Discovery of structural deletions in breast cancer susceptibility genes using whole genome sequencing data from >2,000 African ancestry women

Abstract Structural deletions in breast cancer susceptibility genes could confer to cancer risk, but remain poorly characterized. Here, we conducted in-depth whole genome sequencing (WGS) in germline DNA samples from 1,340 invasive breast cancer cases and 675 controls of African ancestry to discover such deletions. We identified 33 deletions, including five protein-truncating deletions in BRCA1, BRCA2, RAD51C, GEN1, and BRIP1, were observed only in cases but not in controls. Three deletions, including one protein-truncating deletion in TP53, were found to have a higher frequency in cases than in controls. In total, 4.6% of cases and 0.6% of controls carried any of these 36 deletions, resulting in an odds ratio (OR) of 8.0 (95%CI = 2.94 - 30.41). In addition, we identified a low-frequency deletion in NF1 associated with breast cancer risk (OR = 1.93, 95%CI = 1.14 - 3.42). These findings have significant implications for genetic testing for this common cancer.