Germline mutations in RAD51D confer susceptibility to ovarian cancer

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

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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.
Original languageEnglish
Pages (from-to)879-882
Number of pages4
JournalNature Genetics
Volume43
Issue number9
Early online date7 Aug 2011
DOIs
Publication statusPublished - Sep 2011

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Keywords

  • age factors
  • animals
  • CHO cells
  • cricetinae
  • cricetulus
  • DNA-binding proteins
  • drug resistance, neoplasm
  • female
  • genetic predisposition to disease
  • germ-line mutation
  • heterozygote
  • humans
  • ovarian neoplasms
  • pedigree
  • poly(ADP-ribose) polymerases

Cite this

Loveday, C., Turnbull, C., Ramsay, E., Hughes, D., Ruark, E., Frankum, J. R., Bowden, G., Kalmyrzaev, B., Warren-Perry, M., Snape, K., Adlard, J. W., Barwell, J., Berg, J., Brady, A. F., Brewer, C., Brice, G., Chapman, C., Cook, J., Davidson, R., ... Breast Cancer Susceptibility Collaboration (UK) (2011). Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nature Genetics, 43(9), 879-882. https://doi.org/10.1038/ng.893