XRCC1 Arg399Gln and RAD51 5'UTR G135C polymorphisms and their outcome in tumor aggressiveness and survival of Portuguese breast cancer patients

(undefined

TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas

Context: Telomerase promoter mutations (TERT) were recently described in follicular cell-derived thyroid carcinomas (FCDTC) and seem to be more prevalent in aggressive cancers. Objectives: We aimed to evaluate the frequency of TERT promoter mutations in thyroid lesions and to investigate the prognostic significance of such mutations in a large cohort of patients with differentiated thyroid carcinomas (DTCs). Design: This was a retrospective observational study. Setting and Patients: We studied 647 tumors and tumor-like lesions. A total of 469 patients with FCDTC treated and followed in five university hospitals were included. Mean follow-up (±SD) was 7.8 ± 5.8 years. Main Outcome Measures: Predictive value of TERT promoter mutations for distant metastasization, disease persistence at the end of follow-up, and disease-specific mortality. Results: TERT promoter mutations were found in 7.5% of papillary carcinomas (PTCs), 17.1% of follicular carcinomas, 29.0% of poorly differentiated carcinomas, and 33.3% of anaplastic thyroid carcinomas. Patients with TERT-mutated tumors were older (P < .001) and had larger tumors (P = .002). In DTCs, TERT promoter mutations were significantly associated with distant metastases (P < .001) and higher stage (P < .001). Patients with DTC harboring TERT promoter mutations were submitted to more radioiodine treatments (P = .009) with higher cumulative dose (P = .004) and to more treatment modalities (P = .001). At the end of follow-up, patients with TERT-mutated DTCs were more prone to have persistent disease (P = .001). TERT promoter mutations were significantly associated with disease-specific mortality [in the whole FCDTC (P < .001)] in DTCs (P < .001), PTCs (P = .001), and follicular carcinomas (P < .001). After adjusting for age at diagnosis and gender, the hazard ratio was 10.35 (95% confidence interval 2.01–53.24; P = .005) in DTC and 23.81 (95% confidence interval 1.36–415.76; P = .03) in PTCs. Conclusions: TERT promoter mutations are an indicator of clinically aggressive tumors, being correlated with worse outcome and disease-specific mortality in DTC. TERT promoter mutations have an independent prognostic value in DTC and, notably, in PTC.We acknowledge GENZYME for funding our work through a research project. This study was supported by the Portuguese Foundation for Science and Technology through PhD Grant SFRH/BD/81940/2011 (to J.V.); PhD Grant SFRH/BD/87887/2012 (to C.T.); PhD Grant SFRH/BD/79135/2011 (to A.A.); and the Scientific Investigation Project PIC/IC/83037/2007. Further funding was obtained from the project “Microenvironment, Metabolism and Cancer,” partially supported by Programa Operacional Regional do Norte (ON.2-O Novo Norte), under the Quadro de Referência Estratégico Nacional, and through the European Regional Development Fund. The work of J.M.C.-T. was supported by Grant PI12/00749-FEDER from the Instituto de Salud Carlos III, the Ministry of Economy and Competitiveness (Madrid, Spain). The Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) is an associate laboratory of the Portuguese Ministry of Science, Technology, and Higher Education, which is partially supported by the Foundation for Science and Technology

Frequency of TERT promoter mutations in human cancers

Reactivation of telomerase has been implicated in human tumorigenesis, but the underlying mechanisms remain poorly understood. Here we report the presence of recurrent somatic mutations in the TERT promoter in cancers of the central nervous system (43%), bladder (59%), thyroid (follicular cell-derived, 10%) and skin (melanoma, 29%). In thyroid cancers, the presence of TERT promoter mutations (when occurring together with BRAF mutations) is significantly associated with higher TERT mRNA expression, and in glioblastoma we find a trend for increased telomerase expression in cases harbouring TERT promoter mutations. Both in thyroid cancers and glioblastoma, TERT promoter mutations are significantly associated with older age of the patients. Our results show that TERT promoter mutations are relatively frequent in specific types of human cancers, where they lead to enhanced expression of telomerase.We thank to Mrs Mafalda Rocha for the excellent technical support in the sequencing work. This work was partially supported by the Portuguese Science and Technology Foundation (FCT) through BPD (SFRH/BPD/85249/2012 to H. P.), PhD (SFRH/BD/81940/2011 to J.V. and SFRH/BD/79135/2011 to A. A.) and BI grants, and the grant through the Program Ciencia 2008 (J.L.) and the project (PIC/IC/83037/2007). Further funding was obtained from the project 'Microenvironment, metabolism and cancer' partially supported by Programa Operacional Regional do Norte (ON.2-O Novo Norte), under the Quadro de Referencia Estrategico Nacional (QREN), and through the Fundo Europeu de Desenvolvimento Regional (FEDER). IPATIMUP is an associate laboratory of the Portuguese Ministry of Science, Technology and Higher Education and is partially supported by the FCT

TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas

Funding: This study was supported by the Portuguese Foundation for Science and Technology through PhD Grant SFRH/BD/81940/ 2011 (to J.V.); PhD Grant SFRH/BD/87887/2012 (to C.T.); PhD Grant SFRH/BD/79135/2011 (to A.A.); and the Scientific Investigation Project PIC/IC/83037/2007. Further funding was obtained from the project “Microenvironment, Metabolism and Cancer,” partially supported by Programa Operacional Regional do Norte (ON.2-O Novo Norte), under the Quadro de Referência Estratégico Nacional, and through the European Regional Development Fund. The work of J.M.C.-T. was supported by Grant PI12/00749-FEDER from the Instituto de Salud Carlos III, the Ministry of Economy and Competitiveness (Madrid, Spain). The Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) is an associate laboratory of the Portuguese Ministry of Science, Technology, and Higher Education, which is partially supported by the Foundation for Science and Technology.Context: Telomerase promoter mutations (TERT) were recently described in follicular cell-derived thyroid carcinomas (FCDTC) and seem to be more prevalent in aggressive cancers. Objectives:Weaimed to evaluate the frequency of TERT promoter mutations in thyroid lesions and to investigate the prognostic significance of such mutations in a large cohort of patients with differentiated thyroid carcinomas (DTCs). Design: This was a retrospective observational study. Setting and Patients: We studied 647 tumors and tumor-like lesions. A total of 469 patients with FCDTC treated and followed in five university hospitals were included. Mean follow-up (±SD) was 7.8 ± 5.8 years. Main Outcome Measures: Predictive value of TERT promoter mutations for distant metastasization, disease persistence at the end of follow-up, and disease-specific mortality. Results: TERT promoter mutations were found in 7.5% of papillary carcinomas (PTCs), 17.1% of follicular carcinomas, 29.0% of poorly differentiated carcinomas, and 33.3% of anaplastic thyroid carcinomas. Patients with TERT-mutated tumors were older (P < .001) and had larger tumors (P = .002). In DTCs, TERT promoter mutations were significantly associated with distant metastases (P< .001) and higher stage (P < .001). Patients with DTC harboring TERT promoter mutations were submitted to more radioiodine treatments (P = .009) with higher cumulative dose (P = .004) and to more treatment modalities (P=.001). At the end of follow-up, patients with TERT-mutated DTCs were more prone to have persistent disease (P=.001). TERT promoter mutations were significantly associated with disease-specific mortality [in the whole FCDTC (P < .001)] in DTCs (P < .001), PTCs (P = .001), and follicular carcinomas (P < .001). After adjusting for age at diagnosis and gender, the hazard ratio was 10.35 (95% confidence interval 2.01-53.24; P = .005) in DTC and 23.81 (95% confidence interval 1.36-415.76; P = .03) in PTCs. Conclusions: TERT promoter mutations are an indicator of clinically aggressive tumors, being correlated with worse outcome and disease-specific mortality in DTC. TERT promoter mutations have an independent prognostic value in DTC and, notably, in PTC.publishersversionpublishe

Importance of TP53 codon 72 and intron 3 duplication 16bp polymorphisms in prediction of susceptibility on breast cancer

<p>Abstract</p> <p>Background</p> <p><it>TP53 </it>is one of major tumour suppressor genes being essential in preservation of genome integrity. Two very common polymorphisms have been demonstrated to contribute to cancer susceptibility and tumour behaviour. The purpose of this study was to evaluate the role of <it>Arg72Pro </it>and <it>PIN3 Ins16bp </it>polymorphisms in <it>TP53 </it>gene as genetic susceptibility and predictive markers to breast cancer.</p> <p>Methods</p> <p>We analysed DNA samples from 264 breast cancer patients and 440 controls, for <it>TP53 Arg72Pro </it>and <it>PIN3 Ins16bp </it>polymorphisms using PCR-RFLP.</p> <p>Results</p> <p>We observed that women with <it>A2A2 </it>genotype have increased risk for developing breast cancer, either in women with or without familial history (FH) of the disease (OR = 4.40, 95% CI 1.60–12.0; p = 0.004; OR = 3.88, 95% CI 1.18–12.8; p = 0.026, respectively). In haplotype analysis, statistically significant differences were found between <it>TP53 Arg-A2 </it>haplotype frequencies and familial breast cancer cases and the respective control group (OR = 2.10, 95% CI 1.08–4.06; p = 0.028). Furthermore, both <it>TP53 </it>polymorphisms are associated with higher incidence of lymph node metastases.</p> <p>Conclusion</p> <p>Our findings suggest <it>TP53 PIN3 Ins16bp </it>polymorphism as a real risk modifier in breast cancer disease, either in sporadic and familial breast cancer. Furthermore, both TP53 polymorphisms are associated with higher incidence of lymph node metastases.</p