Abstract

Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia–like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the 'common disease, rare allele' hypothesis.

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Acknowledgements

We thank all the families for providing samples for this study. We are deeply indebted to German Cancer Aid for establishing the GC-HBOC and their longstanding patronage. This work was supported by grants from the German Cancer Aid (grant numbers 107054 and 107353), the Juergen-Manchot-Stiftung (L.H., H.S.), the Cancer Society Northrhine-Westphalia (D.N., E.H., H.S.), the Forschungskommission of the Heinrich-Heine-University, Düsseldorf (M.F., D.N., H.S., H. Hanenberg), the Bundesministerium für Bildung und Forschung network for Inherited Bone Marrow Failure Syndromes (H.S., H. Hanenberg) and the Deutsche Forschungsgemeinschaft SPP1230 (H. Hanenberg). We also thank N. Arnold, C. Bartram, U. Bick, W. Diestler, M. Loeffler, T. Grimm, R. Kreienberg, C. Nestle-Kraemling, B. Schlegelberger and P. Wieacker for their long-standing collaboration within the GC-HBOC. Finally, we acknowledge the excellent technical assistance of B. Kau, G. Krebsbach, J. Koehler, W. Kuss, R. Friedl and S. Engert.

Author information

Author notes

    • Heide Hellebrand
    •  & Constanze Wiek

    These authors contributed equally to the work.

    • Rita K Schmutzler
    •  & Helmut Hanenberg

    These authors contributed equally to the direction of the work.

Affiliations

  1. Department of Obstetrics and Gynecology, Division of Tumor Genetics, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Munich, Germany.

    • Alfons Meindl
    • , Heide Hellebrand
    • , Juliane Ramser
    •  & Marion Kiechle
  2. Department of Pediatric Hematology, Oncology and Clinical Immunology, Children's Hospital, Heinrich-Heine-University, Düsseldorf, Germany.

    • Constanze Wiek
    • , Verena Erven
    • , Marcel Freund
    •  & Helmut Hanenberg
  3. Center for Familial Breast and Ovarian Cancer and Center for Integrated Oncology, University Hospital, Cologne, Germany.

    • Barbara Wappenschmidt
    •  & Rita K Schmutzler
  4. Department of Obstetrics and Gynecology, Heinrich-Heine-University, Düsseldorf, Germany.

    • Dieter Niederacher
    •  & Ellen Honisch
  5. Institute of Human Genetics, Helmholtz Zentrum Muenchen, Neuherberg, Germany.

    • Peter Lichtner
  6. Institute of Virology, Heinrich-Heine-University, Düsseldorf, Germany.

    • Linda Hartmann
    •  & Heiner Schaal
  7. Institute of Human Genetics, Center for Molecular Medicine Cologne and Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany.

    • Christian Kubisch
  8. Institute of Epidemiology, Helmholtz Zentrum Muenchen, Neuherberg, Germany.

    • Hans E Wichmann
  9. Department of Obstetrics and Gynecology, Carl Gustav Carus University, Dresden, Germany.

    • Karin Kast
  10. Department of Obstetrics and Gynecology, Ulm University, Ulm, Germany.

    • Helmut Deißler
  11. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.

    • Christoph Engel
  12. Max-Planck-Institute of Psychiatry, Munich, Germany.

    • Bertram Müller-Myhsok
  13. Department of Human Genetics, University of Würzburg, Würzburg, Germany.

    • Kornelia Neveling
    •  & Detlev Schindler
  14. Department of Medical and Molecular Genetics, Kings College, Guy's Hospital, London, UK.

    • Christopher G Mathew
  15. Department of Pediatrics, Wells Center for Pediatric Research, Riley Hospital, Indiana University School of Medicine, Indianapolis, Indiana, USA.

    • Helmut Hanenberg

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Contributions

The study was designed by A.M., R.K.S. and H. Hanenberg. The screening experiments were performed by H. Hellebrand, D.N., B.W., K.K., H.D. and E.H. under the direction of A.M. Cloning, virus production, transductions and functional complementation tests were set up by C.W., V.E., K.N. and M.F. under the direction of H. Hanenberg and D.S. L.H. and H.S. performed splicing experiments. MALDI-TOF experiments were performed by P.L. under the direction of H.E.W. The statistical analyses were done by B.M.-M., R.K.S. and C.E. C.E. also provided clinical and histopathological data. Control samples were collected by C.K. and H.E.W. The search for families was initiated by M.K. and R.K.S., and families were provided by the GC-HBOC. J.R. and C.G.M. participated in discussing and revising the manuscript. The manuscript was written by A.M., R.K.S., D.N. and H. Hanenberg.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Alfons Meindl or Helmut Hanenberg.

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DOI

https://doi.org/10.1038/ng.569

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