Identification of new hereditary ovarian cancer genes through investigation of exceptional responders to platinum-based therapy

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A significant proportion of ovarian cancer incidence is attributed to the inherited germ-line mutations. Approximately 15% of ovarian cancer patients carry germ-line mutations in BRCA1 and BRCA2, and there are additional hereditary variants in recently identified ovarian cancer susceptibility genes, with the most comprehensive data obtained for BRIP1, RAD51C and RAD51D. Yet a large proportion of familial ovarian cancer clustering remains unexplained by known germ-line mutations. Given the failure of family-based studies to identify additional ovarian cancer susceptibility genes, there is a need for alternative approaches for discovery of new hereditary ovarian cancer genes. Because the hitherto known gene mutations impact on DNA crosslink and homologous recombinational repair, we hypothesize that the exome analysis of mutation-negative exceptional responders to platinum therapy will greatly help to identify previously unappreciated genes for hereditary ovarian cancer.In this project we aim to identify hereditary mutations in new ovarian cancer genes through whole exome sequencing analysis of 100 patients with high-grade serous epithelial ovarian cancer and an exceptional response to platinum. We expect that we can identify at least 24 mutations in strong candidate repair genes that may affect the platinum response through their impact on DNA crosslink repair. We will test 24 recurrent mutations for their impact on ovarian cancer risk in a large case-control study including 2,000 ovarian cancer cases. We will furthermore test up to 24 genes with individually rare mutations for their impact on ovarian cancer risk in a large amplicon sequencing study of the same series of ovarian cancer cases. We will also sequence the exomes of ovarian tumours for somatic mutations in up to 50 patients for whom no candidate gene has been obtained in the germline exome. From the combined analyses of these approaches we will select a final set of 20 mutations for functional assessments through genome editing in immortalized normal ovarian epithelial cell lines. Wildtype and mutant counterparts will be comparatively tested for their DNA damage response and their drug response towards platinum. We expect that these studies will identify new ovarian cancer susceptibility genes and provide insights into their magnitudes of risk, their functional role and their predictive value for platinum-based therapy of malignancies.