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Germline mutations in RAD51D confer susceptibility to ovarian cancer

Lookup NU author(s): Dr Fiona Douglas, Dr Chris Lord

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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.


Publication metadata

Author(s): Loveday C, Turnbull C, Ramsay E, Hughes D, Ruark E, Frankum JR, Bowden G, Kalmyrzaev B, Warren-Perry M, Snape K, Adlard JW, Barwell J, Berg J, Brady AF, Brewer C, Brice G, Chapman C, Cook J, Davidson R, Donaldson A, Douglas F, Greenhalgh L, Henderson A, Izatt L, Kumar A, Lalloo F, Miedzybrodzka Z, Morrison PJ, Paterson J, Porteous M, Rogers MT, Shanley S, Walker L, Eccles D, Evans DG, Renwick A, Seal S, Lord CJ, Ashworth A, Reis-Filho JS, Antoniou AC, Rahman N, Breast Canc Susceptibility

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2011

Volume: 43

Issue: 9

Pages: 879-882

Print publication date: 01/09/2011

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/ng.893

DOI: 10.1038/ng.893


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Funding

Funder referenceFunder name
Breakthrough Breast Cancer
Institute of Cancer Research (UK)
NHS
US Military Acquisition (ACQ) Activity
068545/Z/02Wellcome Trust
C12292/A11174Cancer Research UK
C8620/A8372Cancer Research UK
C8620/A8857Cancer Research UK
G0000934Medical Research Council (MRC)
W81XWH-05-1-0204Era of Hope Award

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