title: Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer.
abstract: Biallelic mutations in the ataxia-telangiectasia mutated (ATM) gene result in ataxia-telangiectasia (A-T). Studies on A-T families have shown that obligate female carriers have increased risk of developing breast cancer. Here we have evaluated the role of known Finnish ATM germ line mutations as possible breast cancer predisposing alleles outside A-T families by analyzing their prevalence in large cohorts of familial and unselected breast cancer cases. Of seven different alterations, two were observed in the studied breast cancer material. ATM 6903insA (causing protein truncation) was seen in 3/541 familial and 5/1124 unselected cases, but not among healthy population controls (0/1107). 7570G>C (Ala2524Pro) occurred in 1/541 familial and 2/1124 unselected cases compared with 1/1107 in controls. Additionally, 8734A>G (Arg2912Gly) associated previously with breast cancer susceptibility and suggested to be causative also for A-T was detected in 2/541 of familial cases, but not in unselected cases (0/1124) or controls (0/1107). In total, heterozygous ATM mutation carriers were observed in 6/541 familial [P = 0.006, odds ratio (OR) 12.4, 95% confidence interval (CI) 1.5-103.3) and 7/1124 unselected cases (P = 0.07, OR 6.9, 95% CI 0.9-56.4), compared with 1/1107 in controls, suggesting an apparent yet overall limited contribution to predisposition to cancer. The current results also provided evidence for founder effects in the geographical distribution of these mutations. Interestingly, results from functional analysis of the breast cancer-associated ATM mutations indicated that cancer susceptibility is not restricted to mutations with dominant-negative effect on kinase activity, displayed only by 7570G>C, whereas 8734A>G showed only a partial defect in the phosphorylation of ATM substrates, and 6903insA seemed to be a null allele.
authors.affiliation: Department of Clinical Genetics, University of Oulu/Oulu University Hospital, FIN-90029 OYS Oulu, Finland.
authors.forename: Katri
authors.initials: K
authors.lastname: Pylkäs
authors.forename: Johanna
authors.initials: J
authors.lastname: Tommiska
authors.forename: Kirsi
authors.initials: K
authors.lastname: Syrjäkoski
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Magtouf
authors.initials: M
authors.lastname: Gatei
authors.forename: Nicola
authors.initials: N
authors.lastname: Waddell
authors.forename: Minna
authors.initials: M
authors.lastname: Allinen
authors.forename: Sanna-Maria
authors.initials: SM
authors.lastname: Karppinen
authors.forename: Katrin
authors.initials: K
authors.lastname: Rapakko
authors.forename: Helena
authors.initials: H
authors.lastname: Kääriäinen
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Aki
authors.initials: A
authors.lastname: Mustonen
authors.forename: Kaija
authors.initials: K
authors.lastname: Holli
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna
authors.forename: Olli-Pekka
authors.initials: OP
authors.lastname: Kallioniemi
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
authors.forename: Robert
authors.initials: R
authors.lastname: Winqvist
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000502:physiology*; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D005387:Finland; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases