title: Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations.
abstract: Mutations in BRCA1 and BRCA2 confer a high risk of breast and ovarian cancer, but account for only a small fraction of breast cancer susceptibility. 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 activity, 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.
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
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authors.lastname: Meijers-Heijboer
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authors.lastname: Eccles
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authors.forename: D Gareth
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authors.lastname: Houlston
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authors.lastname: Murday
authors.forename: Steven
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authors.forename: Catherine
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authors.lastname: Phelan
authors.forename: Hong Xiang
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authors.lastname: Zhang
authors.forename: Csilla
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authors.lastname: Szabo
authors.forename: Peter
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authors.lastname: Devilee
authors.forename: David
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authors.lastname: Goldgar
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: Barbara
authors.initials: B
authors.lastname: Weber
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authors.lastname: Stratton
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D064447:Checkpoint Kinase 2; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D010375:Pedigree; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D012307:Risk Factors; D017384:Sequence Deletion
chemical_list: D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases