Germline mutations in RAD51D confer susceptibility to ovarian cancer

Abstract

Recently, RAD51C mutations were identified in families with breast and ovarian cancer. This observation prompted us to investigate the role of RAD51D in cancer susceptibility. We identified eight inactivating RAD51D mutations in unrelated individuals from 911 breast-ovarian cancer families compared with one inactivating mutation identified in 1,060 controls (P = 0.01). The association found here was principally with ovarian cancer, with three mutations identified in the 59 pedigrees with three or more individuals with ovarian cancer (P = 0.0005). The relative risk of ovarian cancer for RAD51D mutation carriers was estimated to be 6.30 (95% CI 2.86-13.85, P = 4.8 × 10(-6)). By contrast, we estimated the relative risk of breast cancer to be 1.32 (95% CI 0.59-2.96, P = 0.50). These data indicate that RAD51D mutation testing may have clinical utility in individuals with ovarian cancer and their families. Moreover, we show that cells deficient in RAD51D are sensitive to treatment with a PARP inhibitor, suggesting a possible therapeutic approach for cancers arising in RAD51D mutation carriers.

Figure 1

Abridged pedigrees of eight families with RAD51D mutations. Individuals with ovarian cancer are shown as red circles, individuals with breast cancer are shown as black circles, other cancers are shown as unfilled circles or squares. Where known, the age of cancer diagnosis is under the individual, with two ages given for metachronas bilateral breast cancers. The relevant RAD51D mutation is given under the affected individuals analysed but not the unaffected individuals, to preserve confidentiality. BC, breast cancer; BC bilat., bilateral breast cancer; OC, ovarian cancer; CRC, colorectal cancer; LC, lung cancer; NHL, non-Hodgkin lymphoma; PaC, pancreatic cancer; Pr, prostate cancer.

Figure 2

Average age-related cumulative risk of ovarian cancer in RAD51D mutation carriers, BRCA1 and BRCA2 mutation carriers and the population .

Figure 3

Effect of RAD51D silencing on Olaparib sensitivity. CAL51 (a) or MCF7 (b) cells were transfected with siCONTROL, siRNA directed against RAD51D or siRNA directed against BRCA2 and then treated with olaparib for 7 days before assaying for cell viability. Wild-type CHO cells or CHO cells mutated in RAD51D were treated with olaparib for 7 days before assaying for cell viability (c).