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Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene

Nature Genetics volume 42, pages 410–414 (2010)Cite this article

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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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Figure 1: RAD51C mutations in familial breast and ovarian cancer pedigrees.
Figure 2: Functional analysis of the splice donor mutations 145+1G>T and 904+5G>T.
Figure 3: Function of RAD51C missense mutations in Rad51c-deficient DT40 cells.
Figure 4: Function of RAD51C missense mutations in human RAD51C-mutated fibroblasts.

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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.

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Author notes

  1. Heide Hellebrand and Constanze Wiek: These authors contributed equally to the work.

  2. Rita K Schmutzler and Helmut Hanenberg: These authors contributed equally to the direction of the work.

Authors and 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

    Constanze Wiek, Verena Erven, Marcel Freund & Helmut Hanenberg

  3. Germany,

    Constanze Wiek, Verena Erven, Marcel Freund & Helmut Hanenberg

  4. Center for Familial Breast and Ovarian Cancer and Center for Integrated Oncology, University Hospital, Cologne, Germany

    Barbara Wappenschmidt & Rita K Schmutzler

  5. Department of Obstetrics and Gynecology, Heinrich-Heine-University, Düsseldorf, Germany

    Dieter Niederacher & Ellen Honisch

  6. Institute of Human Genetics, Helmholtz Zentrum Muenchen, Neuherberg, Germany

    Peter Lichtner

  7. Institute of Virology, Heinrich-Heine-University, Düsseldorf, Germany

    Linda Hartmann & Heiner Schaal

  8. 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

  9. Institute of Epidemiology, Helmholtz Zentrum Muenchen, Neuherberg, Germany

    Hans E Wichmann

  10. Department of Obstetrics and Gynecology, Carl Gustav Carus University, Dresden, Germany

    Karin Kast

  11. Department of Obstetrics and Gynecology, Ulm University, Ulm, Germany

    Helmut Deißler

  12. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany

    Christoph Engel

  13. Max-Planck-Institute of Psychiatry, Munich, Germany

    Bertram Müller-Myhsok

  14. Department of Human Genetics, University of Würzburg, Würzburg, Germany

    Kornelia Neveling & Detlev Schindler

  15. Department of Medical and Molecular Genetics, Kings College, Guy's Hospital, London, UK

    Christopher G Mathew

  16. Department of Pediatrics, Wells Center for Pediatric Research, Riley Hospital, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Helmut Hanenberg

Authors
  1. Alfons Meindl
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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.

Corresponding authors

Correspondence to Alfons Meindl or Helmut Hanenberg.

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The authors declare no competing financial interests.

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Meindl, A., Hellebrand, H., Wiek, C. et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 42, 410–414 (2010). https://doi.org/10.1038/ng.569

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