title: CHEK2 variant I157T may be associated with increased breast cancer risk.
abstract: Cell cycle checkpoint kinase 2 (CHEK2) is a transducer of cellular responses to DNA damage. The CHEK2 1100delC has previously been shown to be a low-penetrance breast cancer susceptibility allele. We have evaluated the role of another CHEK2 variant, I157T in the FHA domain of the gene, for association with breast cancer. I157T was found at a significantly higher frequency in the population-based series of breast cancer patients (77/1035, 7.4%, odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.06-1.95, p = 0.021) than among population controls (100/1885, 5.3%). The frequency in the familial breast cancer patients was not elevated (28/507, 5.5%, OR = 1.04, 95% CI = 0.68-1.61). The I157T protein, that undermines cellular responses to ionizing radiation and shows deficiency in substrate recognition in vivo, was expressed at normal level in tumor tissues as well as in cultured cells. The I157T protein was stable and it dimerized with the wild-type CHEK2 co-expressed in human cells. These functional properties of the I157T protein suggest that this variant may have negative effect on the pool of normal CHEK2 protein in heterozygous carrier cells by formation of heterodimers with wild-type CHEK2. The I157T variant may be associated with breast cancer risk, but the risk is lower than for 1100delC.
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Central Hospital (HUCH), Helsinki, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Kilpivaara
authors.forename: Pia
authors.initials: P
authors.lastname: Vahteristo
authors.forename: Jacob
authors.initials: J
authors.lastname: Falck
authors.forename: Kirsi
authors.initials: K
authors.lastname: Syrjäkoski
authors.forename: Hannaleena
authors.initials: H
authors.lastname: Eerola
authors.forename: Douglas
authors.initials: D
authors.lastname: Easton
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.forename: Jiri
authors.initials: J
authors.lastname: Lukas
authors.forename: Päivi
authors.initials: P
authors.lastname: Heikkilä
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Kaija
authors.initials: K
authors.lastname: Holli
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Olli-Pekka
authors.initials: OP
authors.lastname: Kallioniemi
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D001943:Breast Neoplasms / Q000209:etiology* / Q000235:genetics*; D016022:Case-Control Studies; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004261:DNA Replication; D005260:Female; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D016017:Odds Ratio; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011836:Radiation Tolerance
chemical_list: D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases