Setton Jeremy, Selenica Pier, Mukherjee Semanti, Shah Rachna, Pecorari Isabella, McMillan Biko, Pei Isaac X, Kemel Yelena, Ceyhan-Birsoy Ozge, Sheehan Margaret, Tkachuk Kaitlyn, Brown David N, Zhang Liying, Cadoo Karen, Powell Simon, Weigelt Britta, Robson Mark, Riaz Nadeem, Offit Kenneth, Reis-Filho Jorge S, Mandelker Diana
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
NPJ Breast Cancer. 2021 Oct 11;7(1):135. doi: 10.1038/s41523-021-00339-0.
Pathogenic germline mutations in the RAD51 paralog genes RAD51C and RAD51D, are known to confer susceptibility to ovarian and triple-negative breast cancer. Here, we investigated whether germline loss-of-function variants affecting another RAD51 paralog gene, RAD51B, are also associated with breast and ovarian cancer. Among 3422 consecutively accrued breast and ovarian cancer patients consented to tumor/germline sequencing, the observed carrier frequency of loss-of-function germline RAD51B variants was significantly higher than control cases from the gnomAD population database (0.26% vs 0.09%), with an odds ratio of 2.69 (95% CI: 1.4-5.3). Furthermore, we demonstrate that tumors harboring biallelic RAD51B alteration are deficient in homologous recombination DNA repair deficiency (HRD), as evidenced by analysis of sequencing data and in vitro functional assays. Our findings suggest that RAD51B should be considered as an addition to clinical germline testing panels for breast and ovarian cancer susceptibility.
已知RAD51旁系同源基因RAD51C和RAD51D中的致病性种系突变会使人易患卵巢癌和三阴性乳腺癌。在此，我们研究了影响另一个RAD51旁系同源基因RAD51B的种系功能丧失变异是否也与乳腺癌和卵巢癌有关。在3422名连续入组并同意进行肿瘤/种系测序的乳腺癌和卵巢癌患者中，种系RAD51B功能丧失变异的观察到的携带频率显著高于gnomAD群体数据库中的对照病例（0.26%对0.09%），优势比为2.69（95%CI：1.4 - 5.3）。此外，我们证明，通过测序数据分析和体外功能试验证明，携带双等位基因RAD51B改变的肿瘤在同源重组DNA修复缺陷（HRD）方面存在缺陷。我们的研究结果表明，RAD51B应被视为乳腺癌和卵巢癌易感性临床种系检测面板的补充。
