Germline Mutations in RAD51D Confer Susceptibility to Ovarian Cancer

Nat Genet. 2011 Aug 7;43(9):879-882. doi: 10.1038/ng.893.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Age Factors
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • DNA-Binding Proteins / genetics*
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Germ-Line Mutation*
  • Heterozygote
  • Humans
  • Ovarian Neoplasms / genetics*
  • Pedigree
  • Poly(ADP-ribose) Polymerase Inhibitors

Substances

  • DNA-Binding Proteins
  • Poly(ADP-ribose) Polymerase Inhibitors
  • RAD51D protein, human