Dataset Information

RAD51B in Familial Breast Cancer.

ABSTRACT: Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

SUBMITTER: Pelttari LM

PROVIDER: S-EPMC4858276 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Publications

RAD51B in Familial Breast Cancer.

Pelttari Liisa M LM Khan Sofia S Vuorela Mikko M Kiiski Johanna I JI Vilske Sara S Nevanlinna Viivi V Ranta Salla S Schleutker Johanna J Winqvist Robert R Kallioniemi Anne A Dörk Thilo T Bogdanova Natalia V NV Figueroa Jonine J Pharoah Paul D P PD Schmidt Marjanka K MK Dunning Alison M AM García-Closas Montserrat M Bolla Manjeet K MK Dennis Joe J Michailidou Kyriaki K Wang Qin Q Hopper John L JL Southey Melissa C MC Rosenberg Efraim H EH Fasching Peter A PA Beckmann Matthias W MW Peto Julian J Dos-Santos-Silva Isabel I Sawyer Elinor J EJ Tomlinson Ian I Burwinkel Barbara B Surowy Harald H Guénel Pascal P Truong Thérèse T Bojesen Stig E SE Nordestgaard Børge G BG Benitez Javier J González-Neira Anna A Neuhausen Susan L SL Anton-Culver Hoda H Brenner Hermann H Arndt Volker V Meindl Alfons A Schmutzler Rita K RK Brauch Hiltrud H Brüning Thomas T Lindblom Annika A Margolin Sara S Mannermaa Arto A Hartikainen Jaana M JM Chenevix-Trench Georgia G Van Dyck Laurien L Janssen Hilde H Chang-Claude Jenny J Rudolph Anja A Radice Paolo P Peterlongo Paolo P Hallberg Emily E Olson Janet E JE Giles Graham G GG Milne Roger L RL Haiman Christopher A CA Schumacher Fredrick F Simard Jacques J Dumont Martine M Kristensen Vessela V Borresen-Dale Anne-Lise AL Zheng Wei W Beeghly-Fadiel Alicia A Grip Mervi M Andrulis Irene L IL Glendon Gord G Devilee Peter P Seynaeve Caroline C Hooning Maartje J MJ Collée Margriet M Cox Angela A Cross Simon S SS Shah Mitul M Luben Robert N RN Hamann Ute U Torres Diana D Jakubowska Anna A Lubinski Jan J Couch Fergus J FJ Yannoukakos Drakoulis D Orr Nick N Swerdlow Anthony A Darabi Hatef H Li Jingmei J Czene Kamila K Hall Per P Easton Douglas F DF Mattson Johanna J Blomqvist Carl C Aittomäki Kristiina K Nevanlinna Heli H

PloS one 20160505 5

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible ...[more]

PMID: 27149063

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Project description:BACKGROUND:Germline mutations in the BRIP1 gene have been described as conferring a moderate risk for ovarian cancer (OC), while the role of BRIP1 in breast cancer (BC) pathogenesis remains controversial. METHODS:To assess the role of deleterious BRIP1 germline mutations in BC/OC predisposition, 6341 well-characterized index patients with BC, 706 index patients with OC, and 2189 geographically matched female controls were screened for loss-of-function (LoF) mutations and potentially damaging missense variants. All index patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germline testing and tested negative for pathogenic BRCA1/2 variants. RESULTS:BRIP1 LoF mutations confer a high OC risk in familial index patients (odds ratio (OR)?=?20.97, 95% confidence interval (CI)?=?12.02-36.57, P?<?0.0001) and in the subgroup of index patients with late-onset OC (OR?=?29.91, 95% CI?=?14.99-59.66, P?<?0.0001). No significant association of BRIP1 LoF mutations with familial BC was observed (OR?=?1.81 95% CI?=?1.00-3.30, P?=?0.0623). In the subgroup of familial BC index patients without a family history of OC there was also no apparent association (OR?=?1.42, 95% CI?=?0.70-2.90, P?=?0.3030). In 1027 familial BC index patients with a family history of OC, the BRIP1 mutation prevalence was significantly higher than that observed in controls (OR?=?3.59, 95% CI?=?1.43-9.01; P?=?0.0168). Based on the negative association between BRIP1 LoF mutations and familial BC in the absence of an OC family history, we conclude that the elevated mutation prevalence in the latter cohort was driven by the occurrence of OC in these families. Compared with controls, predicted damaging rare missense variants were significantly more prevalent in OC (P?=?0.0014) but not in BC (P?=?0.0693) patients. CONCLUSIONS:To avoid ambiguous results, studies aimed at assessing the impact of candidate predisposition gene mutations on BC risk might differentiate between BC index patients with an OC family history and those without. In familial cases, we suggest that BRIP1 is a high-risk gene for late-onset OC but not a BC predisposition gene, though minor effects cannot be excluded.

Project description:Understanding the gene-specific risks for development of breast cancer will lead to improved clinical care for those carrying germline mutations in cancer predisposition genes. We sought to detail the spectrum of mutations and refine risk estimates for known and proposed breast cancer susceptibility genes. Targeted massively-parallel sequencing was performed to identify mutations and copy number variants in 26 known or proposed breast cancer susceptibility genes in 2134 BRCA1/2-negative women with familial breast cancer (proband with breast cancer and a family history of breast or ovarian cancer) from a largely European-Caucasian multi-institutional cohort. Case-control analysis was performed comparing the frequency of internally classified mutations identified in familial breast cancer women to Exome Aggregation Consortium controls. Mutations were identified in 8.2% of familial breast cancer women, including mutations in high-risk (odds ratio > 5) (1.4%) and moderate-risk genes (2 < odds ratio < 5) (2.9%). The remaining familial breast cancer women had mutations in proposed breast cancer genes (1.7%), Lynch syndrome genes (0.5%), and six cases had two mutations (0.3%). Case-control analysis demonstrated associations with familial breast cancer for ATM, PALB2, and TP53 mutations (odds ratio > 3.0, p < 10-4), BARD1 mutations (odds ratio = 3.2, p = 0.012), and CHEK2 truncating mutations (odds ratio = 1.6, p = 0.041). Our results demonstrate that approximately 4.7% of BRCA1/2 negative familial breast cancer women have mutations in genes statistically associated with breast cancer. We classified PALB2 and TP53 as high-risk, ATM and BARD1 as moderate risk, and CHEK2 truncating mutations as low risk breast cancer predisposition genes. This study demonstrates that large case-control studies are needed to fully evaluate the breast cancer risks associated with mutations in moderate-risk and proposed susceptibility genes.

Dataset Information

RAD51B in Familial Breast Cancer.

Publications

RAD51B in Familial Breast Cancer.

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