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 Canc Susceptibility

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    Abstract

    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 x 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
    DOIs
    Publication statusPublished - Sep 2011

    Keywords

    • BREAST-CANCER
    • FANCONI-ANEMIA
    • BRCA2 MUTATIONS
    • HOMOLOGOUS RECOMBINATION
    • FAMILIAL OVARIAN
    • SPLICING SIGNALS
    • GENE
    • DNA
    • PREDICTION
    • SEQUENCE

    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 Canc Susceptibility (2011). Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nature Genetics, 43(9), 879-882. https://doi.org/10.1038/ng.893