Journal Article

Germline mutations in RAD51D confer susceptibility to ovarian cancer

Miedzybrodzka, Zosia, Brady, Angela F, Paterson, Joan, Walker, Lisa, Hughes, Deborah, Barwell, Julian, Chapman, Cyril, Brewer, Carole, Porteous, Mary, Adlard, Julian W, Morrison, Patrick J, Kumar, Ajith, Eccles, Diana, Turnbull, Clare, Ramsay, Emma, Seal, Sheila, Cook, Jackie, Donaldson, Alan, Izatt, Louise, Kalmyrzaev, Bolot, Davidson, Rosemarie, Ashworth, Alan, Berg, Jonathan, Loveday, Chey, Henderson, Alex, Brice, Glen, Lalloo, Fiona, Evans, D Gareth, Frankum, Jessica R, Warren-Perry, Margaret, Lord, Christopher J, Ruark, Elise, Antoniou, Antonis C, Renwick, Anthony, Rahman, Nazneen, Greenhalgh, Lynn, Bowden, Georgina, Shanley, Susan, Reis-Filho, Jorge S, Rogers, Mark T, Douglas, Fiona, Snape, Katie

2011

Overview

Nazneen Rahman and colleagues show that germline inactivating mutations in RAD51D confer susceptibility to ovarian cancer. They further show that RAD51D-deficient cells are sensitive to PARP inhibition, suggesting a possible strategy for treating cancers arising in RAD51D mutation carriers. Recently, RAD51C mutations were identified in families with breast and ovarian cancer 1 . 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/727/2000 / 631/208/737 / 631/67/1059/99 / 692/699/67/1517/1709 / Age Factors / Agriculture / Animal Genetics and Genomics / Animals / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Breast cancer / Cancer Research / CHO Cells / Cricetinae / Cricetulus / DNA-Binding Proteins - genetics / Drug Resistance, Neoplasm - genetics / Female / Female genital diseases / Fundamental and applied biological sciences. Psychology / Gene Function / Gene mutations / Genetic aspects / Genetic Predisposition to Disease / Genetics of eukaryotes. Biological and molecular evolution / Germ-Line Mutation / Gynecology. Andrology. Obstetrics / Heterozygote / Human Genetics / Humans / letter / Medical research / Medical sciences / Mutation / Ovarian cancer / Ovarian Neoplasms - genetics / Pedigree / Poly(ADP-ribose) Polymerase Inhibitors / Polymerase chain reaction / Studies / Tumors