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


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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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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Authors and Affiliations



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.

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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).

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