title: The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families.
abstract: The frame-shifting mutation 1100delC in the cell-cycle-checkpoint kinase 2 gene (CHEK2) has been reported to be associated with familial breast cancer in families in which mutations in BRCA1 and BRCA2 were excluded. To investigate the role of this variant as a candidate breast cancer susceptibility allele, we determined its prevalence in 237 breast cancer patients and 331 healthy relatives derived from 71 non-BRCA1/BRCA2 multiple-case early onset breast cancer families. Twenty-seven patients (11.4%) were carrying the CHEK2*1100delC variant. At least one carrier was found in 15 of the 71 families (21.1%). There was no evidence of cosegregation between the variant and breast cancer, but carrier patients developed breast cancer earlier than did noncarriers. We studied CHEK2 protein expression in 111, and loss of heterozygosity at CHEK2 in 88 breast tumors from these patients. Twelve of 15 tumors from carriers showed absent protein expression as opposed to 3 of 76 tumors from noncarriers (P < 0.001). CHEK2 loss of heterozygosity was associated with absence of protein expression but not with 1100delC carrier status. Thus, selecting for breast cancer cases with a strong familial background not accounted for by BRCA1 or BRCA2 strongly enriches for carriers of CHEK2*1100delC. Our results support a model in which CHEK2*1100delC interacts with an as yet unknown gene (or genes) to increase breast cancer risk.
authors.affiliation: Centre for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Rogier A
authors.initials: RA
authors.lastname: Oldenburg
authors.forename: Karin
authors.initials: K
authors.lastname: Kroeze-Jansema
authors.forename: Jaennelle
authors.initials: J
authors.lastname: Kraan
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.forename: Jan G M
authors.initials: JG
authors.lastname: Klijn
authors.forename: Nicoline
authors.initials: N
authors.lastname: Hoogerbrugge
authors.forename: Marjolein J L
authors.initials: MJ
authors.lastname: Ligtenberg
authors.forename: Christi J
authors.initials: CJ
authors.lastname: van Asperen
authors.forename: Hans F A
authors.initials: HF
authors.lastname: Vasen
authors.forename: Carel
authors.initials: C
authors.lastname: Meijers
authors.forename: Hanne
authors.initials: H
authors.lastname: Meijers-Heijboer
authors.forename: Truuske H
authors.initials: TH
authors.lastname: de Bock
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Cornelisse
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D064447:Checkpoint Kinase 2; D005260:Female; D016368:Frameshift Mutation; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases