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

Alfons Meindl; Heide Hellebrand; Constanze Wiek; Verena Erven; Barbara Wappenschmidt; Dieter Niederacher; Marcel Freund; Peter Lichtner; Linda Hartmann; Heiner Schaal; Juliane Ramser; Ellen Honisch; Christian Kubisch; Hans E. Wichmann; Karin Kast; Helmut Deissler; Christoph Engel; Bertram Mueller-Myhsok; Kornelia Neveling; Marion Kiechle; Christopher G. Mathew; Detlev Schindler; Rita K. Schmutzler; Helmut Hanenberg

doi:10.1038/ng.569

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

Alfons Meindl, Heide Hellebrand, Constanze Wiek, Verena Erven, Barbara Wappenschmidt, Dieter Niederacher, Marcel Freund, Peter Lichtner, Linda Hartmann, Heiner Schaal, Juliane Ramser, Ellen Honisch, Christian Kubisch, Hans E. Wichmann, Karin Kast, Helmut Deissler, Christoph Engel, Bertram Mueller-Myhsok, Kornelia Neveling, Marion KiechleChristopher G. Mathew, Detlev Schindler, Rita K. Schmutzler, Helmut Hanenberg

Medical & Molecular Genetics

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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.

Original language	English
Pages (from-to)	410 - U65
Number of pages	5
Journal	Nature Genetics
Volume	42
Issue number	5
DOIs	https://doi.org/10.1038/ng.569
Publication status	Published - May 2010

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Meindl, A., Hellebrand, H., Wiek, C., Erven, V., Wappenschmidt, B., Niederacher, D., Freund, M., Lichtner, P., Hartmann, L., Schaal, H., Ramser, J., Honisch, E., Kubisch, C., Wichmann, H. E., Kast, K., Deissler, H., Engel, C., Mueller-Myhsok, B., Neveling, K., ... Hanenberg, H. (2010). Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nature Genetics, 42(5), 410 - U65. https://doi.org/10.1038/ng.569

@article{edd034030b304e5b976cc2906b252b8e,

title = "Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene",

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.",

author = "Alfons Meindl and Heide Hellebrand and Constanze Wiek and Verena Erven and Barbara Wappenschmidt and Dieter Niederacher and Marcel Freund and Peter Lichtner and Linda Hartmann and Heiner Schaal and Juliane Ramser and Ellen Honisch and Christian Kubisch and Wichmann, {Hans E.} and Karin Kast and Helmut Deissler and Christoph Engel and Bertram Mueller-Myhsok and Kornelia Neveling and Marion Kiechle and Mathew, {Christopher G.} and Detlev Schindler and Schmutzler, {Rita K.} and Helmut Hanenberg",

year = "2010",

month = may,

doi = "10.1038/ng.569",

language = "English",

volume = "42",

pages = "410 -- U65",

journal = "Nature Genetics",

issn = "1546-1718",

publisher = "Nature Research",

number = "5",

}

Meindl, A, Hellebrand, H, Wiek, C, Erven, V, Wappenschmidt, B, Niederacher, D, Freund, M, Lichtner, P, Hartmann, L, Schaal, H, Ramser, J, Honisch, E, Kubisch, C, Wichmann, HE, Kast, K, Deissler, H, Engel, C, Mueller-Myhsok, B, Neveling, K, Kiechle, M, Mathew, CG, Schindler, D, Schmutzler, RK & Hanenberg, H 2010, 'Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene', Nature Genetics, vol. 42, no. 5, pp. 410 - U65. https://doi.org/10.1038/ng.569

TY - JOUR

T1 - Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene

AU - Meindl, Alfons

AU - Hellebrand, Heide

AU - Wiek, Constanze

AU - Erven, Verena

AU - Wappenschmidt, Barbara

AU - Niederacher, Dieter

AU - Freund, Marcel

AU - Lichtner, Peter

AU - Hartmann, Linda

AU - Schaal, Heiner

AU - Ramser, Juliane

AU - Honisch, Ellen

AU - Kubisch, Christian

AU - Wichmann, Hans E.

AU - Kast, Karin

AU - Deissler, Helmut

AU - Engel, Christoph

AU - Mueller-Myhsok, Bertram

AU - Neveling, Kornelia

AU - Kiechle, Marion

AU - Mathew, Christopher G.

AU - Schindler, Detlev

AU - Schmutzler, Rita K.

AU - Hanenberg, Helmut

PY - 2010/5

Y1 - 2010/5

N2 - 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.

AB - 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.

U2 - 10.1038/ng.569

DO - 10.1038/ng.569

M3 - Article

SN - 1546-1718

VL - 42

SP - 410 - U65

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

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

Abstract

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