title: Heterozygous ATM mutations do not contribute to early onset of breast cancer.
abstract: Ataxia telangiectasia (AT) is a recessive syndrome, including cerebellar degeneration, immunologic defects and cancer predisposition, attributed to mutations in the recently isolated ATM (ataxia telangiectasia, mutated) gene. AT is diagnosed in 1/40,000 to 1/100,000 live births, with carriers calculated to comprise approximately 1% of the population. Studies of AT families have suggested that female relatives presumed to be carriers have a 5 to 8-fold increased risk for developing breast cancer, raising the possibility that germline ATM mutations may account for approximately 5% of all breast cancer cases. The increased risk for breast cancer reported for AT family members has been most evident among younger women, leading to an age-specific relative risk model predicting that 8% of breast cancer in women under age 40 arises in AT carriers, compared with 2% of cases between 40-59 years. To test this hypothesis, we undertook a germ-line mutational analysis of the ATM gene in a population of women with early onset of breast cancer, using a protein truncation (PTT) assay to detect chain-terminating mutations, which account for 90% of mutations identified in children with AT. We detected a heterozygous ATM mutation in 2/202 (1%) controls, consistent with the frequency of AT carriers predicted from epidemiologic studies. ATM mutations were present in only 2/401 (0.5%) women with early onset of breast cancer (P = 0.6). We conclude that heterozygous ATM mutations do not confer genetic predisposition to early onset of breast cancer.
authors.affiliation: Center for Cancer Risk Analysis, Massachusetts General Hospital Cancer Center, Charlestown, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: FitzGerald
authors.forename: J M
authors.initials: JM
authors.lastname: Bean
authors.forename: S R
authors.initials: SR
authors.lastname: Hegde
authors.forename: H
authors.initials: H
authors.lastname: Unsal
authors.forename: D J
authors.initials: DJ
authors.lastname: MacDonald
authors.forename: D P
authors.initials: DP
authors.lastname: Harkin
authors.forename: D M
authors.initials: DM
authors.lastname: Finkelstein
authors.forename: K J
authors.initials: KJ
authors.lastname: Isselbacher
authors.forename: D A
authors.initials: DA
authors.lastname: Haber
mesh_terms: D000328:Adult; D017668:Age of Onset; D001213:Asian; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D044383:Black People / Q000235:genetics; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology*; D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D006580:Genetic Carrier Screening; D006801:Humans; D007438:Introns; D007585:Jews; D016350:Leucine Zippers; D008875:Middle Aged; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics*; D017384:Sequence Deletion; D025521:Tumor Suppressor Proteins; D014481:United States; D001741:Black or African American
chemical_list: D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases