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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat. Genet. 42, 410–414 (2010).

  2. 2.

    , & Regulation of homologous recombination in eukaryotes. Annu. Rev. Genet. 44, 113–139 (2010).

  3. 3.

    et al. A census of human cancer genes. Nat. Rev. Cancer 4, 177–183 (2004).

  4. 4.

    & Genetic predisposition to breast cancer: past, present, and future. Annu. Rev. Genomics Hum. Genet. 9, 321–345 (2008).

  5. 5.

    , , & Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am. J. Hum. Genet. 52, 678–701 (1993).

  6. 6.

    et al. The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: no evidence for other ovarian cancer-susceptibility genes. Am. J. Hum. Genet. 65, 1021–1029 (1999).

  7. 7.

    et al. Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer. Hum. Mutat. 28, 1207–1215 (2007).

  8. 8.

    , , , & Risk models for familial ovarian and breast cancer. Genet. Epidemiol. 18, 173–190 (2000).

  9. 9.

    et al. Cloning of human, mouse and fission yeast recombination genes homologous to RAD51 and recA. Nat. Genet. 4, 239–243 (1993).

  10. 10.

    et al. Identification and purification of two distinct complexes containing the five RAD51 paralogs. Genes Dev. 15, 3296–3307 (2001).

  11. 11.

    et al. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat. Genet. 31, 55–59 (2002).

  12. 12.

    et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat. Genet. 38, 873–875 (2006).

  13. 13.

    et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat. Genet. 39, 165–167 (2007).

  14. 14.

    et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat. Genet. 38, 1239–1241 (2006).

  15. 15.

    et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297, 606–609 (2002).

  16. 16.

    et al. The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat. Genet. 37, 934–935 (2005).

  17. 17.

    et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat. Genet. 39, 162–164 (2007).

  18. 18.

    et al. Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat. Genet. 42, 406–409 (2010).

  19. 19.

    et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

  20. 20.

    et al. Repression of mutagenesis by Rad51D-mediated homologous recombination. Nucleic Acids Res. 34, 1358–1368 (2006).

  21. 21.

    , & Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J. Natl. Cancer Inst. 101, 80–87 (2009).

  22. 22.

    et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am. J. Hum. Genet. 72, 1117–1130 (2003).

  23. 23.

    International Agency for Research on Cancer. Cancer incidence in five continents. Volume VIII. IARC Sci. Publ. 1–781 (2002).

  24. 24.

    , & Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 30, 3894–3900 (2002).

  25. 25.

    & Predicting deleterious amino acid substitutions. Genome Res. 11, 863–874 (2001).

  26. 26.

    , , & Improved splice site detection in Genie. J. Comput. Biol. 4, 311–323 (1997).

  27. 27.

    & Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J. Comput. Biol. 11, 377–394 (2004).

  28. 28.

    , & Prediction of human mRNA donor and acceptor sites from the DNA sequence. J. Mol. Biol. 220, 49–65 (1991).

  29. 29.

    et al. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 37, e67 (2009).

  30. 30.

    & Prediction of complete gene structures in human genomic DNA. J. Mol. Biol. 268, 78–94 (1997).

  31. 31.

    et al. Molecular analysis reveals a genetic basis for the phenotypic diversity of metaplastic breast carcinomas. J. Pathol. 220, 562–573 (2010).

  32. 32.

    et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

  33. 33.

    , & Programs for pedigree analysis: MENDEL, FISHER, and dGENE. Genet. Epidemiol. 5, 471–472 (1988).

  34. 34.

    & Polygenic inheritance of breast cancer: implications for design of association studies. Genet. Epidemiol. 25, 190–202 (2003).

  35. 35.

    et al. Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study. Genet. Epidemiol. 21, 1–18 (2001).

Download references

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.

Author information

Author notes

    • Chey Loveday
    •  & Clare Turnbull

    These authors contributed equally to this work.

Affiliations

  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

Consortia

  1. Breast Cancer Susceptibility Collaboration (UK)

    A full list of members appears in the Supplementary Note.

Authors

  1. Search for Chey Loveday in:

  2. Search for Clare Turnbull in:

  3. Search for Emma Ramsay in:

  4. Search for Deborah Hughes in:

  5. Search for Elise Ruark in:

  6. Search for Jessica R Frankum in:

  7. Search for Georgina Bowden in:

  8. Search for Bolot Kalmyrzaev in:

  9. Search for Margaret Warren-Perry in:

  10. Search for Katie Snape in:

  11. Search for Julian W Adlard in:

  12. Search for Julian Barwell in:

  13. Search for Jonathan Berg in:

  14. Search for Angela F Brady in:

  15. Search for Carole Brewer in:

  16. Search for Glen Brice in:

  17. Search for Cyril Chapman in:

  18. Search for Jackie Cook in:

  19. Search for Rosemarie Davidson in:

  20. Search for Alan Donaldson in:

  21. Search for Fiona Douglas in:

  22. Search for Lynn Greenhalgh in:

  23. Search for Alex Henderson in:

  24. Search for Louise Izatt in:

  25. Search for Ajith Kumar in:

  26. Search for Fiona Lalloo in:

  27. Search for Zosia Miedzybrodzka in:

  28. Search for Patrick J Morrison in:

  29. Search for Joan Paterson in:

  30. Search for Mary Porteous in:

  31. Search for Mark T Rogers in:

  32. Search for Susan Shanley in:

  33. Search for Lisa Walker in:

  34. Search for Diana Eccles in:

  35. Search for D Gareth Evans in:

  36. Search for Anthony Renwick in:

  37. Search for Sheila Seal in:

  38. Search for Christopher J Lord in:

  39. Search for Alan Ashworth in:

  40. Search for Jorge S Reis-Filho in:

  41. Search for Antonis C Antoniou in:

  42. Search for Nazneen Rahman in:

Contributions

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.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1 and 2, Supplementary Tables 1–4 and Supplementary Note.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.893