Population-based targeted sequencing of 54 candidate genes identifies <i>PALB2</i> as a susceptibility gene for high-grade serous ovarian cancer.

Abstract

The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. The ORs associated for high-grade serous ovarian cancer were 3.01 for <i>PALB2</i> (95% CI 1.59 to 5.68; p=0.00068), 1.99 for <i>POLK</i> (95% CI 1.15 to 3.43; p=0.014) and 4.07 for <i>SLX4</i> (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in <i>FBXO10</i> were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for <i>PALB2</i> in high-grade serous ovarian cancer is likely to represent a true positive. We have found strong evidence that carriers of <i>PALB2</i> deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of <i>PALB2</i> in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.