The known genetic variance for epithelial ovarian cancer (EOC) accounts for less than half the familial risks of the disease. BRCA1 and BRCA2 are the major high-penetrance EOC susceptibility genes. More recently genes that interact with BRCA1 and BRCA2 in the same biological pathways, but conferring more moderate penetrance (e.g. RAD51C, RAD51D) have also been identified. Mutations in these genes result in defects in homologous recombination and double strand break repair (HR/DSB). We hypothesized that other genes operating in these and other DNA repair pathways may also confer EOC susceptibility. Whole exome sequencing data, available from more than 400 high-grade serous ovarian cancers, were used to identify 24 candidate genes harboring germline truncating mutations in at least 2 cases, followed by replication analysis using targeted resequencing in ~3,000 cases and 3,000 controls. Subjects were also sequenced for the known susceptibility genes listed above. The data confirmed the previously reported contributions of BRCA1, BRCA2, RAD51C and RAD51D to EOC. In addition, we identified BRIP1, and FANCM as candidate EOC susceptibility genes. Surprisingly, for several genes we found truncating mutations were equally prevalent in cases as they were in controls. These mutations may still represent rare low-penetrance susceptibility alleles for EOC, which we are too limited in sample size and power to confirm; or more likely, it indicates that cells can tolerate heterozygous loss-of-function mutations in apparently critical DNA repair genes without any impact on neoplastic development. These findings may have implications for risk prediction and prevention strategies for EOC and possibly for the identification of novel therapeutic targets.

Citation Format: Susan J. Ramus, Honglin Song, Ed Dicks, Maria Intermaggio, Jane Hayward, Jonathan P. Tyrer, Jacek Gronwald, Susanne Krüger Kjær, Alice Wittemore, Beth Karlan, Kunle Odunsi, Usha Menon, David D. Bowtell, Ellen L. Goode, Paul D.P. Pharoah, Simon A. Gayther. Whole exome and targeted resequencing, of population based ovarian cancer cases and controls, identifies susceptibility genes for ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1213.