title: A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer.
abstract: CHEK2 (previously known as "CHK2") is a cell-cycle-checkpoint kinase that phosphorylates p53 and BRCA1 in response to DNA damage. A protein-truncating mutation, 1100delC in exon 10, which abolishes the kinase function of CHEK2, has been found in families with Li-Fraumeni syndrome (LFS) and in those with a cancer phenotype that is suggestive of LFS, including breast cancer. In the present study, we found that the frequency of 1100delC was 2.0% among an unselected population-based cohort of 1,035 patients with breast cancer. This was slightly, but not significantly (P=.182), higher than the 1.4% frequency found among 1,885 population control subjects. However, a significantly elevated frequency was found among those 358 patients with a positive family history (11/358 [3.1%]; odds ratio [OR] 2.27; 95% confidence interval [CI] 1.11-4.63; P=.021, compared with population controls). Furthermore, patients with bilateral breast cancer were sixfold more likely to be 1100delC carriers than were patients with unilateral cancer (95% CI 1.87-20.32; P=.007). Analysis of the 1100delC variant in an independent set of 507 patients with familial breast cancer with no BRCA1 and BRCA2 mutations confirmed a significantly elevated frequency of 1100delC (28/507 [5.5%]; OR 4.2; 95% CI 2.4-7.2; P=.0002), compared with controls, with a high frequency also seen in patients with only a single affected first-degree relative (18/291 [6.2%]). Finally, tissue microarray analysis indicated that breast tumors from patients with 1100delC mutations show reduced CHEK2 immunostaining. The results suggest that CHEK2 acts as a low-penetrance tumor-suppressor gene in breast cancer and that it makes a significant contribution to familial clustering of breast cancer-including families with only two affected relatives, which are more common than families that include larger numbers of affected women.
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Haartmaninkatu 8, FIN-00029 HUS, Helsinki, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Vahteristo
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.forename: Hannaleena
authors.initials: H
authors.lastname: Eerola
authors.forename: Kirsi
authors.initials: K
authors.lastname: Syrjäkoski
authors.forename: Salla
authors.initials: S
authors.lastname: Ojala
authors.forename: Outi
authors.initials: O
authors.lastname: Kilpivaara
authors.forename: Anitta
authors.initials: A
authors.lastname: Tamminen
authors.forename: Juha
authors.initials: J
authors.lastname: Kononen
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Päivi
authors.initials: P
authors.lastname: Heikkilä
authors.forename: Kaija
authors.initials: K
authors.lastname: Holli
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Olli-P
authors.initials: OP
authors.lastname: Kallioniemi
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics*; D064447:Checkpoint Kinase 2; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018816:Genes, cdc; D006801:Humans; D007150:Immunohistochemistry; D010375:Pedigree; D017354:Point Mutation; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases
chemical_list: D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases