive of HBCS, genetic testing of the BRCA1, BRCA2, TP53, and CHEK2 genes was offered. Of 902 women submitted to GCRA, 214 had pedigrees suggestive of HBCS. Fifty of them underwent genetic testing: 18 and 40 for BRCA1/BRCA2 and TP53 mutation screening, respectively, and 7 for CHEK2 1100delC testing. A deleterious BRCA2 mutation was identified in one of the HBOC probands and the CHEK2 1100delC mutation occurred in one of the HBCC families. No deleterious germline alterations were identified in BRCA1 or TP53. Although strict inclusion criteria and a comprehensive testing approach were used, the suspected genetic risk in these families remains unexplained. Further studies in a larger cohort are necessary to better understand the genetic component of hereditary breast cancer in Southern Brazil. PMID:27223485

  7. Next Generation Sequencing of Cytokeratin 20-Negative Merkel Cell Carcinoma Reveals Ultraviolet Signature Mutations and Recurrent TP53 and RB1 Inactivation

    PubMed Central

    Harms, Paul W.; Collie, Angela M. B.; Hovelson, Daniel H.; Cani, Andi K.; Verhaegen, Monique E.; Patel, Rajiv M.; Fullen, Douglas R.; Omata, Kei; Dlugosz, Andrzej A.; Tomlins, Scott A.; Billings, Steven D.

    2016-01-01

    Merkel cell carcinoma is a rare but highly aggressive cutaneous neuroendocrine carcinoma. Cytokeratin-20 (CK20) is expressed in approximately 95% of Merkel cell carcinomas and is useful for distinction from morphologically similar entities including metastatic small cell lung carcinoma. Lack of CK20 expression may make diagnosis of Merkel cell carcinoma more challenging, and has unknown biological significance. Approximately 80% of CK20-positive Merkel cell carcinomas are associated with the oncogenic Merkel cell polyomavirus. Merkel cell carcinomas lacking Merkel cell polyomavirus display distinct genetic changes from Merkel cell polyomavirus-positive Merkel cell carcinoma, including RB1 inactivating mutations. Unlike CK20-positive Merkel cell carcinoma, the majority of CK20-negative Merkel cell carcinomas are Merkel cell polyomavirus-negative, suggesting CK20-negative Merkel cell carcinomas predominantly arise through virus-independent pathway(s) and may harbor additional genetic differences from conventional Merkel cell carcinoma. Hence, we analyzed 15 CK20-negative Merkel cell carcinoma tumors (ten Merkel cell polyomavirus-negative, four Merkel cell polyomavirus-positive, and one undetermined) using the Ion Ampliseq Comprehensive Cancer Panel, which assesses copy number alterations and mutations in 409 cancer-relevant genes. Twelve tumors displayed prioritized high-level chromosomal gains or losses (average 1.9 per tumor). Non-synonymous high confidence somatic mutations were detected in 14 tumors (average 11.9 per tumor). Assessing all somatic coding mutations, an ultraviolet-signature mutational profile was present, and more prevalent in Merkel cell polyomavirus-negative tumors. Recurrent deleterious tumor suppressor mutations affected TP53 (9/15, 60%), RB1 (3/15, 20%), and BAP1 (2/15, 13%). Oncogenic activating mutations included PIK3CA (3/15, 20%), AKT1 (1/15, 7%)) and EZH2 (1/15, 7%). In conclusion, CK20-negative Merkel cell carcinoma display overlapping

  8. Alterations in TP53, cyclin D2, c-Myc, p21WAF1/CIP1 and p27KIP1 expression associated with progression in B-CLL.

    PubMed

    Halina, Antosz; Artur, Paterski; Barbara, Marzec-Kotarska; Joanna, Sajewicz; Anna, Dmoszyńska

    2010-12-01

    B-cell chronic lymphocytic leukaemia (B-CLL) originates from B lymphocytes that may differ in the activation level, maturation state or cellular subgroups in peripheral blood. Tumour progression in CLL B cells seems to result in gradual accumulation of the clone of resting B lymphocytes in the early phases (G0/G1) of the cell cycle. The G1 phase is impaired in B-CLL. We investigated the gene expression of five key cell cycle regulators: TP 53, c-Myc, cyclin D2, p21WAF1/CIP1 and p27KIP1, which primarily regulate the G1 phase of the cell cycle, or S-phase entry and ultimately control the proliferation and cell growth as well as their role in B-CLL progression. The study was conducted in peripheral blood CLL lymphocytes of 40 previously untreated patients. Statistical analysis of correlations of TP53, cyclin D2, c-Myc, p21WAF1/CIP1 and p27KIP1 expressions in B-CLL patients with different Rai stages demonstrated that the progression of disease was accompanied by increases in p53, cyclin D2 and c-Myc mRNA expression. The expression of p27KIP1 was nearly statistically significant whereas that of p21 WAF1/CIP1 showed no such correlation. Moreover, high expression levels of TP53 and c-Myc genes were found to be closely associated with more aggressive forms of the disease requiring earlier therapy.

  9. Genomic profile of a Li-Fraumeni-like syndrome patient with a 45,X/46,XX karyotype, presenting neither mutations in TP53 nor clinical stigmata of Turner syndrome.

    PubMed

    Basso, Tatiane R; Villacis, Rolando A R; Canto, Luisa M; Alves, Vinicius M F; Lapa, Rainer M L; Nóbrega, Amanda F; Achatz, Maria I; Rogatto, Silvia R

    2015-06-01

    Li-Fraumeni syndrome (LFS) is a hereditary disorder that predisposes patients to several types of cancer and is associated with TP53 germline mutations. Turner syndrome (TS) is one of the most common aneuploidies in women. Patients with TS have a higher risk of developing cancer, although multiple malignant tumors are extremely rare. Herein, we describe a patient with a 45,X/46,XX karyotype with no classic phenotype of TS. She presented with a clinical diagnosis of Li-Fraumeni-like syndrome (LFL), showing papillary thyroid carcinoma and fibrosarcoma of the left flank, and had no TP53 germline mutations. Genome-wide analysis of copy number variations (CNVs) was assessed in DNA from peripheral blood cells and saliva. A total of 109 rare CNVs in the blood cells, including mosaic loss of the X chromosome (76% of cells), were identified. In saliva, three rare CNVs were detected, all of them were also detected in the blood cells: loss of 8q24.11 (EXT1), gain of 16q24.3 (PRDM7 and GAS8), and the mosaic loss of the X chromosome (50% of cells). Results of conventional G-banding confirmed the 45,X/46,XX karyotype. Surprisingly, the patient presented with an apparently normal phenotype. The PRDM and GAS8 genes are potential candidates to be associated with the risk of developing cancer in this LFL/TS patient.

  10. Kras, Egfr, and Tp53 Mutations in B6C3F1/N Mouse and F344/NTac Rat Alveolar/Bronchiolar Carcinomas Resulting from Chronic Inhalation Exposure to Cobalt Metal.

    PubMed

    Hong, Hue-Hua L; Hoenerhoff, Mark J; Ton, Thai-Vu; Herbert, Ronald A; Kissling, Grace E; Hooth, Michelle J; Behl, Mamta; Witt, Kristine L; Smith-Roe, Stephanie L; Sills, Robert C; Pandiri, Arun R

    2015-08-01

    Rodent lung tumors are morphologically similar to a subtype of human lung adenocarcinomas. The objective of this study was to evaluate Kirsten rat sarcoma oncogene homolog (Kras), epidermal growth factor receptor (Egfr), and tumor protein 53 (Tp53) mutations, which are relevant to human lung cancer, in cobalt metal dust (CMD)-induced alveolar/bronchiolar tumors of B6C3F1/N mice and F344/NTac rats. Kras mutations were detected in 67% (mice) and 31% (rats) of CMD-induced lung tumors and were predominantly exon 1 codon 12 G to T transversions (80% in mice and 57% in rats). Egfr mutations were detected in 17% (both mice and rats) of CMD-induced lung tumors and were predominantly in exon 20 with 50% G to A transitions (mice and rats). Tp53 mutations were detected in 19% (mice) and 23% (rats) of CMD-induced lung tumors and were predominant in exon 5 (mice, 69% transversions) and exon 6 (rats, all transitions). No mutations were observed for these genes in spontaneous lung tumors or normal lungs from untreated controls. Ames assay indicated that CMD is mutagenic in the absence but not in the presence of S9 mix. Thus, the mutation data (G to T transversions) and Ames assay results suggest that oxidative damage to DNA may be a contributing factor in CMD-induced pulmonary carcinogenesis in rodents.

  11. Kras, Egfr, and Tp53 Mutations in B6C3F1/N Mouse and F344/NTac Rat Alveolar/Bronchiolar Carcinomas Resulting from Chronic Inhalation Exposure to Cobalt Metal

    PubMed Central

    Hong, Hue-Hua L.; Hoenerhoff, Mark J.; Ton, Thai-Vu; Herbert, Ronald A.; Kissling, Grace E.; Hooth, Michelle J.; Behl, Mamta; Witt, Kristine L.; Smith-Roe, Stephanie L.; Sills, Robert C.; Pandiri, Arun R.

    2015-01-01

    Rodent lung tumors are morphologically similar to a subtype of human lung adenocarcinomas. The objective of this study was to evaluate Kras, Egfr and Tp53 mutations, which are relevant to human lung cancer, in cobalt metal dust (CMD) induced alveolar/bronchiolar tumors of B6C3F1/N mice and F344/NTac rats. Kras mutations were detected in 67% (mice) and 31% (rats) of CMD-induced lung tumors, and were predominantly exon 1 codon 12 G to T transversions (80% in mice and 57% in rats). Egfr mutations were detected in 17% (both mice and rats) of CMD-induced lung tumors, and were predominantly in exon 20 with 50% G to A transitions (mice and rats). Tp53 mutations were detected in 19% (mice) and 23% (rats) of CMD-induced lung tumors and were predominantly in exon 5 (mice, 69% transversions) and exon 6 (rats, all transitions). No mutations were observed for these genes in spontaneous lung tumors or normal lungs from untreated controls. Ames assays indicated that CMD is mutagenic in the absence but not in the presence of S9 mix. Thus, the mutation data (G to T transversions) and Ames assay results suggest that oxidative damage to DNA may be a contributing factor in CMD-induced pulmonary carcinogenesis in rodents. PMID:26059825

  12. A case of duplication 17p13.1p13.3 confirmed by FISH

    SciTech Connect

    Stephenson, C.F.; Berger, C.S.; Bull, R.M.

    1994-09-01

    There are many reports in the literature of deletions of the p arm of chromosome 17 in the region of p13.3 due to the association with Miller-Dieker Syndrome. However, very little is known about duplications of 17p. We report a duplication of part of 17p in an 8-year-old girl with attention deficit disorder and mild mental retardation. Cytogenetically, the duplicated region appears to include 17p13.1 to p13.3. FISH with a cosmid probe to the Miller-Dieker region at 17p13.3 shows a double hybridization signal, confirming that the duplicated material does indeed include 17q13.3.

  13. Uniparental disomies, homozygous deletions, amplifications, and target genes in mantle cell lymphoma revealed by integrative high-resolution whole-genome profiling

    PubMed Central

    Beà, Sílvia; Salaverria, Itziar; Armengol, Lluís; Pinyol, Magda; Fernández, Verónica; Hartmann, Elena M.; Jares, Pedro; Amador, Virginia; Hernández, Luís; Navarro, Alba; Ott, German; Rosenwald, Andreas; Estivill, Xavier

    2009-01-01

    Mantle cell lymphoma (MCL) is genetically characterized by the t(11;14)(q13;q32) translocation and a high number of secondary chromosomal alterations. However, only a limited number of target genes have been identified. We have studied 10 MCL cell lines and 28 primary tumors with a combination of a high-density single-nucleotide polymorphism array and gene expression profiling. We detected highly altered genomes in the majority of the samples with a high number of partial uniparental disomies (UPDs). The UPD at 17p was one of the most common, and it was associated with TP53 gene inactivation. Homozygous deletions targeted 4 known tumor suppressor genes (CDKN2C, BCL2L11, CDKN2A, and RB1) and 6 new genes (FAF1, MAP2, SP100, MOBKL2B, ZNF280A, and PRAME). Gene amplification coupled with overexpression was identified in 35 different regions. The most recurrent amplified regions were 11q13.3-q13.5, 13q31.3, and 18q21.33, which targeted CCND1, C13orf25, and BCL2, respectively. Interestingly, the breakpoints flanking all the genomic alterations, including UPDs, were significantly associated with genomic regions enriched in copy number variants and segmental duplications, suggesting that the recombination at these regions may play a role in the genomic instability of MCL. This integrative genomic analysis has revealed target genes that may be potentially relevant in MCL pathogenesis. PMID:18984860

  14. Microdeletions of chromosome 17p13 as a cause of isolated lissencephaly

    SciTech Connect

    Ledbetter, S.A.; Kuwano, Akira; Ledbetter, D.H. ); Dobyns, W.B. )

    1992-01-01

    Lissencephaly (agyria-pachygyria) is a brain malformation manifested by a smooth cerebral surface, resulting from arrest of neuronal migration at 10-14 wk gestation. Type I, or classical, lissencephaly can occur either in association with the Miller-Dieker syndrome (MDS) or as an isolated finding, termed isolated lissencephaly sequence (ILS). About 90% of MDS patients have visible or submicroscopic deletions of 17p13.3. The authors therefore investigated the possibility that some ILS patients have smaller deletions in this chromosomal region. Forty-five ILS patients with gyral abnormalities ranging from complete agyria to mixed agyria/pachygyria and complete pachygyria were studied. RFLP analysis with five polymorphic loci in 17p13.3 was performed on all patients and their parents. Somatic cell hybrids were constructed on three patients, to confirm a deletion or to determine the boundaries of a deletion. These data demonstrate that a locus on 17p13 represents a major genetic etiology for patients with lissencephaly, ranging from complete agyria to pachygyria. In situ hybridization allows rapid and sensitive deletion detection and is the preferred method for diagnostic evaluation of MDA and ILS patients.

  15. Interstitial 13q14 deletions detected in the karyotype and translocations with concomitant deletion at 13q14 in chronic lymphocytic leukemia: different genetic mechanisms but equivalent poorer clinical outcome.

    PubMed

    Puiggros, Anna; Venturas, Marta; Salido, Marta; Blanco, Gonzalo; Fernandez-Rodriguez, Concepción; Collado, Rosa; Valiente, Alberto; Ruiz-Xivillé, Neus; Carrió, Ana; Ortuño, Francisco José; Luño, Elisa; Calasanz, María José; Ardanaz, María Teresa; Piñán, María Ángeles; Talavera, Elisabet; González, María Teresa; Ortega, Margarita; Marugán, Isabel; Ferrer, Ana; Gimeno, Eva; Bellosillo, Beatriz; Delgado, Julio; Hernández, José Ángel; Hernández-Rivas, Jesús María; Espinet, Blanca

    2014-09-01

    Deletion of 13q14 as the sole abnormality is a good prognostic marker in chronic lymphocytic leukemia (CLL). Nonetheless, the prognostic value of reciprocal 13q14 translocations [t(13q)] with related 13q losses has not been fully elucidated. We described clinical and biological characteristics of 25 CLL patients with t(13q), and compared with 62 patients carrying interstitial del(13q) by conventional G-banding cytogenetics (CGC) [i-del(13q)] and 295 patients with del(13q) only detected by fluorescence in situ hybridization (FISH) [F-del(13q)]. Besides from the CLL FISH panel (D13S319, CEP12, ATM, TP53), we studied RB1 deletions in all t(13q) cases and a representative group of i-del(13q) and F-del(13q). We analyzed NOTCH1, SF3B1, and MYD88 mutations in t(13q) cases by Sanger sequencing. In all, 25 distinct t(13q) were described. All these cases showed D13S319 deletion while 32% also lost RB1. The median percentage of 13q-deleted nuclei did not differ from i-del(13q) patients (73% vs. 64%), but both were significantly higher than F-del(13q) (52%, P < 0.001). Moreover, t(13q) patients showed an increased incidence of biallelic del(13q) (52% vs. 11.3% and 14.9%, P < 0.001) and higher rates of concomitant 17p deletion (37.5% vs. 8.6% and 7.2%, P < 0.001). RB1 involvement was significantly higher in the i-del(13q) group (79%, P < 0.001). Two t(13q) patients (11.8%) carried NOTCH1 mutations. Time to first treatment in t(13q) and i-del(13q) was shorter than F-del(13q) (67, 44, and 137 months, P = 0.029), and preserved significance in the multivariate analysis. In conclusion, t(13q) and del(13q) patients detected by CGC constitute a subgroup within the 13q-deleted CLL patients associated with a worse clinical outcome.

  16. Promyelocytic Leukemia Zinc Finger-Retinoic Acid Receptor α (PLZF-RARα), an Oncogenic Transcriptional Repressor of Cyclin-dependent Kinase Inhibitor 1A (p21WAF/CDKN1A) and Tumor Protein p53 (TP53) Genes*

    PubMed Central

    Choi, Won-Il; Yoon, Jae-Hyeon; Kim, Min-Young; Koh, Dong-In; Licht, Jonathan D.; Kim, Kunhong; Hur, Man-Wook

    2014-01-01

    Promyelocytic leukemia zinc finger-retinoic acid receptor α (PLZF-RARα) is an oncogene transcriptional repressor that is generated by a chromosomal translocation between the PLZF and RARα genes in acute promyelocytic leukemia (APL-type) patients. The molecular interaction between PLZF-RARα and the histone deacetylase corepressor was proposed to be important in leukemogenesis. We found that PLZF-RARα can repress transcription of the p21WAF/CDKN1A gene, which encodes the negative cell cycle regulator p21 by binding to its proximal promoter Sp1-binding GC-boxes 3, 4, 5/6, a retinoic acid response element (RARE), and distal p53-responsive elements (p53REs). PLZF-RARα also acts as a competitive transcriptional repressor of p53, RARα, and Sp1. PLZF-RARα interacts with co-repressors such as mSin3A, NCoR, and SMRT, thereby deacetylating histones Ac-H3 and Ac-H4 at the CDKN1A promoter. PLZF-RARα also interacts with the MBD3-NuRD complex, leading to epigenetic silencing of CDKN1A through DNA methylation. Furthermore, PLZF-RARα represses TP53 and increases p53 protein degradation by ubiquitination, further repressing p21 expression. Resultantly, PLZF-RARα promotes cell proliferation and significantly increases the number of cells in S-phase. PMID:24821728

  17. Analysis of chromosome 17p13 (p53 locus) alterations in gastric carcinoma cells by dual-color fluorescence in situ hybridization.

    PubMed

    Kobayashi, M; Kawashima, A; Mai, M; Ooi, A

    1996-11-01

    Chromosome 17 and p53 gene locus alterations were determined on 67 gastric carcinomas by dual-color fluorescence in situ hybridization, using probes for centromere 17 and the 17p13.1 (p53 locus). The results were compared with loss of heterozygosity (LOH) at 17p13.3, direct sequencing of exons 5 to 9 of p53, and nuclear overexpression of p53 protein. Deletion of p53 was found in 26 of 67 tumors (39%). All 26 also showed LOH at 17p13.3, frequently overexpressed p53 protein, and had polysomy 17. The functional loss of p53 gene in these tumors, 85% of which were of intestinal type, appears to be caused by both deletion of 17p13.1 and missense mutation of the remaining allele. There were 9 tumors that had neither deletion nor LOH but had a large proportion of cancer cells that overexpressed p53 election. Despite evidence of LOH, there was no p53 deletion in 11 tumors. Finally, 21 tumors, mostly of diffuse type, showed neither deletions, LOH, nor p53 overexpression. Our data suggest that in gastric cancer, deletion of 17p is principally responsible for the allelic loss at the p53 gene and that analysis of deletions by the dual-color fluorescence in situ hybridization is a sensitive and useful approach to clarify chromosomal aberrations.

  18. Congenital diaphragmatic hernia in Smith-Magenis syndrome: a possible locus at chromosome 17p11.2.

    PubMed

    Sanford, E F; Bermudez-Wagner, K; Jeng, L J B; Rauen, K A; Slavotinek, Anne M

    2011-11-01

    We report on a 7-month-old girl with Smith-Magenis syndrome (SMS) due to a 4.76-Mb deletion of 17p12-17p11.2 detected by array comparative genomic hybridization. She was also affected with a left-sided congenital diaphragmatic hernia (CDH) and cardiac anomalies including an atypical atrioventricular canal defect and a cleft mitral valve. To our knowledge, this is the first reported case of a patient with both SMS and CDH. There are numerous chromosomal regions in which duplications, deletions, inversions, or translocations have been associated with CDH, but none have previously been reported at or close to 17p11.2. We discuss candidate genes for the diaphragmatic defect in this patient. Our case demonstrates that it is important to consider the possibility of SMS in non-isolated cases of diaphragmatic hernia.

  19. TNF-α modulates genome-wide redistribution of ΔNp63α/TAp73 and NF-κB c-REL interactive binding on TP53 and AP-1 motifs to promote an oncogenic gene program in squamous cancer

    PubMed Central

    Si, Han; Lu, Hai; Yang, Xinping; Mattox, Austin; Jang, Minyoung; Bian, Yansong; Sano, Eleanor; Viadiu, Hector; Yan, Bin; Yau, Christina; Ng, Sam; Lee, Steven K.; Romano, Rose-Anne; Davis, Sean; Walker, Robert L.; Xiao, Wenming; Sun, Hongwei; Wei, Lai; Sinha, Satrajit; Benz, Christopher C; Stuart, Joshua M.; Meltzer, Paul S.; Van Waes, Carter; Chen, Zhong

    2016-01-01

    The Cancer Genome Atlas (TCGA) network study of 12 cancer types (PanCancer 12) revealed frequent mutation of TP53, and amplification and expression of related TP63 isoform ΔNp63 in squamous cancers. Further, aberrant expression of inflammatory genes and TP53/p63/p73 targets were detected in the PanCancer 12 project, reminiscent of gene programs co-modulated by cREL/ΔNp63/TAp73 transcription factors we uncovered in head and neck squamous cell carcinomas (HNSCC). However, how inflammatory gene signatures and cREL/p63/p73 targets are co-modulated genome-wide is unclear. Here, we examined how inflammatory factor TNF-α broadly modulates redistribution of cREL with ΔNp63α/TAp73 complexes and signatures genome-wide in the HNSCC model UM-SCC46 using chromatin immunoprecipitation sequencing (ChIP-seq). TNF-α enhanced genome-wide co-occupancy of cREL with ΔNp63α on TP53/p63 sites, while unexpectedly promoting redistribution of TAp73 from TP53 to Activator Protein-1 (AP-1) sites. cREL, ΔNp63α, and TAp73 binding and oligomerization on NF-κB, TP53 or AP-1 specific sequences were independently validated by ChIP-qPCR, oligonucleotide-binding assays, and analytical ultracentrifugation. Function of the binding activity was confirmed using TP53, AP-1, and NF-κB specific response elements, or p21, SERPINE1, and IL-6 promoter luciferase reporter activities. Concurrently, TNF-α regulated a broad gene network with co-binding activities for cREL, ΔNp63α, and TAp73 observed upon array profiling and RT-PCR. Overlapping target gene signatures were observed in squamous cancer subsets and in inflamed skin of transgenic mice overexpressing ΔNp63α. Furthermore, multiple target genes identified in this study were linked to TP63 and TP73 activity and increased gene expression in large squamous cancer samples from PanCancer 12 TCGA by CircleMap. PARADIGM inferred pathway analysis revealed the network connection of TP63 and NF-κB complexes through an AP-1 hub, further supporting

  20. Mammary analogue secretory carcinoma of salivary glands with high-grade transformation: report of 3 cases with the ETV6-NTRK3 gene fusion and analysis of TP53, β-catenin, EGFR, and CCND1 genes.

    PubMed

    Skálová, Alena; Vanecek, Tomas; Majewska, Hanna; Laco, Jan; Grossmann, Petr; Simpson, Roderick H W; Hauer, Lukas; Andrle, Pavel; Hosticka, Lubor; Branžovský, Jindrich; Michal, Michal

    2014-01-01

    Mammary analogue secretory carcinoma of salivary gland origin (MASC) is a recently described tumor resembling secretory carcinoma of the breast characterized by strong S-100 protein, mammaglobin, and vimentin immunoexpression and which harbors a t(12;15) (p13;q25) translocation resulting in ETV6-NTRK3 fusion product. Histologically, conventional MASC displays bland histomorphology and a lobulated growth pattern and is often composed of microcystic, tubular, and solid structures with abundant eosinophilic homogenous or bubbly secretions. Colloid-like secretory material stains positively for periodic acid-Schiff with and without diastase as well as for Alcian Blue. We present for the first time, 3 patients with MASC of the parotid gland in which high-grade (HG) transformation developed in each case characterized by an accelerated clinical course and poor outcome. The HG component revealed strong membrane staining for EGFR and β-catenin, cytoplasmic/nuclear staining for S-100 protein, and nuclear staining for cyclin-D1, whereas HER-2/neu was absent. Analysis for the presence of the ETV6-NTRK3 fusion transcript revealed positivity in both HG and low-grade component of MASC in 2 of the 3 studied cases. The tumor in case 2 was negative in both its elements for the t(12;15) translocation, but ETV6 gene rearrangement was detected in both components in all 3 cases. Analysis of TP53 and CTNNB1 gene mutations in the HG component of MASCs as well as detection of copy number aberration of EGFR and CCND1 gene did not harbor any abnormalities. All 3 patients with HG-transformed MASC died of disseminated disease within 2 to 6 years after diagnosis. Recognizing HG-transformed MASC and testing for ETV6 rearrangement may be of potential value in patient treatment, because the presence of the ETV6-NTRK3 translocation may represent a therapeutic target in MASC.

  1. Evaluation of Single Nucleotide Polymorphisms (SNPs) in the p53 Binding Protein 1 (TP53BP1) Gene in Breast Cancer Patients Treated With Breast-Conserving Surgery and Whole-Breast Irradiation (BCS + RT)

    SciTech Connect

    Haffty, Bruce G.; Goyal, Sharad; Kulkarni, Diptee; Green, Camille; Vazquez, Alexi; Schiff, Devora; Moran, Meena S.; Yang Qifeng; Ganesan, Shridar; Hirsfield, Kim M.

    2011-06-01

    Purpose: TP53BP1 is a key component of radiation-induced deoxyribonucleic acid damage repair. The purpose of this study was to evaluate the significance of a known common single nucleotide polymorphism in this gene (rs560191) in patients treated with breast-conserving surgery and whole-breast irradiation (BCS + RT). Methods and Materials: The population consisted of 176 premenopausal women treated with BCS + RT (median follow-up, 12 years). Genomic deoxyribonucleic acid was processed by use of TaqMan assays. Each allele for rs560191 was either C or G, so each patient was therefore classified as CC, CG, or GG. Patients were grouped as GG if they were homozygous for the variant G allele or CC-CG if they carried at least one copy of the common C allele (CC or CG). Results: Of the 176 women, 124 (71%) were CC-CG and 52 (29%) were GG. The mean age was 44 years for GG vs. 38 years for CC-CG (p < 0.001). GG was more common in African-American women than white women (69% vs. 13%, p < 0.001) and more commonly estrogen receptor negative (70% vs. 49%, p = 0.02). There were no significant correlations of rs560191 with other critical variables. Despite the fact that GG patients were older, the 10-year rate of local relapses was higher (22% for GG vs. 12% for CC-CG, p = 0.04). Conclusions: This novel avenue of investigation of polymorphisms in radiation repair/response genes in patients treated with BCS + RT suggests a correlation to local relapse. Additional evaluation is needed to assess the biological and functional significance of these single nucleotide polymorphisms, and larger confirmatory validation studies will be required to determine the clinical implications.

  2. Complex chromosome 17p rearrangements associated with low-copy repeats in two patients with congenital anomalies

    PubMed Central

    Vissers, L. E. L. M.; Stankiewicz, P.; Yatsenko, S. A.; Crawford, E.; Creswick, H.; Proud, V. K.; de Vries, B. B. A.; Pfundt, R.; Marcelis, C. L. M.; Zackowski, J.; Bi, W.; van Kessel, A. Geurts; Lupski, J. R.

    2007-01-01

    Recent molecular cytogenetic data have shown that the constitution of complex chromosome rearrangements (CCRs) may be more complicated than previously thought. The complicated nature of these rearrangements challenges the accurate delineation of the chromosomal breakpoints and mechanisms involved. Here, we report a molecular cytogenetic analysis of two patients with congenital anomalies and unbalanced de novo CCRs involving chromosome 17p using high-resolution array-based comparative genomic hybridization (array CGH) and fluorescent in situ hybridization (FISH). In the first patient, a 4-month-old boy with developmental delay, hypotonia, growth retardation, coronal synostosis, mild hypertelorism, and bilateral club feet, we found a duplication of the Charcot-Marie–Tooth disease type 1A and Smith-Magenis syndrome (SMS) chromosome regions, inverted insertion of the Miller-Dieker lissencephaly syndrome region into the SMS region, and two microdeletions including a terminal deletion of 17p. The latter, together with a duplication of 21q22.3-qter detected by array CGH, are likely the unbalanced product of a translocation t(17;21)(p13.3;q22.3). In the second patient, an 8-year-old girl with mental retardation, short stature, microcephaly and mild dysmorphic features, we identified four submicroscopic interspersed 17p duplications. All 17 breakpoints were examined in detail by FISH analysis. We found that four of the breakpoints mapped within known low-copy repeats (LCRs), including LCR17pA, middle SMS-REP/LCR17pB block, and LCR17pC. Our findings suggest that the LCR burden in proximal 17p may have stimulated the formation of these CCRs and, thus, that genome architectural features such as LCRs may have been instrumental in the generation of these CCRs. PMID:17457615

  3. Gender specific association of TP53 polymorphisms (EX4 215G>C Arg72Pro, IVS3+40-41ins16, and IVS6+62G>A), with risk of oral cancer subtypes and overall survival of the patients.

    PubMed

    Nagam, Srivani L S S; Katta, Saritha; Prasad, Vidudala V T S

    2017-03-01

    Reports on the association of TP53 polymorphisms with oral cancer are not only limited but also not specific to site and/or gender. Hence, we examined the effect of TP53 polymorphisms (EX4 215G>C, IVS3+40-41ins16 and IVS6+62G>A) on buccal mucosa cancer (BMC) and tongue cancer (TC) risk, survival of patients in relation to risk and clinical factors, gender wise (excepting for estimating hazards ratio [HR]), using Fisher's Exact Test, Kaplan-Meier analysis, and Cox-proportional hazards models. The exonic polymorphism increased BMC and TC risk in males by 2-4-fold. The IVS3+40-41ins16 was protective against BMC and TC in both genders, whereas IVS6+62G>A protected only males against TC. Genotype combinations and haplotypes which altered the risk of cancers in males and females were different. TC males, aged 40-44 years and females, aged 55-59 years survived better than BMC patients. The IVS3+40-41ins16 polymorphism differentially impacted survival of female patients exposed to tobacco. TC patients with EX4 215GC with lymphovascular spread (LVS) and metastasis exhibited higher HR while, patients with EX4 215CC and perineural invasion (PNI) showed lower HR. Impact of the intronic variants along with clinical parameters on survival and HR estimates varied between BMC and TC. Our bioinformatics analysis revealed the presence of CTCF binding site within TP53 gene. In conclusion, the polymorphisms altered risk and survival of BMC and TC in a gender specific manner, which varied with mode of tobacco and/or alcohol use. The current study, therefore underscores strong need for research, stratified by tumor site and gender. © 2016 Wiley Periodicals, Inc.

  4. Penicillium chrysogenum Pex14/17p--a novel component of the peroxisomal membrane that is important for penicillin production.

    PubMed

    Opaliński, Lukasz; Kiel, Jan A K W; Homan, Tim G; Veenhuis, Marten; van der Klei, Ida J

    2010-08-01

    By genome analysis, we previously identified Pex14/17p as a putative novel peroxin of Penicillium chrysogenum. Here, we show that Pex14/17p is a component of the peroxisomal membrane that is essential for efficient peroxisomal targeting signal 1 and peroxisomal targeting signal 2 matrix protein import, implying that the protein is indeed a genuine peroxin. Additionally, a PEX14/17 deletion strain is affected in conidiospore formation. Pex14/17p has properties of both Pex14p and Pex17p, in that the N-terminus of this protein is similar to the highly conserved Pex5p-binding region present in the N-termini of Pex14p proteins, whereas its C-terminus shows weak similarity to yeast Pex17p proteins. We have identified a novel motif in both Pex17p and Pex14/17p that is absent in Pex14p. We show that an N-terminally truncated, but not a C-terminally truncated, Pex14/17p is able to complement both the matrix protein import and sporulation defects of a Delta pex14/17 strain, implying that it is the Pex17p-related portion of the protein that is crucial for its function as a peroxin. Possibly, this compensates for the fact that P. chrysogenum lacks an authenthic Pex17p. We also show that, in P. chrysogenum, Pex14/17p plays a role in making the penicillin biosynthesis process more efficient.

  5. EXTINCTION IN THE COMA OF COMET 17P/HOLMES

    SciTech Connect

    Lacerda, Pedro; Jewitt, David

    2012-11-20

    On 2007 October 29, the outbursting comet 17P/Holmes passed within 0.''79 of a background star. We recorded the event using optical, narrowband photometry and detect a 3%-4% dip in stellar brightness bracketing the time of closest approach to the comet nucleus. The detected dimming implies an optical depth {tau} Almost-Equal-To 0.04 at 1.''5 from the nucleus and an optical depth toward the nucleus center {tau}{sub n} < 13.3. At the time of our observations, the coma was optically thick only within {rho} {approx}< 0.''01 from the nucleus. By combining the measured extinction and the scattered light from the coma, we estimate a dust red albedo p{sub d} = 0.006 {+-} 0.002 at {alpha} = 16 Degree-Sign phase angle. Our measurements place the most stringent constraints on the extinction optical depth of any cometary coma.

  6. Diagnosing Smith-Magenis syndrome and duplication 17p11.2 syndrome by RAI1 gene copy number variation using quantitative real-time PCR.

    PubMed

    Truong, Hoa T; Solaymani-Kohal, Sara; Baker, Kevin R; Girirajan, Santhosh; Williams, Stephen R; Vlangos, Christopher N; Smith, Ann C M; Bunyan, David J; Roffey, Paul E; Blanchard, Christopher L; Elsea, Sarah H

    2008-03-01

    Smith-Magenis syndrome (SMS) and duplication 17p11.2 (dup17p11.2) syndrome are multiple congenital anomalies/mental retardation disorders resulting from either a deletion or duplication of the 17p11.2 region, respectively. The retinoic acid induced 1 (RAI1) gene is the causative gene for SMS and is included in the 17p11.2 region of dup17p11.2 syndrome. Currently SMS and dup17p11.2 syndrome are diagnosed using a combination of clinically recognized phenotypes and molecular cytogenetic analyses such as fluorescent in situ hybridization (FISH). However, these methods have proven to be highly expensive, time consuming, and dependent upon the low resolving capabilities of the assay. To address the need for improved diagnostic methods for SMS and dup17p11.2 syndrome, we designed a quantitative real-time PCR (Q-PCR) assay that measures RAI1 copy number using the comparative C(t) method, DeltaDeltaC(t). We tested our assay with samples blinded to their previous SMS or dup17p11.2 syndrome status. In all cases, we were able to determine RAI1 copy number status and render a correct diagnosis accordingly. We validated these results by both FISH and multiplex ligation-dependent probe amplification (MLPA). We conclude that Q-PCR is an accurate, reproducible, low-cost, and reliable assay that can be employed for routine use in SMS and dup17p11.2 diagnosis.

  7. Apparent mosaicism for del(17)(p11.2) ruled out by fluorescence in situ hybridization in a Smith-Magenis syndrome patient

    SciTech Connect

    Juyal, R.C.; Shaffer, L.G.; Lupski, J.R.; Greenberg, F.; Baldini, A.; Patel, P.I.

    1995-11-20

    Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation syndrome typically associated with a deletion of band p11.2 of human chromosome 17. Finucane et al. reported a 14-year-old boy with mild physical and behavior manifestations of SMS. No evidence for deletion was initially evident in 20 peripheral blood lymphocytes examined at 850 band level of resolution. Examination of metaphase chromosomes of skin fibroblasts showed a deletion of 17p11.2 in 25/25 cells examined which was consistent with the patient`s clinical manifestations of SMS. Subsequent examination of 25 cells from peripheral blood cultures indicated that 11% of cells harbored a deletion at 17p11.2, thus suggesting a mosaicism for the deletion. A third study of 20 peripheral blood lymphocytes examined at 550-850 band length resolution in a different laboratory, indicated that 13 cells had no apparent deletion, 4 cells had an apparent deletion and 3 cells were questionable. 7 refs.

  8. Diffuse large B-cell lymphomas with CDKN2A deletion have a distinct gene expression signature and a poor prognosis under R-CHOP treatment: a GELA study.

    PubMed

    Jardin, Fabrice; Jais, Jean-Philippe; Molina, Thierry-Jo; Parmentier, Françoise; Picquenot, Jean-Michel; Ruminy, Philippe; Tilly, Hervé; Bastard, Christian; Salles, Gilles-André; Feugier, Pierre; Thieblemont, Catherine; Gisselbrecht, Christian; de Reynies, Aurelien; Coiffier, Bertrand; Haioun, Corinne; Leroy, Karen

    2010-08-19

    Genomic alterations play a crucial role in the development and progression of diffuse large B-cell lymphomas (DLBCLs). We determined gene copy number alterations (GCNAs) of TP53, CDKN2A, CDKN1B, BCL2, MYC, REL, and RB1 with a single polymerase chain reaction (PCR) assay (quantitative multiplex PCR of short fragments [QMPSF]) in a cohort of 114 patients with DLBCL to assess their prognostic value and relationship with the gene expression profile. Losses of TP53 and CDKN2A, observed in 8% and 35% of patients, respectively, were significantly associated with a shorter survival after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment, independently of the International Prognostic Index and of the cell of origin. Analysis of the 9p21 genomic region indicated that transcripts encoding p14ARF and p16INK4A were both disrupted in most patients with CDKN2A deletion. These patients predominantly had an activated B-cell profile and showed a specific gene expression signature, characterized by dysregulation of the RB/E2F pathway, activation of cellular metabolism, and decreased immune and inflammatory responses. These features may constitute the molecular basis sustaining the unfavorable outcome and chemoresistance of this DLBCL subgroup. Detection of TP53 and CDKN2A loss by QMPSF is a powerful tool that could be used for patient stratification in future clinical trials.

  9. Lingering grains of truth around comet 17P/HOLMES

    SciTech Connect

    Stevenson, R.; Bauer, J. M.; Mainzer, A. K.; Masiero, J. R.; Kramer, E. A.; Grav, T.

    2014-06-01

    Comet 17P/Holmes underwent a massive outburst in 2007 October, brightening by a factor of almost a million in under 48 hr. We used infrared images taken by the Wide-Field Infrared Survey Explorer mission to characterize the comet as it appeared at a heliocentric distance of 5.1 AU almost 3 yr after the outburst. The comet appeared to be active with a coma and dust trail along the orbital plane. We constrained the diameter, albedo, and beaming parameter of the nucleus to 4.135 ± 0.610 km, 0.03 ± 0.01, and 1.03 ± 0.21, respectively. The properties of the nucleus are consistent with those of other Jupiter family comets. The best-fit temperature of the coma was 134 ± 11 K, slightly higher than the blackbody temperature at that heliocentric distance. Using Finson-Probstein modeling, we found that the morphology of the trail was consistent with ejection during the 2007 outburst and was made up of dust grains between 250 μm and a few cm in radius. The trail mass was ∼1.2-5.3 × 10{sup 10} kg.

  10. Immune complex-mediated autoimmunity in a patient With Smith-Magenis syndrome (del 17p11.2).

    PubMed

    Yang, Jianying; Chandrasekharappa, Settara C; Vilboux, Thierry; Smith, Ann C M; Peterson, Erik J

    2014-08-01

    Smith-Magenis syndrome (SMS) is a sporadic congenital disorder involving multiple organ systems caused by chromosome 17p11.2 deletions. Smith-Magenis syndrome features craniofacial and skeletal anomalies, cognitive impairment, and neurobehavioral abnormalities. In addition, some SMS patients may exhibit hypogammaglobulinemia. We report the first case of SMS-associated autoimmunity in a woman who presented with adult onset of multiple autoimmune disorders, including systemic lupus erythematosus, antiphospholipid antibody syndrome, and autoimmune hepatitis. Molecular analysis using single-nucleotide polymorphism array confirmed a de novo 3.8-Mb deletion (breakpoints, chr17: 16,660,721-20,417,975), resulting in haploinsufficiency for TACI (transmembrane activator and CAML interactor). Our data are consistent with potential loss of function for the BAFF (B cell-activating factor) receptor TACI as a contributing factor to human autoimmune phenomena.

  11. Cloning of a human ortholog (RPH3AL) of (RNO)Rph3al from a candidate 17p13.3 medulloblastoma tumor suppressor locus.

    PubMed

    Smith, J S; Tachibana, I; Allen, C; Chiappa, S A; Lee, H K; McIver, B; Jenkins, R B; Raffel, C

    1999-07-01

    Allelic loss of 17p13.3 is observed in approximately 40% of medulloblastomas, suggesting the presence of a tumor suppressor gene in this region. Deletion mapping has defined a region of common loss flanking the telomeric marker D17S34, and a recent report delineated a 9-kb homozygous deletion within the D17S34 locus in one such tumor. Using cDNA selection, we have identified a transcript spanning this deletion, designated (HSA)RPH3AL (rabphillin-3A-like), based on its 77% overall amino acid identity with a recently cloned rat gene, (RNO)Rph3al (originally termed Noc2), a gene putatively involved in regulated endocrine exocytosis through its interactions with the cytoskeleton. We determined the exon-intron boundaries of RPH3AL and screened the coding region for mutations by direct sequencing in DNA extracted from 33 tumor samples with allelic loss of 17p13, including 10 medulloblastoma, 14 follicular thyroid cancer (FTC), and 9 ovarian cancer specimens. No mutations were identified. Thus, despite its location in a homozygously deleted 17p13.3 locus, it is unlikely that RPH3AL is a gene involved in the oncogenesis of medulloblastoma, FTC, or ovarian cancer.

  12. Diagnostic FISH probes for del(17)(p11.2p11.2) associated with Smith-Magenis syndrome should contain the RAI1 gene.

    PubMed

    Vlangos, Christopher N; Wilson, Meredith; Blancato, Jan; Smith, Ann C M; Elsea, Sarah H

    2005-01-30

    Smith-Magenis syndrome (SMS) is a mental retardation syndrome with distinctive behavioral characteristics, dysmorphic features, and congenital anomalies usually associated with an interstitial deletion of chromosome 17p11.2. While high quality G-banding will identify most SMS patients, fluorescent in situ hybridization (FISH) is the recommended test for confirmation of an SMS diagnosis. Recently, haploinsufficiency of the RAI1 gene due to deletion or mutation was determined to be the likely cause of SMS. All diagnostic FISH probes available commercially contain the FLII gene and are approximately 580 kb centromeric to RAI1. We present two patients with SMS who have interstitial deletions at 17p11.2 but are not deleted for currently available commercial FISH probes that include FLII; both patients have deletions that are demonstrated with probes containing the RAI1 gene. We recommend that for diagnostic accuracy, all future FISH tests for SMS be performed with probes containing the RAI1 gene, as some atypical deletions in the region critical to the SMS phenotype will otherwise be missed.

  13. Water outburst activity in Comet 17P/Holmes

    NASA Astrophysics Data System (ADS)

    de Almeida, Amaury A.; Boice, Daniel C.; Picazzio, Enos; Huebner, Walter F.

    2016-08-01

    Cometary outbursts are sporadic events whose mechanisms are not well known where the activity and consequently the brightness can increase hundreds of thousands of times within a few hours to several days. This indicates a dramatic departure from thermal equilibrium between the comet and interplanetary space and is usually documented by ;light curves;. In a typical cometary outburst, the brightness can increase by 2-5 magnitudes (Whitney, 1955; Gronkowski and Wesolowski, 2015). In only 42 h, Comet 17P/Holmes was reported to brighten from a magnitude of about 17 to about 2.4 at the height of the burst, representing the largest known outburst by a comet. We present the H2O production rate of Holmes for the megaburst occurring between 23 and 24 October 2007. For this, we selected more than 1900 photometric observations from the International Comet Quarterly Archive of Photometric Data (Green, 2007) and use the Semi-Empirical Method of Visual Magnitudes (SEMVM; de Almeida et al., 2007). We clearly show that the comet achieved an average water production rate of 5 × 1029 molecules s-1, corresponding to a water gas loss rate of 14,960 kg s-1, in very good agreement with Schleicher (2009) who derived the water production rate using OH measurements on 1 Nov 2007 (about 8 days after the outburst). We discuss possible physical processes that might cause cometary outbursts and propose a new qualitative mechanism, the Pressurized Obstructed Pore (POP) model. The key feature of POP is the recrystallization of water in the surface regolith as it cools, plugging pores and blocking the release of subsurface gas flow. As the interior gas pressure increases, an outburst is eventually triggered. POP is consistent with current observations and can be tested in the future with observations (e.g., Rosetta in situ measurements) and detailed simulations.

  14. Smith-Magenis syndrome and Moyamoya disease in a patient with del(17)(p11.2p13.1).

    PubMed

    Girirajan, Santhosh; Mendoza-Londono, Roberto; Vlangos, Christopher N; Dupuis, Lucie; Nowak, Norma J; Bunyan, David J; Hatchwell, Eli; Elsea, Sarah H

    2007-05-01

    Chromosomal rearrangements causing microdeletions and microduplications are a major cause of congenital malformation and mental retardation. Because they are not visible by routine chromosome analysis, high resolution whole-genome technologies are required for the detection and diagnosis of small chromosomal abnormalities. Recently, array-comparative genomic hybridization (aCGH) and multiplex ligation-dependent probe amplification (MLPA) have been useful tools for the identification and mapping of deletions and duplications at higher resolution and throughput. Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation syndrome caused by deletion or mutation of the retinoic acid induced 1 (RAI1) gene and is often associated with a chromosome 17p11.2 deletion. We report here on the clinical and molecular analysis of a 10-year-old girl with SMS and moyamoya disease (occlusion of the circle of Willis). We have employed a combination of aCGH, FISH, and MLPA to characterize an approximately 6.3 Mb deletion spanning chromosome region 17p11.2-p13.1 in this patient, with the proximal breakpoint within the RAI1 gene. Further, investigation of the genomic architecture at the breakpoint intervals of this large deletion documented the presence of palindromic repeat elements that could potentially form recombination substrates leading to unequal crossover.

  15. Clinical and molecular characterization of a combined 17p13.3 microdeletion with partial monosomy 21q21.3 in a 26-year-old man.

    PubMed

    Hannachi, H; Mougou-Zerelli, S; BenAbdallah, I; Mama, N; Hamdi, I; Labalme, A; Elghezal, H; Sanlaville, D; Saad, A

    2011-01-01

    We led a clinical and molecular characterization of a patient with mild mental delay and dysmorphic features initially referred for cytogenetic exploration of an azoospermia. We employed FISH and array CGH techniques for a better definition and refinement of a double chromosome aberration associating a 17p microdeletion with partial monosomy 21q due to 1:3 meiotic segregation of a maternal reciprocal translocation t(17;21)(p13.3;q21.2) revealed after banding analysis. Brain MRI depicted partial callosal and mild diffuse cerebral atrophies, but without expected signs of lissencephaly. The patient's karyotype formula was: 45,XY,der(17)t(17;21)(p13.3;q21.2)mat,-21. FISH study confirmed these rearrangements and array CGH analysis estimated the loss sizes to at least 635 kb on chromosome 17 and to 15.6 Mb on chromosome 21. The absence of lissencephaly and major brain malformations often associated with 17p terminal deletions could be attributed to the retention of PAFAH1B1, YWHAE and CRK genes. Dysmorphic features, moderate mental impairment and minor brain malformations could result from the 21q monosomy and particularly the partial deletion of the APP-SOD1 region. Azoospermia should result from gamete apoptosis induced by a control mechanism triggered in response to chromosome imbalances. Our study provides an additional case for better understanding and delineating both 17p and 21q deletions.

  16. Epilepsy and chromosomal rearrangements in Smith-Magenis Syndrome [del(17)(p11.2p11.2)].

    PubMed

    Goldman, Alica M; Potocki, Lorraine; Walz, Katherina; Lynch, Jennifer K; Glaze, Daniel G; Lupski, James R; Noebels, Jeffrey L

    2006-02-01

    Smith-Magenis syndrome is a multiple congenital anomalies/mental retardation syndrome associated with a heterozygous deletion of chromosome 17p11.2. Seizures have not been formally studied in this population. Our objectives were to estimate the prevalence of seizures and electroencephalographic (EEG) epileptiform abnormalities in patients with Smith-Magenis syndrome with defined chromosomal rearrangements and to describe the spectrum of abnormal EEG patterns. Prolonged video-EEGs were obtained in 60 patients. Eighteen percent of patients reported a seizure history; however, abnormal EEGs were identified in 31 of the 60 subjects and 27 of 31 were epileptiform. Generalized epileptiform patterns were the most common (73%). Most patients with either small or large deletions had an abnormal EEG (83%; 75%) in contrast to those with a common deletion (49%). Our results indicate that epileptiform EEG abnormalities are frequent in patients with Smith-Magenis syndrome. Considering that close to one third of individuals with Smith-Magenis syndrome with epileptiform abnormalities also had a history of clinical seizures, cortical hyperexcitability and epilepsy should be considered an important component of the Smith-Magenis syndrome clinical phenotype.

  17. Molecular genetic analysis of the 17p11.2 region in patients with hereditary neuropathy with liability to pressure palsies (HNPP).

    PubMed

    Timmerman, V; Löfgren, A; Le Guern, E; Liang, P; De Jonghe, P; Martin, J J; Verhalle, D; Robberecht, W; Gouider, R; Brice, A; Van Broeckhoven, C

    1996-01-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is in most cases associated with an interstitial deletion of the same 1.5-Mb region at 17p11.2 that is duplicated in Charcot-Marie-Tooth type 1A (CMT1A) patients. Unequal crossing-over following misalignment at flanking repeat sequences (CMT1A-REP), either leads to tandem duplication in CMT1A patients or deletion in HNPP patients. With the use of polymorphic DNA markers located within the CMT1A/HNPP duplication/deletion region we detected the HNPP deletion in 16 unrelated HNPP patients, 11 of Belgian and 5 of French origin. In all cases, the 1.5-Mb size of the HNPP deletion was confirmed by EcoRI dosage analysis using a CMT1A-REP probe. In the 16 HNPP patients, the same 370/320-kb EagI deletion-junction fragments were detected with pulsed field gel electrophoresis (PFGE), while in CMT1A patients, a 150-kb EagI duplication-junction fragment was seen. Thus, PFGE analysis of EagI-digested DNA with a CMT1A-REP probe allows direct detection of the HNPP deletion or the CMT1A duplication for DNA diagnostic purposes.

  18. Neurologic and developmental features of the Smith-Magenis syndrome (del 17p11.2).

    PubMed

    Gropman, Andrea L; Duncan, Wallace C; Smith, Ann C M

    2006-05-01

    The Smith-Magenis syndrome is a rare, complex multisystemic disorder featuring, mental retardation and multiple congenital anomalies caused by a heterozygous interstitial deletion of chromosome 17p11.2. The phenotype of Smith-Magenis syndrome is characterized by a distinct pattern of features including infantile hypotonia, generalized complacency and lethargy in infancy, minor skeletal (brachycephaly, brachydactyly) and craniofacial features, ocular abnormalities, middle ear and laryngeal abnormalities including hoarse voice, as well as marked early expressive speech and language delays, psychomotor and growth retardation, and a 24-hour sleep disturbance. A striking neurobehavioral pattern of stereotypies, hyperactivity, polyembolokoilamania, onychotillomania, maladaptive and self-injurious and aggressive behavior is observed with increasing age. The diagnosis of Smith-Magenis syndrome is based upon the clinical recognition of a constellation of physical, developmental, and behavioral features in combination with a sleep disorder characterized by inverted circadian rhythm of melatonin secretion. Many of the features of Smith-Magenis syndrome are subtle in infancy and early childhood, and become more recognizable with advancing age. Infants are described as looking "cherubic" with a Down syndrome-like appearance, whereas with age the facial appearance is that of relative prognathism. Early diagnosis requires awareness of the often subtle clinical and neurobehavioral phenotype of the infant period. Speech delay with or without hearing loss is common. Most children are diagnosed in mid-childhood when the features of the disorder are most recognizable and striking. While improvements in cytogenetic analysis help to bring cases to clinical recognition at an earlier age, this review seeks to increase clinical awareness about Smith-Magenis syndrome by presenting the salient features observed at different ages including descriptions of the neurologic and behavioral

  19. Cancer of the ampulla of Vater: chromosome 17p allelic loss is associated with poor prognosis

    PubMed Central

    Scarpa, A; Di, P; Talamini, G; Falconi, M; Lemoine, N; Iacono, C; Achille, A; Baron, A; Zamboni, G

    2000-01-01

    BACKGROUND—Cancer of the ampulla of Vater kills 60% of affected patients. Local spread of the tumour (T stage) is the only reliable prognostic factor. Nevertheless, any cancer stage includes long term survivors and patients dying from the disease. The molecular anomalies involved in this process have the potential to serve as additional prognostic markers.
AIM—To evaluate if allelic losses (LOH) of chromosomes 17p and 18q may be of prognostic value in multivariate survival analysis.
METHODS—We examined 53 ampullary cancers for chromosome 17p and 18q LOH using microsatellite markers and DNA from paraffin embedded tumours. All patients were treated by surgery alone (pancreaticoduodenectomy). Multivariate survival analysis included age, sex, tumour size, macroscopic appearance, grade of differentiation, T stage, lymph node metastasis, and chromosome 17p and 18q status.
RESULTS—Chromosome 17p and 18q LOH were detected in 28 (53%) and 18 (34%) cancers, respectively. Multivariate survival analysis indicated chromosome 17p status as an independent prognostic factor together with T stage. The five year survival for chromosome 17p retention and 17p loss was 80% and 7%, respectively. The risk of death from cancer within the five year follow up period for patients with cancers harbouring chromosome 17p LOH was 11 times higher than that of patients with cancers retaining chromosome 17p (p<0.0001), regardless of the tumour stage at diagnosis.
CONCLUSIONS—Chromosome 17p status is an independent prognostic factor among ampullary cancers at the same stage. The combined use of T stage and chromosome 17p status may help in deciding whether ampullary cancer patients require additional therapy other than surgery alone.


Keywords: ampulla of Vater; cancer; loss of heterozygosity; microsatellites; allelotyping; microsatellite instability PMID:10807898

  20. Mosaic microdeletion of 17p11.2-p12 and duplication of 17q22-q24 in a girl with Smith-Magenis phenotype and peripheral neuropathy.

    PubMed

    Goh, Elaine Suk-Ying; Banwell, Brenda; Stavropoulos, Dimitri James; Shago, Mary; Yoon, Grace

    2014-03-01

    We report on a girl with a de novo mosaic derivative chromosome 17 involving a 7.4 Mb deletion of chromosome region 17p11.2 to 17p12 and a duplication of a 12.35 Mb region at 17q22 to 17q24. She was ascertained because of developmental delay, peripheral neuropathy, brachydactyly and minor anomalies. The derivative chromosome was present in approximately 12% of lymphocytes based on FISH studies, and was detected by array comparative genomic hybridization. To our knowledge, this is the third case of mosaicism involving deletion of the 17p11.2 region and the lowest level of mosaicism reported in a patient with Smith-Magenis syndrome (SMS).

  1. 17 CFR 170.10 - Proficiency examinations (sections 4p and 17(p) of the Act).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Proficiency examinations (sections 4p and 17(p) of the Act). 170.10 Section 170.10 Commodity and Securities Exchanges COMMODITY... examinations (sections 4p and 17(p) of the Act). A futures association may prescribe different...

  2. 17 CFR 170.10 - Proficiency examinations (sections 4p and 17(p) of the Act).

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 2 2014-04-01 2014-04-01 false Proficiency examinations (sections 4p and 17(p) of the Act). 170.10 Section 170.10 Commodity and Securities Exchanges COMMODITY... Proficiency examinations (sections 4p and 17(p) of the Act). A futures association may prescribe...

  3. 17 CFR 170.10 - Proficiency examinations (sections 4p and 17(p) of the Act).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 1 2011-04-01 2011-04-01 false Proficiency examinations (sections 4p and 17(p) of the Act). 170.10 Section 170.10 Commodity and Securities Exchanges COMMODITY... examinations (sections 4p and 17(p) of the Act). A futures association may prescribe different...

  4. 17 CFR 170.10 - Proficiency examinations (sections 4p and 17(p) of the Act).

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 1 2012-04-01 2012-04-01 false Proficiency examinations (sections 4p and 17(p) of the Act). 170.10 Section 170.10 Commodity and Securities Exchanges COMMODITY... examinations (sections 4p and 17(p) of the Act). A futures association may prescribe different...

  5. 17 CFR 170.10 - Proficiency examinations (sections 4p and 17(p) of the Act).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 1 2013-04-01 2013-04-01 false Proficiency examinations (sections 4p and 17(p) of the Act). 170.10 Section 170.10 Commodity and Securities Exchanges COMMODITY... examinations (sections 4p and 17(p) of the Act). A futures association may prescribe different...

  6. MicroRNAs/TP53 feedback circuitry in glioblastoma multiforme

    PubMed Central

    Suh, Sung-Suk; Yoo, Ji Young; Nuovo, Gerard J.; Jeon, Young-Jun; Kim, Seokho; Lee, Tae Jin; Kim, Taewan; Bakàcs, Arianna; Alder, Hansjuerg; Kaur, Balveen; Aqeilan, Rami I.; Pichiorri, Flavia; Croce, Carlo M.

    2012-01-01

    MicroRNAs (miRNAs) are increasingly implicated in regulating cancer initiation and progression. In this study, two miRNAs, miR-25 and -32, are identified as p53-repressed miRNAs by p53-dependent negative regulation of their transcriptional regulators, E2F1 and MYC. However, miR-25 and -32 result in p53 accumulation by directly targeting Mdm2 and TSC1, which are negative regulators of p53 and the mTOR (mammalian target of rapamycin) pathway, respectively, leading to inhibition of cellular proliferation through cell cycle arrest. Thus, there is a recurrent autoregulatory circuit involving expression of p53, E2F1, and MYC to regulate the expression of miR-25 and -32, which are miRNAs that, in turn, control p53 accumulation. Significantly, overexpression of transfected miR-25 and -32 in glioblastoma multiforme cells inhibited growth of the glioblastoma multiforme cells in mouse brain in vivo. The results define miR-25 and -32 as positive regulators of p53, underscoring their role in tumorigenesis in glioblastoma. PMID:22431589

  7. MicroRNAs/TP53 feedback circuitry in glioblastoma multiforme.

    PubMed

    Suh, Sung-Suk; Yoo, Ji Young; Nuovo, Gerard J; Jeon, Young-Jun; Kim, Seokho; Lee, Tae Jin; Kim, Taewan; Bakàcs, Arianna; Alder, Hansjuerg; Kaur, Balveen; Aqeilan, Rami I; Pichiorri, Flavia; Croce, Carlo M

    2012-04-03

    MicroRNAs (miRNAs) are increasingly implicated in regulating cancer initiation and progression. In this study, two miRNAs, miR-25 and -32, are identified as p53-repressed miRNAs by p53-dependent negative regulation of their transcriptional regulators, E2F1 and MYC. However, miR-25 and -32 result in p53 accumulation by directly targeting Mdm2 and TSC1, which are negative regulators of p53 and the mTOR (mammalian target of rapamycin) pathway, respectively, leading to inhibition of cellular proliferation through cell cycle arrest. Thus, there is a recurrent autoregulatory circuit involving expression of p53, E2F1, and MYC to regulate the expression of miR-25 and -32, which are miRNAs that, in turn, control p53 accumulation. Significantly, overexpression of transfected miR-25 and -32 in glioblastoma multiforme cells inhibited growth of the glioblastoma multiforme cells in mouse brain in vivo. The results define miR-25 and -32 as positive regulators of p53, underscoring their role in tumorigenesis in glioblastoma.

  8. Role of additional chromosomal changes in the prognostic value of t(4;14) and del(17p) in multiple myeloma: the IFM experience

    PubMed Central

    Hebraud, Benjamin; Magrangeas, Florence; Cleynen, Alice; Lauwers-Cances, Valerie; Chretien, Marie-Lorraine; Hulin, Cyrille; Leleu, Xavier; Yon, Edwige; Marit, Gerald; Karlin, Lionel; Roussel, Murielle; Stoppa, Anne-Marie; Belhadj, Karim; Voillat, Laurent; Garderet, Laurent; Macro, Margaret; Caillot, Denis; Mohty, Mohamad; Facon, Thierry; Moreau, Philippe; Attal, Michel; Munshi, Nikhil; Corre, Jill; Minvielle, Stephane

    2015-01-01

    In multiple myeloma, cytogenetic changes are important predictors of patient outcome. In this setting, the most important changes are deletion 17p, del(17p), and translocation of chromosomes 4 and 14, t(4;14), conferring a poor outcome. However, a certain degree of heterogeneity is observed in the survival of these high-risk patients. We hypothesized that other chromosomal changes may impact the outcome. We retrospectively analyzed a large series of 242 patients displaying either t(4;14) (157 patients) or del(17p) (110 patients), 25 patients presenting both abnormalities, using single nucleotide polymorphism array. In patients with t(4;14), del(1p32), del22q, and >30 chromosomal structural changes negatively impacted progression-free survival (PFS). For overall survival (OS), del(13q14), del(1p32), and the number of chromosomal structural changes worsened the prognosis of patients. For patients with del(17p), del6q worsened the prognosis of patients, whereas trisomy 15 and monosomy 14 were found to have a protective effect on PFS. For OS, del(1p32) worsened the prognosis of patients, whereas having >8 numerical changes was found to have a protective effect on survival. This study, which is the largest series of high-risk patients analyzed with the most modern genomic technique, identified 1 main factor negatively impacting survival: del(1p32). PMID:25636340

  9. The brain finger protein gene (ZNF179), a member of the RING finger family, maps within the Smith-Magenis syndrome region at 17p11.2

    SciTech Connect

    Kimura, Toshiyuki; Arakawa, Yoshiki; Inazawa, Johji

    1997-03-31

    Smith-Magenis syndrome (SAIS) is caused by a microdeletion of 17p11.2 and comprises developmental and growth delay, facial abnormalities, unusual behavior and sleep problems. This phenotype may be due to haploinsufficiency of several contiguous genes. The human brain finger protein gene (ZNF179), a member of the RING finger protein family, has been isolated and mapped to l7p11.2. FISH analyses of metaphase or interphase chromosomes of 6 patients with SMS show that ZNF179 was deleted in one of the 2 homologs (17p11.2), indicating a possible association of the defect of this gene with the pathogenesis of SMS. Furthermore, using a prophase FISH ordering system, we sublocalized ZNF179 proximally to LLGL which lies on the critical region for SMS. 27 refs., 2 figs.

  10. Screening of the 17p11.2--p12 region in a large cohort of patients with Charcot-Marie-Tooth (CMT) disease or hereditary neuropathy with liability to pressure palsies (HNPP).

    PubMed

    Kabzinska, D; Pierscinska, J; Kochanski, A

    2009-01-01

    Within the last decade, numerous methods have been applied to detect the most common mutation in patients affected with Charcot-Marie-Tooth (CMT) disease, i.e. submicroscopic duplication in the 17p11.2--p12 region. In 1993, another neuropathy - known as hereditary neuropathy with liability to pressure palsies (HNPP) - has been shown to be caused by a 17p11.2--p12 deletion. Historically, Southern blot analysis was the first approach to identify CMT1A duplication or HNPP deletion. This time- and labor-consuming method requires prior selection of DNA samples. In fact, only CMT patients affected with the demyelinating form of CMT1 have been screened for CMT1A duplication. After the 17p11.2--p12 duplication was identified in the CMT1 families, subsequent studies revealed additional axonal features in the patients harboring the 17p11.2--p12 duplication. Thus it seems reasonable to test all patients affected with CMT for the presence of the 17p11.2--p12 duplication. To evaluate the utility of real-time polymerase chain reaction (Q-PCR) and restriction fragment length polymorphism PCR (RFLP-PCR), we screened a large group of 179 families with the diagnosis of CMT/HNPP for the presence of the 17p11.2--p12 duplication/deletion. Due to a high frequency of CMT1A duplication in familial cases of CMT, we propose (in contrast to the previous studies) to perform Q-PCR analysis in all patients diagnosed with CMT.

  11. Microdeletion on 17p11.2 in a Smith-Magenis syndrome patient with mental retardation and congenital heart defect: first report from China.

    PubMed

    Huang, C; Yang, Y-F; Zhang, H; Xie, L; Chen, J-L; Wang, J; Tan, Z-P; Luo, H

    2012-08-13

    Smith-Magenis syndrome (SMS) is a rare syndrome with multiple congenital malformations, including development and mental retardation, behavioral problems and a distinct facial appearance. SMS is caused by haploinsufficiency of RAI1 (deletion or mutation of RAI1). We describe an eight-year-old female Chinese patient with multiple malformations, congenital heart defect, mental retardation, and behavioral problems (self hugging, sleeping disturbance). High-resolution genome wide single nucleotide polymorphism array revealed a 3.7-Mb deletion in chromosome region 17p11.2. This chromosome region contains RAI1, a critical gene involved in SMS. To the best of our knowledge, this is the first report of an SMS patient in mainland China.

  12. 40 CFR 401.17 - pH Effluent limitations under continuous monitoring.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 29 2011-07-01 2009-07-01 true pH Effluent limitations under continuous monitoring. 401.17 Section 401.17 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) EFFLUENT GUIDELINES AND STANDARDS GENERAL PROVISIONS § 401.17 pH Effluent limitations...

  13. 40 CFR 401.17 - pH Effluent limitations under continuous monitoring.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 30 2013-07-01 2012-07-01 true pH Effluent limitations under... (CONTINUED) EFFLUENT GUIDELINES AND STANDARDS GENERAL PROVISIONS § 401.17 pH Effluent limitations under continuous monitoring. (a) Where a permittee continuously measures the pH of wastewater pursuant to...

  14. 40 CFR 401.17 - pH Effluent limitations under continuous monitoring.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 29 2014-07-01 2012-07-01 true pH Effluent limitations under... (CONTINUED) EFFLUENT GUIDELINES AND STANDARDS GENERAL PROVISIONS § 401.17 pH Effluent limitations under continuous monitoring. (a) Where a permittee continuously measures the pH of wastewater pursuant to...

  15. 40 CFR 401.17 - pH Effluent limitations under continuous monitoring.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 30 2012-07-01 2012-07-01 false pH Effluent limitations under... (CONTINUED) EFFLUENT GUIDELINES AND STANDARDS GENERAL PROVISIONS § 401.17 pH Effluent limitations under continuous monitoring. (a) Where a permittee continuously measures the pH of wastewater pursuant to...

  16. 40 CFR 401.17 - pH Effluent limitations under continuous monitoring.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 28 2010-07-01 2010-07-01 true pH Effluent limitations under... (CONTINUED) EFFLUENT GUIDELINES AND STANDARDS GENERAL PROVISIONS § 401.17 pH Effluent limitations under continuous monitoring. (a) Where a permittee continuously measures the pH of wastewater pursuant to...

  17. MiRNA expression profile of chronic lymphocytic leukemia patients with 13q deletion.

    PubMed

    Hernández-Sánchez, María; Rodríguez-Vicente, Ana E; Hernández, José-Ángel; Lumbreras, Eva; Sarasquete, María-Eugenia; Martín, Ana-África; Benito, Rocío; Vicente-Gutiérrez, Carlos; Robledo, Cristina; Heras, Natalia de Las; Rodríguez, Juan-Nicolás; Alcoceba, Miguel; Coca, Alfonso García de; Aguilar, Carlos; González, Marcos; Hernández-Rivas, Jesús-María

    2016-07-01

    Deletion 13q (13q-) is the most common cytogenetic aberration in chronic lymphocytic leukemia (CLL) and is associated with the most favorable prognosis as the sole cytogenetic abnormality. However, it is heterogeneous whereby CLL patients with higher percentages of 13q- cells (13q-H) have a more aggressive clinical course and a distinct gene expression profile. The microRNA (miRNA) expression profile of CLL gives additional biological and prognostic information, but its expression in 13q- CLL has not been examined in detail. The miRNA expression of clonal B cell lymphocytes (CD19+ cells) of 38 CLL patients and normal B cells of six healthy donors was analyzed. CLL patients with higher percentages of 13q- cells (≥80%) showed a different level of miRNA expression from patients with lower percentages (<80%). Interestingly, miR-143 was downregulated and miR-155 was overexpressed in 13q-H. This deregulation affected important validated target genes involved in apoptosis (BCL2, MDM2, TP53INP1) and proliferation (KRAS, PI3K-AKT signaling), that could lead to decreased apoptosis and increased proliferation in 13q-H patients. This study provides new evidence about the heterogeneity of the 13q deletion in CLL patients, showing that miRNA regulation could be involved in several significant pathways deregulated in CLL patients with a high number of losses in 13q.

  18. Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with del(17)(p11.2).

    PubMed Central

    Greenberg, F; Guzzetta, V; Montes de Oca-Luna, R; Magenis, R E; Smith, A C; Richter, S F; Kondo, I; Dobyns, W B; Patel, P I; Lupski, J R

    1991-01-01

    We undertook clinical evaluation (32 cases) and molecular evaluation (31 cases) of unrelated patients affected with Smith-Magenis syndrome (SMS) associated with an interstitial deletion of band p11.2 of chromosome 17. Patients were evaluated both clinically and electrophysiologically for peripheral neuropathy, since markers showing close linkage to one form of Charcot-Marie-Tooth disease (CMT1A) map to this chromosomal region. The common clinical findings were broad flat midface with brachycephaly, broad nasal bridge, brachydactyly, speech delay, and hoarse, deep voice. Fifty-five percent of the patients showed clinical signs (e.g., decreased or absent deep tendon reflexes, pes planus or pes cavus, decreased sensitivity to pain, and decreased leg muscle mass) suggestive of peripheral neuropathy. However, unlike patients with CMT1A, these patients demonstrated normal nerve conduction velocities. Self-destructive behaviors, primarily onychotillomania and polyembolokoilamania, were observed in 67% of the patients, and significant symptoms of sleep disturbance were observed in 62%. The absence of REM sleep was demonstrated by polysomnography in two patients. Southern analysis indicated that most patients were deleted for five 17p11.2 markers--FG1 (D17S446), 1516 (D17S258), pYNM67-R5 (D17S29), pA10-41 (D17S71), and pS6.1-HB2 (D17S445)--thus defining a region which appears to be critical to SMS. The deletion was determined to be of paternal origin in nine patients and of maternal origin in six patients. The apparent random parental origin of deletion documented in 15 patients suggests that genomic imprinting does not play a role in the expression of the SMS clinical phenotype. Our findings suggest that SMS is likely a contiguous-gene deletion syndrome which comprises characteristic clinical features, developmental delay, clinical signs of peripheral neuropathy, abnormal sleep function, and specific behavioral anomalies. Images Figure 2 Figure 3 PMID:1746552

  19. CHANDRA OBSERVATIONS OF COMETS 8P/TUTTLE AND 17P/HOLMES DURING SOLAR MINIMUM

    SciTech Connect

    Christian, D. J.; Bodewits, D.; Lisse, C. M.; Dennerl, K.; Wolk, S. J.; Hsieh, H.; Zurbuchen, T. H.; Zhao, L. E-mail: damian.christian@csun.edu E-mail: carey.lisse@jhuapl.edu E-mail: swolk@cfa.harvard.edu E-mail: thomasz@umich.edu

    2010-04-01

    We present results for Chandra X-ray Observatory observations of two comets made during the minimum of solar cycle 24. The two comets, 17P/Holmes (17P) and 8P/Tuttle (8P), were very different in their activity and geometry. 17P was observed, for 30 ks right after its major outburst, on 2007 October 31 (10:07 UT), and comet 8P/Tuttle was observed in 2008 January for 47 ks. During the two Chandra observations, 17P was producing at least 100 times more water than 8P but was 2.2 times further away from the Sun. Also, 17P was at a relatively high solar latitude (+19.{sup 0}1) while 8P was observed at a lower solar latitude (3.{sup 0}4). The X-ray spectrum of 17P is unusually soft with little significant emission at energies above 500 eV. Depending on our choice of background, we derive a 300-1000 eV flux of 0.5-4.5 x 10{sup -13} erg cm{sup -2} s{sup -1}, with over 90% of the emission in the 300-400 eV range. This corresponds to an X-ray luminosity between 0.4 and 3.3 x 10{sup 15} erg s{sup -1}. However, we cannot distinguish between this significant excess emission and possible instrumental effects, such as incomplete charge transfer across the CCD. 17P is the first comet observed at high latitude during solar minimum. Its lack of X-rays in the 400-1000 eV range, in a simple picture, may be attributed to the polar solar wind, which is depleted in highly charged ions. 8P/Tuttle was much brighter, with an average count rate of 0.20 counts s{sup -1} in the 300-1000 eV range. We derive an average X-ray flux in this range of 9.4 x 10{sup -13} erg cm{sup -2} s{sup -1} and an X-ray luminosity for the comet of 1.7 x 10{sup 14} erg s{sup -1}. The light curve showed a dramatic decrease in flux of over 60% between observations on January 1 and 4. When comparing outer regions of the coma to inner regions, its spectra showed a decrease in ratios of C VI/C V, O VIII/O VII, as predicted by recent solar wind charge exchange (SWCX) emission models. There are remarkable differences

  20. COMET 17P/HOLMES IN OUTBURST: THE NEAR INFRARED SPECTRUM

    SciTech Connect

    Yang Bin; Jewitt, David; Bus, Schelte J. E-mail: jewitt@ifa.hawaii.edu

    2009-05-15

    Jupiter family comet 17P/Holmes underwent a remarkable outburst on UT 2007 October 24, in which the integrated brightness abruptly increased by about a factor of a million. We obtained near infrared (0.8-4.2 {mu}m) spectra of 17P/Holmes on UT 2007 October 27, 28, and 31, using the 3.0 m NASA Infrared Telescope Facility atop Mauna Kea. Two broad absorption bands were found in the reflectance spectra with centers (at 2 {mu}m and 3 {mu}m, respectively) and overall shapes consistent with the presence of water ice grains in the coma. Synthetic mixing models of these bands suggest an origin in cold ice grains of micron size. Curiously, though, the expected 1.5 {mu}m band of water ice was not detected in our data, an observation for which we have no explanation. Simultaneously, excess thermal emission in the spectra at wavelengths beyond 3.2 {mu}m has a color temperature of 360 {+-} 40 K (corresponding to a superheat factor of {approx}2.0 {+-} 0.2 at 2.45 AU). This is too hot for these grains to be icy. The detection of both water ice spectral features and short-wavelength thermal emission suggests that the coma of 17P/Holmes has two components (hot, refractory dust and cold ice grains) which are not in thermal contact. A similarity to grains ejected into the coma of 9P/Tempel 1 by the Deep Impact spacecraft is noted.

  1. A Family Harboring CMT1A Duplication and HNPP Deletion.

    PubMed

    Lee, Jung Hwa; Kang, Hee Jin; Song, Hyunseok; Hwang, Su Jin; Cho, Sun-Young; Kim, Sang-Beom; Kim, Joonki; Chung, Ki Wha; Choi, Byung-Ok

    2007-06-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with duplication of chromosome 17p11.2-p12, whereas hereditary neuropathy with liability to pressure palsies (HNPP), which is an autosomal dominant neuropathy showing characteristics of recurrent pressure palsies, is associated with 17p11.2-p12 deletion. An altered gene dosage of PMP22 is believed to the main cause underlying the CMT1A and HNPP phenotypes. Although CMT1A and HNPP are associated with the same locus, there has been no report of these two mutations within a single family. We report a rare family harboring CMT1A duplication and HNPP deletion.

  2. Conditional deletion of nonmuscle myosin II-A in mouse tongue epithelium results in squamous cell carcinoma.

    PubMed

    Conti, Mary Anne; Saleh, Anthony D; Brinster, Lauren R; Cheng, Hui; Chen, Zhong; Cornelius, Shaleeka; Liu, Chengyu; Ma, Xuefei; Van Waes, Carter; Adelstein, Robert S

    2015-09-15

    To investigate the contribution of nonmuscle myosin II-A (NM II-A) to early cardiac development we crossed Myh9 floxed mice and Nkx2.5 cre-recombinase mice. Nkx2.5 is expressed in the early heart (E7.5) and later in the tongue epithelium. Mice homozygous for deletion of NM II-A (A(Nkx)/A(Nkx)) are born at the expected ratio with normal hearts, but consistently develop an invasive squamous cell carcinoma (SCC) of the tongue (32/32 A(Nkx)/A(Nkx)) as early as E17.5. To assess reproducibility a second, independent line of Myh9 floxed mice derived from a different embryonic stem cell clone was tested. This second line also develops SCC indistinguishable from the first (15/15). In A(Nkx)/A(Nkx) mouse tongue epithelium, genetic deletion of NM II-A does not affect stabilization of TP53, unlike a previous report for SCC. We attribute the consistent, early formation of SCC with high penetrance to the role of NM II in maintaining mitotic stability during karyokinesis.

  3. Comet 17P/Holmes: contrast in activity between before and after the 2007 outburst

    SciTech Connect

    Ishiguro, Masateru; Kim, Yoonyoung; Warjurkar, Dhanraj S.; Ham, Ji-Beom; Kim, Junhan; Usui, Fumihiko; Vaubaillon, Jeremie J.; Ishihara, Daisuke; Hanayama, Hidekazu; Sarugaku, Yuki; Hasegawa, Sunao; Kasuga, Toshihiro; Watanabe, Jun-ichi; Pyo, Jeonghyun; Kuroda, Daisuke; Ootsubo, Takafumi; Sakamoto, Makoto; Narusawa, Shin-ya; Takahashi, Jun; Akisawa, Hiroki

    2013-11-20

    A Jupiter-family comet, 17P/Holmes, underwent outbursts in 1892 and 2007. In particular, the 2007 outburst is known as the greatest outburst over the past century. However, little is known about the activity before the outburst because it was unpredicted. In addition, the time evolution of the nuclear physical status has not been systematically studied. Here, we study the activity of 17P/Holmes before and after the 2007 outburst through optical and mid-infrared observations. We found that the nucleus was highly depleted in its near-surface icy component before the outburst but that it became activated after the 2007 outburst. Assuming a conventional 1 μm sized grain model, we derived a surface fractional active area of 0.58% ± 0.14% before the outburst whereas the area was enlarged by a factor of ∼50 after the 2007 outburst. We also found that large (≥1 mm) particles could be dominant in the dust tail observed around aphelion. Based on the size of the particles, the dust production rate was ≳170 kg s{sup –1} at a heliocentric distance of r{sub h} = 4.1 AU, suggesting that the nucleus was still active around the aphelion passage. The nucleus color was similar to that of the dust particles and average for a Jupiter-family comet but different from that of most Kuiper Belt objects, implying that color may be inherent to icy bodies in the solar system. On the basis of these results, we concluded that more than 76 m of surface material was blown off by the 2007 outburst.

  4. Optical and radio spectra of the comet 17P/Holmes during its outburst

    NASA Astrophysics Data System (ADS)

    Churyumov, Klim; Berezhnoy, Alexey; Churyumov, Klim; Chubko, Larissa; Lukyanyk, Igor; Chavushian, Vahram; Palma, Alejandro; Sandoval, Laurel; Volvach, Alexandr

    Comet 17P/Holmes is the unique comet in which the super outburst of its brightness in 1 million times was observed. We present the preliminary results of spectroscopic study of this comet obtained with the usage of 2.12-m reflector (the Guillermo Haro Astrophysical Observatory, Mexico) on Nov. 2, 2007 at 7h 02m , 7h 24m , 7h 44m , 8h 04m , 8h 26m , 8h 47m , and 9h 08m UT and Nov. 3, 2007 at 6h 45m and 7h 06m UT. The comet was at the heliocentric distance r=2.48 A.U. and geocentric one ∆=1.52 A.U. Total visual magnitude was Nov. 2.85 UT, 2008 m1 =2.0m and Nov. 3.87 UT, 2008 m1 =2.2m (as it was estimated by K.Churyumov naked eye) . Emission lines of the molecules C2 , C3 , CN, NH2 , Na, H2 O+ and others were identified in these spectra. Analyzing distribution of brightness along the spectrograph slit in emission lines C2 and C3 , on Nov. 2-3, 2007 we determined some physical parameters of these neutral molecules - the velocity of expansion of molecules from the nucleus and their lifetimes. Observations of OH emission lines at 1612, 1665, 1667, and 1720 MHz of the comet 17P/Holmes were performed during November 6-10, 25-27, and December 2-3, 2007 with the usage of 22-m radio telescope (Crimean Astrophysical Observatory, Ukraine). Just after the outburst the intensity of OH lines was about 0.2 Jy. Water production rates estimated from intensities of OH radio and H2 O+ optical lines are compared.

  5. Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype.

    PubMed

    Potocki, Lorraine; Bi, Weimin; Treadwell-Deering, Diane; Carvalho, Claudia M B; Eifert, Anna; Friedman, Ellen M; Glaze, Daniel; Krull, Kevin; Lee, Jennifer A; Lewis, Richard Alan; Mendoza-Londono, Roberto; Robbins-Furman, Patricia; Shaw, Chad; Shi, Xin; Weissenberger, George; Withers, Marjorie; Yatsenko, Svetlana A; Zackai, Elaine H; Stankiewicz, Pawel; Lupski, James R

    2007-04-01

    The duplication 17p11.2 syndrome, associated with dup(17)(p11.2p11.2), is a recently recognized syndrome of multiple congenital anomalies and mental retardation and is the first predicted reciprocal microduplication syndrome described--the homologous recombination reciprocal of the Smith-Magenis syndrome (SMS) microdeletion (del(17)(p11.2p11.2)). We previously described seven subjects with dup(17)(p11.2p11.2) and noted their relatively mild phenotype compared with that of individuals with SMS. Here, we molecularly analyzed 28 additional patients, using multiple independent assays, and also report the phenotypic characteristics obtained from extensive multidisciplinary clinical study of a subset of these patients. Whereas the majority of subjects (22 of 35) harbor the homologous recombination reciprocal product of the common SMS microdeletion (~3.7 Mb), 13 subjects (~37%) have nonrecurrent duplications ranging in size from 1.3 to 15.2 Mb. Molecular studies suggest potential mechanistic differences between nonrecurrent duplications and nonrecurrent genomic deletions. Clinical features observed in patients with the common dup(17)(p11.2p11.2) are distinct from those seen with SMS and include infantile hypotonia, failure to thrive, mental retardation, autistic features, sleep apnea, and structural cardiovascular anomalies. We narrow the critical region to a 1.3-Mb genomic interval that contains the dosage-sensitive RAI1 gene. Our results refine the critical region for Potocki-Lupski syndrome, provide information to assist in clinical diagnosis and management, and lend further support for the concept that genomic architecture incites genomic instability.

  6. Interferometric Imaging of the Outburst of Comet 17P/Holmes with the Submillimter Array

    NASA Astrophysics Data System (ADS)

    Qi, Chunhua; Hogerheijde, M. R.; Jewitt, D.; Gurwell, M. A.; Wilner, D. J.; Williams, J. P.

    2010-10-01

    We present high angular resolution (2" or 2400 km) Submillimeter Array observations of the Jupiter-family comet 17P/Holmes during its huge outburst from October 26 through October 31 2007, including detections of CO 3-2, HCN 4-3, H13CN 4-3, CS 7-6, H2CO 31,2-21,1 and H2S 22,0-21,1, and associated dust continuum at 221 and 351 GHz. We find two components from the molecular emissions: one from isotropic outgassing and the other from gas jets. The emissions of CO, CS, H2S and H2CO are much stronger in the gas jet component. Using a molecular excitation code that accounts for the effects of collisions with water and electrons, we determine distinctly different CO/HCN ratios: within the isotropic outgassing component we find CO/HCN < 25, while in the gas jet component, CO/HCN > 100. This difference might reflect the volatile nature of the nucleus material brought out by the outburst.

  7. A gene for Leber's congenital amaurosis maps to chromosome 17p.

    PubMed

    Camuzat, A; Dollfus, H; Rozet, J M; Gerber, S; Bonneau, D; Bonnemaison, M; Briard, M L; Dufier, J L; Ghazi, I; Leowski, C

    1995-08-01

    Leber's congenital amaurosis (LCA) is an autosomal recessive disease responsible for congenital blindness. It is the most early and severe form of inherited retinopathy and accounts for 5% of all inherited retinal dystrophies. Here we report the first mapping of a gene for LCA to the distal short arm of chromosome 17 by linkage analysis in 15 multiplex families (Zmax = 5.14 at theta = 0.15 for probe AFM070xg5 at the D17S1353 locus). When our sample was split into two groups according to the ethnic origin of the patients we were able to confirm the presence of a gene for LCA on chromosome 17p by both homozygosity mapping and linkage analysis in five families of Maghrebian origin (LCA1, Zmax = 7.21 at theta = 0.01 at the D17S1353 locus), while negative results were found in 10 families of French ancestry. Haplotype analyses supported the placement of LCA1 between loci D17S796 and D17S786 (maximum likelihood estimate for location of the disease gene over the D17S1353 locus). The genetic heterogeneity of LCA will complicate the prenatal detection of this frequent cause of congenital blindness.

  8. Fine localization of the locus for autosomal dominant retinitis pigmentosa on chromosome 17p

    SciTech Connect

    Goliath, R.; Janssens, P.; Beighton, P.

    1995-10-01

    The term {open_quotes}retintis pigmentosa{close_quotes} (RP) refers to a group of inherited retinal degenerative disorders. Clinical manifestations include night-blindness, with variable age of onset, followed by constriction of the visual field that may progress to total loss of sight in later life. Previous studies have shown that RP is caused by mutations within different genes and may be inherited as an X-linked recessive (XLRRP), autosomal recessive (ARRP), or autosomal dominant (ADRP) trait. The AD form of this group of conditions has been found to be caused by mutations within the rhodopsin gene in some families and the peripherin/RDS gene in others. In addition, some ADRP families have been found to be linked to anonymous markers on 8cen, 7p, 7q,19q, and, more recently, 17p. The ADRP gene locus on the short arm of chromosome 17 was identified in a large South African family (ADRP-SA) of British origin. The phenotypic expression of the disorder, which has been described elsewhere is consistent in the pedigree with an early onset of disease symptoms. In all affected subjects in the family, onset of symptoms commenced before the age of 10 years. 16 refs., 3 figs., 1 tab.

  9. High levels of loss at the 17p telomere suggest the close proximity of a tumour suppressor.

    PubMed Central

    White, G. R.; Stack, M.; Santibáñez-Koref, M.; Liscia, D. S.; Venesio, T.; Wang, J. C.; Helms, C.; Donis-Keller, H.; Betticher, D. C.; Altermatt, H. J.; Hoban, P. R.; Heighway, J.

    1996-01-01

    High levels of loss of distal markers on 17p13.3 in breast cancer suggested the presence within the region of at least one tumour-suppressor gene. Here we describe the derivation of two biallelic polymorphisms from the 17p telomeric yeast artificial chromosome (YAC) TYAC98. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and multiplex PCR analysis demonstrated that the high level of allelic imbalance observed in breast tumours represented loss of constitutional heterozygosity (LOH) and that this LOH extended to the telomere. Lung carcinoma (but not Wilms' tumour)-derived DNA again revealed a high level of loss of subtelomeric 17p sequences. Telomeric microsatellite polymorphisms from other chromosome arms did not show such elevated loss in either tumour type. This suggested that the 17p loss observed did not reflect a general telomeric instability and provided further evidence for the presence of a breast cancer tumour-suppressor gene in the distal region of 17p13.3. Images Figure 1 Figure 2 Figure 3 PMID:8826850

  10. Smith-Magenis syndrome deletion: A case with equivocal cytogenetic findings resolved by fluorescence in situ hybridization

    SciTech Connect

    Juyal, R.C.; Patel, P.I.; Greenberg, F.

    1995-09-11

    The availability of markers for the 17p11.2 region has enabled the diagnosis of Smith-Magenis syndrome (SMS) by fluorescence in situ hybridization (FISH). SMS is typically associated with a discernible deletion of band 17p11.2 upon cytogenetic analysis at a resolution of 400-550 bands. We present a case that illustrates the importance of using FISH to confirm a cytogenetic diagnosis of del(17)(p11.2). Four independent cytogenetic analyses were performed with different conclusions. Results of low resolution analyses of amniocytes and peripheral blood lymphocytes were apparently normal, while high resolution analyses of peripheral blood samples in two laboratories indicated mosaicism for del(17)(p11.2). FISH clearly demonstrated a 17p deletion on one chromosome of all peripheral blood cells analyzed and ruled out mosaicism unambiguously. The deletion was undetectable by flow cytometric quantitation of chromosomal DNA content, suggesting that it is less than 2 Mb. We conclude that FISH should be used to detect the SMS deletion when routine chromosome analysis fails to detect it and to verify mosaicism. 23 refs., 3 figs., 1 tab.

  11. Schizophrenia and chromosomal deletions

    SciTech Connect

    Lindsay, E.A.; Baldini, A.; Morris, M. A.

    1995-06-01

    Recent genetic linkage analysis studies have suggested the presence of a schizophrenia locus on the chromosomal region 22q11-q13. Schizophrenia has also been frequently observed in patients affected with velo-cardio-facial syndrome (VCFS), a disorder frequently associated with deletions within 22q11.1. It has been hypothesized that psychosis in VCFS may be due to deletion of the catechol-o-methyl transferase gene. Prompted by these observations, we screened for 22q11 deletions in a population of 100 schizophrenics selected from the Maryland Epidemiological Sample. Our results show that there are schizophrenic patients carrying a deletion of 22q11.1 and a mild VCFS phenotype that might remain unrecognized. These findings should encourage a search for a schizophrenia-susceptibility gene within the deleted region and alert those in clinical practice to the possible presence of a mild VCFS phenotype associated with schizophrenia. 9 refs.

  12. The human homologue of the Drosophila melanogaster flightless-I gene (fliI) maps within the Smith-Magenis microdeletion critical region in 17p11.2

    SciTech Connect

    Chen, K.S.; Gunaratne, P.H.; Greenberg, F.; Shaffer, L.G.; Lupski, J.R.; Hoheisel, J.D.; Young, I.G.; Miklos, G.L.G.; Campbell, H.D.

    1995-01-01

    The Smith-Magenis syndrome (SMS) appears to be a contiguous-gene-deletion syndrome associated with a proximal deletion of the short arm of chromosome 17 in band p11.2. The spectrum of clinical findings includes short stature, brachydactyly, developmental delay, dysmorphic features, sleep disturbances, and behavioral problems. The complex phenotypic features suggest deletion of several contiguous genes. However, to date, no protein-encoding gene has been mapped to the SMS critical region. Recently, the Drosophila melanogaster flightless-I gene, fliI, and the homologous human cDNA have been isolated. Mutations in fliI result in loss of flight ability and, when severe, cause lethality due to incomplete cellularization with subsequent abnormal gastrulation. Here, we demonstrate that the human homologue (FLI) maps within the SMS critical region. Genomic cosmids were used as probes for FISH, which localized this gene to the 17p11.2 region. Somatic-cell hybrid-panel mapping further localized this gene to the SMS critical region. Southern blot analysis of somatic-cell hybrids and/or FISH analysis of lymphoblastoid cell lines from 12 SMS patients demonstrates the deletion of one copy of FLI in all SMS patients analyzed. 47 refs., 4 figs., 1 tab.

  13. Chromothripsis Is a Recurrent Genomic Abnormality in High-Risk Myelodysplastic Syndromes

    PubMed Central

    Abáigar, María; Robledo, Cristina; Benito, Rocío; Ramos, Fernando; Díez-Campelo, María; Hermosín, Lourdes; Sánchez-del-Real, Javier; Alonso, Jose M.; Cuello, Rebeca; Megido, Marta; Rodríguez, Juan N.; Martín-Núñez, Guillermo; Aguilar, Carlos; Vargas, Manuel; Martín, Ana A.; García, Juan L.; Kohlmann, Alexander; del Cañizo, M. Consuelo; Hernández-Rivas, Jesús M.

    2016-01-01

    To explore novel genetic abnormalities occurring in myelodysplastic syndromes (MDS) through an integrative study combining array-based comparative genomic hybridization (aCGH) and next-generation sequencing (NGS) in a series of MDS and MDS/myeloproliferative neoplasms (MPN) patients. 301 patients diagnosed with MDS (n = 240) or MDS/MPN (n = 61) were studied at the time of diagnosis. A genome-wide analysis of DNA copy number abnormalities was performed. In addition, a mutational analysis of DNMT3A, TET2, RUNX1, TP53 and BCOR genes was performed by NGS in selected cases. 285 abnormalities were identified in 71 patients (23.6%). Three high-risk MDS cases (1.2%) displayed chromothripsis involving exclusively chromosome 13 and affecting some cancer genes: FLT3, BRCA2 and RB1. All three cases carried TP53 mutations as revealed by NGS. Moreover, in the whole series, the integrative analysis of aCGH and NGS enabled the identification of cryptic recurrent deletions in 2p23.3 (DNMT3A; n = 2.8%), 4q24 (TET2; n = 10%) 17p13 (TP53; n = 8.5%), 21q22 (RUNX1; n = 7%), and Xp11.4 (BCOR; n = 2.8%), while mutations in the non-deleted allele where found only in DNMT3A (n = 1), TET2 (n = 3), and TP53 (n = 4). These cryptic abnormalities were detected mainly in patients with normal (45%) or non-informative (15%) karyotype by conventional cytogenetics, except for those with TP53 deletion and mutation (15%), which had a complex karyotype. In addition to well-known copy number defects, the presence of chromothripsis involving chromosome 13 was a novel recurrent change in high-risk MDS patients. Array CGH analysis revealed the presence of cryptic abnormalities in genomic regions where MDS-related genes, such as TET2, DNMT3A, RUNX1 and BCOR, are located. PMID:27741277

  14. The comet 17P/Holmes 2007 outburst: the early motion of the outburst material

    NASA Astrophysics Data System (ADS)

    Montalto, M.; Riffeser, A.; Hopp, U.; Wilke, S.; Carraro, G.

    2008-03-01

    Context: On October 24, 2007 the periodic comet 17P/Holmes underwent an astonishing outburst that increased its apparent total brightness from magnitude V~17 up to V~2.5 in roughly two days. In this contribution we report on Wendelstein 0.8 m telescope (WST) photometric observations of the early evolution stages of the outburst. Aims: We studied the evolution of the structure morphology and its kinematic and provide an estimate of the ejected dust mass. Methods: We analyzed 126 images of the comet in the BVRI photometric bands spread between October 26, 2007 and November 20, 2007. The bright comet core appeared to be separated from a quickly expanding dust cloud in all the data, and the bulk of the cloud was contained in the field of view of our instrument during the days soon after the outburst, allowing precise estimates both of the separation velocities of the two luminous baricenters and of the expansion velocity of the dust cloud. The ejected dust mass was derived on the basis of differential photometry on background stars occulted by the moving cloud. Results: The two cores were moving apart from each other at a relative, projected constant velocity of (9.87±0.07) arcsec/day (0.135±0.001 km s-1). In the inner regions of the dust cloud we observed a linear increase in size at a mean constant velocity of (14.6±0.3) arcsec/day (0.200±0.004 km s-1). Evidence of a radial velocity gradient in the expanding cloud was also found. Our estimate for the expanding coma's mass was approximately 10-2-1 comet's mass, implying a significant disintegration event. Conclusions: We interpret our observations in the context of an explosive scenario that was more probably triggered by some internal instability processes rather than by an impact with an asteroidal body. Due to the peculiar characteristics of this event, further observations and investigations are necessary to bring the nature of the physical processes that determined it to light. Based on observations taken at

  15. DETECTION OF REMNANT DUST CLOUD ASSOCIATED WITH THE 2007 OUTBURST OF 17P/HOLMES

    SciTech Connect

    Ishiguro, Masateru; Kim, Yoonyoung; Kwon, Yuna G.; Sarugaku, Yuki; Kuroda, Daisuke; Maehara, Hiroyuki; Hanayama, Hidekazu; Takahashi, Jun; Terai, Tsuyoshi; Usui, Fumihiko; Vaubaillon, Jeremie J.; Morokuma, Tomoki; Kobayashi, Naoto; Watanabe, Jun-ichi

    2016-01-20

    This article reports a new optical observation of 17P/Holmes one orbital period after the historical outburst event in 2007. We detected not only a common dust tail near the nucleus but also a long narrow structure that extended along the position angle 274.°6 ± 0.°1 beyond the field of view (FOV) of the Kiso Wide Field Camera, i.e., >0.°2 eastward and >2.°0 westward from the nuclear position. The width of the structure decreased westward with increasing distance from the nucleus. We obtained the total cross section of the long extended structure in the FOV, C{sub FOV} = (2.3 ± 0.5) × 10{sup 10} m{sup 2}. From the position angle, morphology, and mass, we concluded that the long narrow structure consists of materials ejected during the 2007 outburst. On the basis of the dynamical behavior of dust grains in the solar radiation field, we estimated that the long narrow structure would be composed of 1 mm–1 cm grains having an ejection velocity of >50 m s{sup −1}. The velocity was more than one order of magnitude faster than that of millimeter–centimeter grains from typical comets around a heliocentric distance r{sub h} of 2.5 AU. We considered that sudden sublimation of a large amount of water-ice (≈10{sup 30} mol s{sup −1}) would be responsible for the high ejection velocity. We finally estimated a total mass of M{sub TOT} = (4–8) × 10{sup 11} kg and a total kinetic energy of E{sub TOT} = (1–6) × 10{sup 15} J for the 2007 outburst ejecta, which are consistent with those of previous studies that were conducted soon after the outburst.

  16. PECULIAR NEAR-NUCLEUS OUTGASSING OF COMET 17P/HOLMES DURING ITS 2007 OUTBURST

    SciTech Connect

    Qi, Chunhua; Gurwell, Mark A.; Wilner, David J.; Hogerheijde, Michiel R.; Jewitt, David

    2015-01-20

    We present high angular resolution Submillimeter Array observations of the outbursting Jupiter family comet 17P/Holmes on 2007 October 26-29, achieving a spatial resolution of 2.''5, or ∼3000 km at the comet distance. The observations resulted in detections of the rotational lines CO 3-2, HCN 4-3, H{sup 13}CN 4-3, CS 7-6, H{sub 2}CO 3{sub 1,} {sub 2}-2{sub 1,} {sub 1}, H{sub 2}S 2{sub 2,} {sub 0}-2{sub 1,} {sub 1}, and multiple CH{sub 3}OH lines, along with the associated dust continuum at 221 and 349 GHz. The continuum has a spectral index of 2.7 ± 0.3, slightly steeper than blackbody emission from large dust particles. From the imaging data, we identify two components in the molecular emission. One component is characterized by a relatively broad line width (∼1 km s{sup –1} FWHM) exhibiting a symmetric outgassing pattern with respect to the nucleus position. The second component has a narrower line width (<0.5 km s{sup –1} FWHM) with the line center redshifted by 0.1-0.2 km s{sup –1} (cometocentric frame), and shows a velocity shift across the nucleus position with the position angle gradually changing from 66° to 30° within the four days of observations. We determine distinctly different CO/HCN ratios for each of the components. For the broad-line component we find CO/HCN < 7, while in the narrow-line component, CO/HCN = 40 ± 5. We hypothesize that the narrow-line component originates from the ice grain halo found in near-nucleus photometry, believed to be created by sublimating recently released ice grains around the nucleus during the outburst. In this interpretation, the high CO/HCN ratio of this component reflects the more pristine volatile composition of nucleus material released in the outburst.

  17. The human homologue of the Drosophila melanogaster flightless-I gene (fliI) maps within the Smith-Magenis microdeletion critical region in 17p11.2

    SciTech Connect

    Chen, K.S.; Nguyen, D.; Greenberg, F.

    1994-09-01

    The Smith-Magenis syndrome (SMS) appears to be a contiguous gene deletion syndrome associated with a proximal deletion of the short arm of chromosome 17 in band p11.2. The spectrum of clinical findings includes short stature, brachydactyly, developmental delay, dysmorphic features, sleep disturbances and behavioral problems. The complex phenotypic features suggest deletion of several contiguous genes. However, to date no protein encoding gene has been mapped to the SMS critical region. Recently, Campbell described the cloning and characterization of D. melanogaster fli cDNAs and of homologous cDNAs from caenorhabditis elegans and from humans. Mutations in fliI result in loss of flight ability and, when severe, cause lethality due to incomplete cellularization with subsequent abnormal gastrulation. The amino acid sequence deduced from the FLI cDNA has 52% similarity to the human gelsolin protein and also has a N-terminal leucine-rich domain with 16 consecutive leucine-rich repeats (LRR). Here, we demonstrate that the human homologue (FLI) maps within the SMS critical region. Genomic cosmids were used as probes for fluorescence in situ hybridization (FISH) and localized this gene to the 17p11.2 region. Somatic cell hybrids and/or FISH analysis of lymphoblastoid cell lines form 12 SMS patients demonstrate that one copy of the FLI gene is deleted in all SMS patients analyzed with the common deletion. Further studies are required to determine if haploinsufficiency of FLI or other as yet unidentified genes is important for the expression of the SMS phenotype.

  18. Development profile in a patient with monosomy 10q and Dup(17p) associated with a peripheral neuropathy

    SciTech Connect

    Pellegrino, J.E.; Spinner, N.B.; Zackai, E.H.

    1996-02-02

    We report on a patient with dup(17p) and monosomy (10q) resulting from a familial translocation. Manifestations typical of both syndromes were present. The overall development of this patient was better by comparison with similar reported cases of either anomaly. Our evaluation detected severe gross motor delay and signs of a demyelinating peripheral neuropathy. This patient is trisomic for the region of 17p which includes the peripheral myelin protein-22 (PMP-22) gene, known to be duplicated in Charcot-Marie-Tooth neuropathy type 1A (CMT1A). Our analysis in this patient suggests that trisomy for the PMP-22 gene led to the demyelinating neuropathy and contributed to his severe motor development delay. 33 refs., 3 figs., 1 tab.

  19. Prognostic Impact of del(17p) and del(22q) as Assessed by Interphase FISH in Sporadic Colorectal Carcinomas

    PubMed Central

    González-González, María; Muñoz-Bellvis, Luís; Mackintosh, Carlos; Fontanillo, Celia; Gutiérrez, M. Laura; Abad, M. Mar; Bengoechea, Oscar; Teodosio, Cristina; Fonseca, Emilio; Fuentes, Manuel; De Las Rivas, Javier

    2012-01-01

    Background Most sporadic colorectal cancer (sCRC) deaths are caused by metastatic dissemination of the primary tumor. New advances in genetic profiling of sCRC suggest that the primary tumor may contain a cell population with metastatic potential. Here we compare the cytogenetic profile of primary tumors from liver metastatic versus non-metastatic sCRC. Methodology/Principal Findings We prospectively analyzed the frequency of numerical/structural abnormalities of chromosomes 1, 7, 8, 13, 14, 17, 18, 20, and 22 by iFISH in 58 sCRC patients: thirty-one non-metastatic (54%) vs. 27 metastatic (46%) disease. From a total of 18 probes, significant differences emerged only for the 17p11.2 and 22q11.2 chromosomal regions. Patients with liver metastatic sCRC showed an increased frequency of del(17p11.2) (10% vs. 67%;p<.001) and del(22q11.2) (0% vs. 22%;p = .02) versusnon-metastatic cases. Multivariate analysis of prognostic factors for overall survival (OS) showed that the only clinical and cytogenetic parameters that had an independent adverse impact on patient outcome were the presence of del(17p) with a 17p11.2 breakpoint and del(22q11.2). Based on these two cytogenetic variables, patients were classified into three groups: low- (no adverse features), intermediate- (one adverse feature) and high-risk (two adverse features)- with significantly different OS rates at 5-years (p<.001): 92%, 53% and 0%, respectively. Conclusions/Significance Our results unravel the potential implication of del(17p11.2) in sCRC patients with liver metastasis as this cytogenetic alteration appears to be intrinsically related to an increased metastatic potential and a poor outcome, providing additional prognostic information to that associated with other cytogenetic alterations such as del(22q11.2). Additional prospective studies in larger series of patients would be required to confirm the clinical utility of the new prognostic markers identified. PMID:22912721

  20. Insertion/Deletion Polymorphisms in the ΔNp63 Promoter Are a Risk Factor for Bladder Exstrophy Epispadias Complex

    PubMed Central

    Wilkins, Simon; Zhang, Ke Wei; Mahfuz, Istiak; Quantin, Renaud; D'Cruz, Nancy; Hutson, John; Ee, Michael; Bagli, Darius; Aitken, Karen; Fong, Fion Nga-Yin; Ng, Patrick Kwok-Shing; Tsui, Stephen Kwok-Wing; Fung, Wendy Yin-Wan; Banu, Tahmina; Thakre, Atul; Johar, Kaid; Jaureguizar, Enrique; Li, Long; Cheng, Wei

    2012-01-01

    Bladder exstrophy epispadias complex (BEEC) is a severe congenital anomaly; however, the genetic and molecular mechanisms underlying the formation of BEEC remain unclear. TP63, a member of TP53 tumor suppressor gene family, is expressed in bladder urothelium and skin over the external genitalia during mammalian deve