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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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.

Author information

Author notes

    • Chey Loveday
    •  & Clare Turnbull

    These authors contributed equally to this work.


  1. Section of Cancer Genetics, The Institute of Cancer Research, Sutton, UK.

    • Chey Loveday
    • , Clare Turnbull
    • , Emma Ramsay
    • , Deborah Hughes
    • , Elise Ruark
    • , Georgina Bowden
    • , Bolot Kalmyrzaev
    • , Margaret Warren-Perry
    • , Katie Snape
    • , Anthony Renwick
    • , Sheila Seal
    •  & Nazneen Rahman
  2. The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.

    • Jessica R Frankum
    • , Christopher J Lord
    • , Alan Ashworth
    •  & Jorge S Reis-Filho
  3. Yorkshire Regional Centre for Cancer Treatment, Cookridge Hospital, Leeds, UK.

    • Julian W Adlard
  4. Leicestershire Genetics Centre, University Hospitals of Leicester National Health Service (NHS) Trust, Leicester, UK.

    • Julian Barwell
  5. Human Genetics, Division of Medical Sciences, University of Dundee, Dundee, UK.

    • Jonathan Berg
  6. North West Thames Regional Genetics Service, Kennedy Galton Centre, London, UK.

    • Angela F Brady
  7. Peninsula Regional Genetics Service, Royal Devon & Exeter Hospital, Exeter, UK.

    • Carole Brewer
  8. South West Thames Regional Genetics Service, St. George's Hospital, London, UK.

    • Glen Brice
  9. West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham, UK.

    • Cyril Chapman
  10. Sheffield Regional Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.

    • Jackie Cook
  11. West of Scotland Regional Genetics Service, FergusonSmith Centre for Clinical Genetics, Glasgow, UK.

    • Rosemarie Davidson
  12. South Western Regional Genetics Service, University Hospitals of Bristol NHS Foundation Trust, Bristol, UK.

    • Alan Donaldson
  13. Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

    • Fiona Douglas
  14. Cheshire and Merseyside Clinical Genetics Service, Alder Hey Children's NHS Foundation Trust, Liverpool, UK.

    • Lynn Greenhalgh
  15. Northern Genetics Service (Cumbria), Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK.

    • Alex Henderson
  16. South East Thames Regional Genetics Service, Guy′s and St. Thomas NHS Foundation Trust, London, UK.

    • Louise Izatt
  17. North East Thames Regional Genetics Service, Great Ormond St. Hospital, London, UK.

    • Ajith Kumar
  18. University Department of Medical Genetics & Regional Genetics Service, St. Mary's Hospital, Manchester, UK.

    • Fiona Lalloo
  19. University of Aberdeen and North of Scotland Clinical Genetics Service, Aberdeen Royal Infirmary, Aberdeen, UK.

    • Zosia Miedzybrodzka
  20. Northern Ireland Regional Genetics Service, Belfast Health and Social Care (HSC) Trust & Department of Medical Genetics, Queen's University Belfast, Belfast, UK.

    • Patrick J Morrison
  21. East Anglian Regional Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

    • Joan Paterson
  22. South East of Scotland Clinical Genetics Service, Western General Hospital, Edinburgh, UK.

    • Mary Porteous
  23. All Wales Medical Genetics Service, University Hospital of Wales, Cardiff, UK.

    • Mark T Rogers
  24. Royal Marsden NHS Foundation Trust, London, UK.

    • Susan Shanley
  25. Oxford Regional Genetics Service, Oxford Radcliffe Hospitals NHS Trust, Oxford, UK.

    • Lisa Walker
  26. Faculty of Medicine, University of Southampton, Southampton University Hospitals NHS Trust, Southampton, UK.

    • Diana Eccles
  27. University Department of Medical Genetics & Regional Genetics Service, St. Mary's Hospital, Manchester, UK.

    • D Gareth Evans
  28. Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Antonis C Antoniou


  1. Breast Cancer Susceptibility Collaboration (UK)

    A full list of members appears in the Supplementary Note.


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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Nazneen Rahman.

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