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Letter
Nature Genetics  31, 55 - 59 (2002)
Published online: 22 April 2002; | doi:10.1038/ng879

Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations

The CHEK2-Breast Cancer Consortium: 
Group A: Hanne Meijers-Heijboer1, 2, Ans van den Ouweland1, Jan Klijn2, Marijke Wasielewski2, Anja de Snoo1, Rogier Oldenburg1, Antoinette Hollestelle2, Mark Houben3, Ellen Crepin2, Monique van Veghel-Plandsoen1, Fons Elstrodt2, Cornelia van Duijn3, Carina Bartels4, Carel Meijers5 & Mieke Schutte2
Group B: Lesley McGuffog6, Deborah Thompson6 & Douglas F. Easton6
Group C: Nayanta Sodha7, Sheila Seal7, Rita Barfoot7, Jon Mangion7, Jenny Chang-Claude8, Diana Eccles9, Rosalind Eeles7, D Gareth Evans10, Richard Houlston7, Victoria Murday11, Steven Narod12, Tamara Peretz13, Julian Peto14, 15, Catherine Phelan12, Hong Xiang Zhang16, Csilla Szabo17, Peter Devilee18, David Goldgar17, P Andrew Futreal19, Katherine L. Nathanson16, Barbara L. Weber16, Nazneen Rahman7 & Michael R. Stratton7, 19

1  Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.

2  Department of Medical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.

3  Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands.

4  Department of Surgical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.

5  Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.

6  Cancer Research UK Genetic Epidemiology Unit, Strangeways Research Laboratories, University of Cambridge, UK.

7  Cancer Genetics Section, Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK.

8  German Cancer Research Centre, Division of Epidemiology, Heidelberg, Germany.

9  Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.

10  Department of Medical Genetics, St Mary's Hospital, Manchester, UK.

11  Medical Genetics Unit, St Georges Medical School, London, UK.

12  Centre for Research in Women's Health, Women's College Hospital, Toronto, Canada.

13  Sharett Institute of Oncology, Hadassah University Hospital, Jerusalem, Israel.

14  Epidemiology Section, Institute of Cancer Research, Haddow Laboratories, Surrey, UK.

15  London School of Hygiene and Tropical Medicine, London, UK.

16  Department of Hematology/Oncology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA.

17  International Agency for Research on Cancer, Lyon, France.

18  Department of Pathology/Human Genetics, University of Leiden, Leiden, The Netherlands.

19  Cancer Genome Project, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambs, UK.

Correspondence should be addressed to Nazneen Rahman nazneen@icr.ac.uk
Mutations in BRCA1 and BRCA2 confer a high risk of breast and ovarian cancer1, but account for only a small fraction of breast cancer susceptibility1, 2. To find additional genes conferring susceptibility to breast cancer, we analyzed CHEK2 (also known as CHK2), which encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes involving BRCA1 and p53 (refs 3,4,5). We show that CHEK2 *1100delC, a truncating variant that abrogates the kinase activity6, has a frequency of 1.1% in healthy individuals. However, this variant is present in 5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003), including 13.5% of individuals from families with male breast cancer (P = 0.00015). We estimate that the CHEK2 *1100delC variant results in an approximately twofold increase of breast cancer risk in women and a tenfold increase of risk in men. By contrast, the variant confers no increased cancer risk in carriers of BRCA1 or BRCA2 mutations. This suggests that the biological mechanisms underlying the elevated risk of breast cancer in CHEK2 mutation carriers are already subverted in carriers of BRCA1 or BRCA2 mutations, which is consistent with participation of the encoded proteins in the same pathway.


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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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