The purpose of our study is to identify damaging variants in genes that can lead to defects of DNA repair by homologous recombination (HR) in epithelial ovarian cancer (OC) patients, through which the ideal candidates for Poly (adenosine diphosphate– ribose) polymerase (PARP) inhibitor therapies, can be selected. In fact, the recent data of the Phase III clinical trial, SOLO1, suggest a remarkable impact on patient survival when these inhibitors come in the first line of treatment in newly diagnosed OC patients.
We have already completed the comprehensive analysis of genomic DNA from 578 epithelial OC patients for mutations in 94 genes that are involved in DNA repair. In addition to that, we have collected and assessed for somatic BRCA1 & BRCA2 mutations, 121 tumors from OC patients that had negative germline testing. Overall, 25.4% of the patients tested, carried germline loss-of-function (LoF) variants, distributed in 18 genes namely, BRCA1, BRCA2, RAD51C, ATM, FANCL, CHEK2, FANCM, BRIP1, TP53, NBN, FANCA, RECQL4, MLH1, MSH2, MSH6, PMS2, ERCC2 and SLX4, of which the vast majority involves mutations in HR genes. Interestingly, beyond BRCA1/2 mutations, which accounted for 72.1% of the total LoF variants, RAD51C LoF variants were the most frequently identified. Subsequent tumor analysis resulted in the identification of damaging BRCA1/2 variants in a further 11.5% of the OC tested. This is an undergoing study, but the results to date are outstanding, with approximately one in three of OC patients tested prospect to be good candidates for therapies targeting defective DNA repair through HR.