title: Two new CHEK2 germ-line variants detected in breast cancer/sarcoma families negative for BRCA1, BRCA2, and TP53 gene mutations.
abstract: CHEK2 gene mutations occur in a subset of patients with familial breast cancer, acting as moderate/low penetrance cancer susceptibility alleles. Although CHEK2 is no longer recognized as a major determinant of the Li-Fraumeni syndrome, a hereditary condition predisposing to cancer at multiple sites, it cannot be ruled out that mutations of this gene play a role in malignancies arising in peculiar multi-cancer families. To assess the contribution of CHEK2 to the breast cancer/sarcoma phenotype, we screened for germ-line sequence variations of the gene among 12 probands from hereditary breast/ovarian cancer families with one case of sarcoma that tested wild-type for mutations in the BRCA1, BRCA2, and TP53 genes. Two cases harbored previously unreported mutations in CHEK2, the c.507delT and c.38A>G, leading to protein truncation (p.Phe169LeufsX2) and amino acid substitution (p.His13Arg), respectively. These mutations were not considered common polymorphic variants, as they were undetected in 230 healthy controls of the same ethnic origin. While the c.38A>G encodes a mutant protein that behaves in biochemical assays as the wild-type form, the c.507delT is a loss-of-function mutation. The identification of two previously unreported CHEK2 variants, including a truncating mutation leading to constitutional haploinsufficiency, in individuals belonging to families selected for breast cancer/sarcoma phenotype, supports the hypothesis that the CHEK2 gene may act as a factor contributing to individual tumor development in peculiar familial backgrounds.
authors.affiliation: Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Siranoush
authors.initials: S
authors.lastname: Manoukian
authors.forename: Bernard
authors.initials: B
authors.lastname: Peissel
authors.forename: Simona
authors.initials: S
authors.lastname: Frigerio
authors.forename: Daniele
authors.initials: D
authors.lastname: Lecis
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.forename: Gaia
authors.initials: G
authors.lastname: Roversi
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Domenico
authors.initials: D
authors.lastname: Delia
mesh_terms: D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2; D005192:Family Health; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D045325:HCT116 Cells; D006801:Humans; D008875:Middle Aged; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012509:Sarcoma / Q000235:genetics* / Q000378:metabolism
chemical_list: D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases