Germline RAD51B variants confer susceptibility to breast and ovarian cancers deficient in homologous recombination
Jeremy Setton, Pier Selenica, Semanti Mukherjee, Rachna Shah, Isabella L. Pecorari, Biko McMillan, Xin Pei, Yelena Kemel, Ozge Ceyhan‐Birsoy, Margaret Sheehan, Kaitlyn Tkachuk, David N. Brown, Liying Zhang, Karen A. Cadoo, Simon N. Powell, Britta Weigelt, Mark E. Robson, Nadeem Riaz, Kenneth Offit, Jorge S. Reis‐Filho, Diana Mandelker
Abstract
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.