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RAD51 mutations may increase risk for epithelial ovarian cancer
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RAD51C and RAD51D served as moderate ovarian cancer susceptibility genes and should be considered alongside BRCA1 and BRCA2 in routine clinical genetic testing for epithelial ovarian cancer, according to the results of a case-control study.
“Epithelial ovarian cancer has a significant heritable component,” Simon A Gayther, PhD, professor in the department of preventive medicine at University of Southern California’s Keck School of Medicine, and colleagues wrote. “A woman with a single first-degree relative diagnosed with ovarian cancer has a threefold increased risk of the disease. Twin studies suggest that most of the familial clustering results from inherited genetic factors.”
Gayther and colleagues sought to determine the contribution of deleterious mutations in the RAD51B, RAD51C and RAD51D genes to the risk for invasive epithelial ovarian cancer.
The researchers sequenced and analyzed the three RAD51 genes in germline DNA from 3,429 women with invasive epithelial ovarian cancer and 2,772 healthy controls. Further, they studied 2,000 BRCA1/BRCA2-negative women at increased risk for ovarian cancer based on family history from the United Kingdom Familial Ovarian Cancer Screening Study.
Researchers detected predicted deleterious mutations in 28 women with epithelial ovarian cancer and three controls (0.82% vs. 0.11%; P < .001).
The most frequent mutations among women with epithelial ovarian cancer occurred in the RAD51C (n = 14; 0.41%) and RAD51D (n = 12; 0.35%) genes, whereas two women harbored mutations in the RAD51B gene (0.06%).
The ORs associated with a deleterious mutation in any of the three genes was 8.1 (95% CI, 2.4-27) for all ovarian cancer subtypes and 9.3 (95% CI, 2.7-32) for serous ovarian cancer. The ORs for all ovarian cancer subtypes was 5.2 (95% CI, 1.1-24) for RAD51C and 12 (95% CI, 1.5-90) for RAD51D.
Researchers calculated an average cumulative risk for ovarian cancer by age 50 of 1.3% (95% CI, 0.3-6) for RAD51C and 3% (95% CI, 0.4-21) for RAD51D.
Thirteen RAD51 mutations (0.65%) occurred in the BRCA1/2-negative unaffected population (RAD51C, n= 7; RAD51D, n = 5; RAD51B, n = 1), a significantly greater rate than the rate detected among healthy controls (P < .001).
RAD51 mutation carriers had a greater probability than noncarriers of having a family history of ovarian cancer (P < .001).
“We estimate that RAD51B, RAD51C and RAD51D are responsible for approximately one in every 90 high-grade serous epithelial ovarian cancer occurrences and one in every 120 epithelial ovarian cancer occurrences,” Gayther and colleagues wrote. “In addition to the benefit of mutation testing of RAD51C and RAD51D for disease prevention, mutation carriers also may be responsive to treatment with poly(ADP-ribose) polymerase inhibitors, which results in synthetic lethality of cells that have mutant homologous recombination or double-strand DNA break repair. This treatment might improve PFS among these patients. Hence, such testing may be useful in patient decision making.” – by Cameron Kelsall
Disclosure: Gayther reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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