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


Meijers-Heijboer, H; van Den Ouweland, A; Klijn, J; Wasielewski, M; de Snoo, A; Oldenburg, R; Hollestelle, A; Houben, M; Crepin, E; van Veghel-Plandsoen, M; Elstrodt, F; van Duijn, C; Bartels, C; Meijers, C; Schutte, M; McGuffog, L; Thompson, D; Easton, DF; Sodha, N; Seal, S; Barfoot, R; Mangion, J; Chang-Claude, J; Eccles, D; Eeles, R; Evans, DG; Houlston, R; Murday, V; Narod, S; Peretz, T; Peto, J; Phelan, C; Zhang, HX; Szabo, C; Devilee, P; Goldgar, D; Futreal, PA; Nathanson, KL; Weber, BL; Rahman, N; Stratton, MR; (2002) Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nature genetics, 31 (1). pp. 55-59. ISSN 1061-4036 DOI: https://doi.org/10.1038/ng879

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Abstract

Mutations in BRCA1 and BRCA2 confer a high risk of breast and ovarian cancer(1), but account for only a small fraction of breast cancer susceptibility(1,2). 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 3-5). We show that CHEK2*1100delC, a truncating variant that abrogates the kinase activity(6), 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.

Item Type: Article
Keywords: Li-fraumeni-syndrome, dna-damage checkpoint, chk2, genes, p53, phosphorylation, families, atm, Breast Neoplasms, genetics, Case-Control Studies, Female, Genes, BRCA1, Genes, BRCA2, Genetic Screening, Heterozygote, Human, Male, Microsatellite Repeats, Mutation, Pedigree, Protein Kinases, genetics, Risk Factors, Sequence Deletion, Support, Non-U.S. Gov't, Support, U.S. Gov't, P.H.S.
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
PubMed ID: 11967536
Web of Science ID: 175362500014
URI: http://researchonline.lshtm.ac.uk/id/eprint/17331

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