Germline mutations in RAD51D confer susceptibility to ovarian cancer

Abstract

Recently, RAD51C mutations were identified in families with breast and ovarian cancer1. 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.

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Figure 1: Abridged pedigrees of eight families with RAD51D mutations.
Figure 2
Figure 3: Effect of RAD51D silencing on olaparib sensitivity.

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Acknowledgements

We thank all the subjects and families that participated in the research. We thank A. Hall, D. Dudakia, J. Bull, R. Linger and A. Zachariou for their assistance in recruitment, B. Ebbs for assistance in DNA extraction and running the ABI sequencers, L. Thompson for the provision of cell lines and A. Strydom for assistance in preparing the manuscript. We are very grateful to all the clinicians and counselors in the Breast Cancer Susceptibility Collaboration UK (BCSC) that have contributed to the recruitment and collection of the Familial Breast Cancer Study (FBCS) samples. The full list of BCSC contributors is provided in the Supplementary Note. This work was funded by Cancer Research UK (C8620/A8372 and C8620/A8857), US Military Acquisition (ACQ) Activity, Era of Hope Award (W81XWH-05-1-0204), Breakthrough Breast Cancer and the Institute of Cancer Research (UK). We acknowledge NHS funding to the Royal Marsden/Institute of Cancer Research National Institute for Health Research (NIHR) Specialist Cancer Biomedical Research Centre. C.T. is a Medical Research Council (MRC)-funded Clinical Research Fellow. A.C.A. is a Cancer Research UK Senior Cancer Research Fellow (C12292/A11174). We acknowledge the use of DNA from the British 1958 Birth Cohort collection funded by the MRC grant G0000934 and the Wellcome Trust grant 068545/Z/02.

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N.R., C.L. and C.T. designed the experiment. M.W.-P., C.T. and N.R. coordinated recruitment to the FBCS. J.W.A., J. Barwell, J. Berg, A.F.B., C.B., G. Brice, C.C., J.C., R.D., A.D., F.D., D.G.E., D.E., L.G., A.H., L.I., A.K., F.L., Z.M., P.J.M., J.P., M.P., M.T.R., S. Shanley and L.W. coordinated the FBCS sample recruitment from their respective Genetics centers. C.L., E. Ramsay, D.H., G. Bowden, B.K., K.S., A.R. and S. Seal performed sequencing of RAD51D. J.R.F., C.J.L. and A.A. designed and conducted drug sensitivity experiments. J.S.R.-F. undertook examination and dissection of pathological specimens. C.T., E. Ruark and A.C.A. performed statistical analyses. C.L., C.T. and N.R. drafted the manuscript with substantial input from D.G.E., D.E., A.C.A., A.A. and J.S.R.-F. C.T. and N.R. oversaw and managed all aspects of the study.

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Correspondence to Nazneen Rahman.

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The authors declare no competing financial interests.

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A full list of members appears in the Supplementary Note.

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Supplementary Figures 1 and 2, Supplementary Tables 1–4 and Supplementary Note. (PDF 213 kb)

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Loveday, C., Turnbull, C., Ramsay, E. et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 43, 879–882 (2011). https://doi.org/10.1038/ng.893

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