Significant associations with OC were observed in <i>BRCA1, BRCA2, RAD51C</i> and <i>RAD51D.</i> Other homologous recombination genes, <i>BARD1, NBN,</i> and <i>PALB2,</i> were not significantly associated with OC.
The analysis also showed a substantial difference in the profile of genes contributing to either BC or OC risk, including genes specifically associated with a high risk of OC but not BC (e.g., RAD51C, and RAD51D).
Population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing can prevent 1.86%/1.91% of BC and 3.2%/4.88% of OC in UK/US women: 657/655 OC cases and 2420/2386 BC cases prevented per million.
Population panel testing for <i>BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2</i> gene mutations is the most cost-effective genetic-testing strategy in general-population women and can prevent thousands more breast and ovarian cancers than current clinical-criteria based approaches.
RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) have recently been involved in breast and ovarian cancer predisposition: RAD51B, RAD51C, and RAD51D in ovarian cancer, RAD51B and XRCC2 in breast cancer.
RAD51D is a key player in DNA repair by homologous recombination (HR), and <i>RAD51D</i> truncating variant carriers have an increased risk for ovarian cancer.
Two components of the complex, RAD51C and RAD51D, increase the risk of ovarian cancer especially, and the other two, RAD51B and XRCC2 have been associated with breast cancer risk.
Although the cumulative frequency of RAD51C and RAD51D truncating mutations in our patients was lower than that of the BRCA1 and BRCA2 genes, it may explain OC susceptibility in approximately 3% of high-risk OC patients.
Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D.
The results of this study on familial and unselected breast, ovarian, colorectal, and prostate cancer patients suggest that RAD51D is primarily a moderate penetrance susceptibility gene for ovarian cancer, with clinical significance for the carriers.
Recent data show that mutations in RAD51D have an aetiological role in ovarian carcinoma, yet mutations do not appear to be associated with an increased risk for breast cancer.