Pelttari Liisa M, Khan Sofia, Vuorela Mikko, Kiiski Johanna I, Vilske Sara, Nevanlinna Viivi, Ranta Salla, Schleutker Johanna, Winqvist Robert, Kallioniemi Anne, Dörk Thilo, Bogdanova Natalia V, Figueroa Jonine, Pharoah Paul D P, Schmidt Marjanka K, Dunning Alison M, García-Closas Montserrat, Bolla Manjeet K, Dennis Joe, Michailidou Kyriaki, Wang Qin, Hopper John L, Southey Melissa C, Rosenberg Efraim H, Fasching Peter A, Beckmann Matthias W, Peto Julian, Dos-Santos-Silva Isabel, Sawyer Elinor J, Tomlinson Ian, Burwinkel Barbara, Surowy Harald, Guénel Pascal, Truong Thérèse, Bojesen Stig E, Nordestgaard Børge G, Benitez Javier, González-Neira Anna, Neuhausen Susan L, Anton-Culver Hoda, Brenner Hermann, Arndt Volker, Meindl Alfons, Schmutzler Rita K, Brauch Hiltrud, Brüning Thomas, Lindblom Annika, Margolin Sara, Mannermaa Arto, Hartikainen Jaana M, Chenevix-Trench Georgia, Van Dyck Laurien, Janssen Hilde, Chang-Claude Jenny, Rudolph Anja, Radice Paolo, Peterlongo Paolo, Hallberg Emily, Olson Janet E, Giles Graham G, Milne Roger L, Haiman Christopher A, Schumacher Fredrick, Simard Jacques, Dumont Martine, Kristensen Vessela, Borresen-Dale Anne-Lise, Zheng Wei, Beeghly-Fadiel Alicia, Grip Mervi, Andrulis Irene L, Glendon Gord, Devilee Peter, Seynaeve Caroline, Hooning Maartje J, Collée Margriet, Cox Angela, Cross Simon S, Shah Mitul, Luben Robert N, Hamann Ute, Torres Diana, Jakubowska Anna, Lubinski Jan, Couch Fergus J, Yannoukakos Drakoulis, Orr Nick, Swerdlow Anthony, Darabi Hatef, Li Jingmei, Czene Kamila, Hall Per, Easton Douglas F, Mattson Johanna, Blomqvist Carl, Aittomäki Kristiina, Nevanlinna Heli
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Laboratory of Cancer Genetics and Tumor Biology, Cancer Research and Translational Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
PLoS One. 2016 May 5;11(5):e0153788. doi: 10.1371/journal.pone.0153788. eCollection 2016.
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.
14q24.1上靠近RAD51B的常见变异已被证实与乳腺癌有关：rs999737和rs2588809与女性乳腺癌风险相关，rs1314913与男性乳腺癌风险相关。本研究旨在探讨RAD51B变异在乳腺癌易感性中的作用，特别是在芬兰家族性乳腺癌背景下。我们对来自赫尔辛基地区的168例芬兰乳腺癌患者的RAD51B编码区进行了测序，以确定可能的复发性始祖突变。此外，我们在参与乳腺癌协会联盟（BCAC）的40项研究中的44,791例乳腺癌病例和43,583例对照中研究了已知的rs999737、rs2588809和rs1314913单核苷酸多态性（SNP）以及RAD51B单倍型，这些样本在定制芯片（iCOGS）上进行了基因分型。我们在芬兰癌症患者中鉴定出一个推定的致病性错义突变c.541C>T，随后在来自芬兰和白俄罗斯的另外5259例乳腺癌病例和3586例人群对照中对该突变进行了基因分型。在芬兰数据集的荟萃分析或大型BCAC数据集中，未发现与乳腺癌风险有显著关联。在BCAC数据集中，先前确定的风险变异rs999737、rs2588809和rs1314913与所有乳腺癌病例以及家族性病例之间的关联得到了重复验证。在所有病例中（优势比（OR）：1.15，95%置信区间（CI）：1.11 - 1.19，P = 8.88×10 - 16）以及家族性病例中（OR：1.24，95%CI：1.16 - 1.32，P = 6.19×10 - 11），观察到携带所有三个SNP风险等位基因的单倍型与携带相应保护性等位基因的单倍型相比，关联最为显著。我们的结果表明，RAD51B中的功能丧失突变很少见，但RAD51B区域的常见变异与家族性乳腺癌风险显著相关。
