title: Low frequency of CHEK2 1100delC allele in Australian multiple-case breast cancer families: functional analysis in heterozygous individuals.
abstract: A protein-truncating variant of CHEK2, 1100delC, is associated with a moderate increase in breast cancer risk. We have determined the prevalence of this allele in index cases from 300 Australian multiple-case breast cancer families, 95% of which had been found to be negative for mutations in BRCA1 and BRCA2. Only two (0.6%) index cases heterozygous for the CHEK2 mutation were identified. All available relatives in these two families were genotyped, but there was no evidence of co-segregation between the CHEK2 variant and breast cancer. Lymphoblastoid cell lines established from a heterozygous carrier contained approximately 20% of the CHEK2 1100delC mRNA relative to wild-type CHEK2 transcript. However, no truncated CHK2 protein was detectable. Analyses of expression and phosphorylation of wild-type CHK2 suggest that the variant is likely to act by haploinsufficiency. Analysis of CDC25A degradation, a downstream target of CHK2, suggests that some compensation occurs to allow normal degradation of CDC25A. Such compensation of the 1100delC defect in CHEK2 might explain the rather low breast cancer risk associated with the CHEK2 variant, compared to that associated with truncating mutations in BRCA1 or BRCA2.
authors.affiliation: Division of Cancer and Cell Biology, Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Brisbane, QLD 4029, Australia.
authors.forename: C R
authors.initials: CR
authors.lastname: Jekimovs
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Arnold
authors.forename: M
authors.initials: M
authors.lastname: Gatei
authors.forename: D J
authors.initials: DJ
authors.lastname: Richard
authors.forename: A B
authors.initials: AB
authors.lastname: Spurdle
authors.forename: K K
authors.initials: KK
authors.lastname: Khanna
authors.forename: G
authors.initials: G
authors.lastname: Chenevix-Trench
mesh_terms: D000328:Adult; D001315:Australia; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics*; D064447:Checkpoint Kinase 2; D003596:Cytosine; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D019656:Loss of Heterozygosity; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D003596:Cytosine; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases