title: Contribution of mutations in ATM to breast cancer development in the Czech population.
abstract: Mutations in the ATM gene are the cause of a rare autosomal recessive syndrome, ataxia-telangiectasia (AT). Of the general population, approximately 0.35-1% has been estimated to be heterozygous for a germline mutation in the ATM gene. The finding that ATM heterozygotes have an increased breast cancer risk was supported by some studies but not confirmed by others. In our study, the entire coding sequence of the ATM gene was prescreened for mutations by the protein truncation test to detect the chain-terminating mutations that are highly predominant in patients with AT. DNA sequencing then characterized 3 (1.9%) pathogenic mutations among 161 high-risk breast cancer patients. The c.5177+1G>A splicing mutation was a novel gene alteration. No mutation was detected in a group of 183 control individuals. Our results suggest that truncating mutations in ATM increase breast cancer risk and contribute to inherited breast cancer. The analysis further uncovered the c.1066-6T>G splicing mutation once among high-risk patients (0.6%) and twice among controls (1.1%) suggesting that this mutation does not confer an increase in breast cancer risk. On the other hand, individuals heterozygous for this truncating variant displayed loss of exon 11 in approximately 50% of ATM transcripts. Immunohistochemistry did not detect the ATM protein in the tumor sample carrying this mutation. Thus, the association of the c.1066-6T>G mutation with familial breast cancer remains uncertain. Loss of the wild-type ATM allele has not been detected in the tumor samples from heterozygous carriers of the ATM mutation. Our experiments did not detect the hypermethylation of the ATM promoter in any of the DNA samples from tumor tissues.
authors.affiliation: Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic. jproko@lf1.cuni.cz
authors.forename: Jana
authors.initials: J
authors.lastname: Soukupova
authors.forename: Pavel
authors.initials: P
authors.lastname: Dundr
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Kleibl
authors.forename: Petr
authors.initials: P
authors.lastname: Pohlreich
mesh_terms: D000328:Adult; D017668:Age of Onset; D017398:Alternative Splicing; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D003604:Czechoslovakia / Q000453:epidemiology; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D007124:Immunoenzyme Techniques; D019656:Loss of Heterozygosity; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
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