Germline mutations in RAD51D confer susceptibility to ovarian cancer


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 options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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


  1. 1

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

    CAS  Article  Google Scholar 

  2. 2

    Heyer, W.-D., Ehmsen, K.T. & Liu, J. Regulation of homologous recombination in eukaryotes. Annu. Rev. Genet. 44, 113–139 (2010).

    CAS  Article  Google Scholar 

  3. 3

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

    CAS  Article  Google Scholar 

  4. 4

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

    CAS  Article  Google Scholar 

  5. 5

    Easton, D.F., Bishop, D.T., Ford, D. & Crockford, G.P. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Gayther, S.A. 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).

    CAS  Article  Google Scholar 

  7. 7

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

    CAS  Article  Google Scholar 

  8. 8

    Antoniou, A.C., Gayther, S.A., Stratton, J.F., Ponder, B.A. & Easton, D.F. Risk models for familial ovarian and breast cancer. Genet. Epidemiol. 18, 173–190 (2000).

    CAS  Article  Google Scholar 

  9. 9

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

    CAS  Article  Google Scholar 

  10. 10

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

    CAS  Article  Google Scholar 

  11. 11

    Meijers-Heijboer, H. 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).

    CAS  Article  Google Scholar 

  12. 12

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

    CAS  Article  Google Scholar 

  13. 13

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

    CAS  Article  Google Scholar 

  14. 14

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

    CAS  Article  Google Scholar 

  15. 15

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

    CAS  Article  Google Scholar 

  16. 16

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

    CAS  Article  Google Scholar 

  17. 17

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

    CAS  Article  Google Scholar 

  18. 18

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

    CAS  Article  Google Scholar 

  19. 19

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

    CAS  Article  Google Scholar 

  20. 20

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

    CAS  Article  Google Scholar 

  21. 21

    Rebbeck, T.R., Kauff, N.D. & Domchek, S.M. 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).

    CAS  Article  Google Scholar 

  22. 22

    Antoniou, A. 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).

    CAS  Article  Google Scholar 

  23. 23

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

  24. 24

    Ramensky, V., Bork, P. & Sunyaev, S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 30, 3894–3900 (2002).

    CAS  Article  Google Scholar 

  25. 25

    Ng, P.C. & Henikoff, S. Predicting deleterious amino acid substitutions. Genome Res. 11, 863–874 (2001).

    CAS  Article  Google Scholar 

  26. 26

    Reese, M.G., Eeckman, F.H., Kulp, D. & Haussler, D. Improved splice site detection in Genie. J. Comput. Biol. 4, 311–323 (1997).

    CAS  Article  Google Scholar 

  27. 27

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

    CAS  Article  Google Scholar 

  28. 28

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

    CAS  Article  Google Scholar 

  29. 29

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

    Article  Google Scholar 

  30. 30

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

    CAS  Article  Google Scholar 

  31. 31

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

    CAS  Article  Google Scholar 

  32. 32

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

    CAS  Article  Google Scholar 

  33. 33

    Lange, K., Weeks, D. & Boehnke, M. Programs for pedigree analysis: MENDEL, FISHER, and dGENE. Genet. Epidemiol. 5, 471–472 (1988).

    CAS  Article  Google Scholar 

  34. 34

    Antoniou, A.C. & Easton, D.F. Polygenic inheritance of breast cancer: implications for design of association studies. Genet. Epidemiol. 25, 190–202 (2003).

    Article  Google Scholar 

  35. 35

    Antoniou, A.C. 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).

    CAS  Article  Google Scholar 

Download references


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





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.

Corresponding author

Correspondence to Nazneen Rahman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

A full list of members appears in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Loveday, C., Turnbull, C., Ramsay, E. et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 43, 879–882 (2011).

Download citation

Further reading


Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing