Abstract
BACKGROUND: With the widespread use of multigene panel genetic testing, population-based studies are necessary to accurately assess penetrance in unselected individuals. We evaluated the prevalence of germline pathogenic or likely pathogenic variants (mutations) in 12 cancer-predisposition genes and associations with ovarian cancer risk in three population-based prospective studies [Nurses' Health Study (NHS), NHSII, Cancer Prevention Study II]. METHODS: We included women with epithelial ovarian or peritoneal cancer (n = 776) and controls who were alive and had at least one intact ovary at the time of the matched case diagnosis (n = 1,509). Germline DNA was sequenced for mutations in 12 genes. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for ovarian cancer risk by mutation status. RESULTS: The mutation frequency across all 12 genes was 11.2% in cases and 3.3% in controls (P < 0.0001). BRCA1 and BRCA2 were the most frequently mutated (3.5% and 3.8% of cases and 0.3% and 0.5% of controls, respectively) and were associated with increased ovarian cancer risk [OR, BRCA1 = 12.38; 95% confidence interval (CI) = 4.72-32.45; OR, BRCA2 = 9.18; 95% CI = 3.98-21.15]. Mutation frequencies for the other genes were ≤1.0% and only PALB2 was significantly associated with risk (OR = 5.79; 95% CI = 1.09-30.83). There was no difference in survival for women with a BRCA germline mutation versus no mutation. CONCLUSIONS: Further research is needed to better understand the role of other mutations in ovarian cancer among unselected populations. IMPACT: Our data support guidelines for germline genetic testing for BRCA1 and BRCA2 among women diagnosed with epithelial ovarian cancer; testing for PALB2 may be warranted.