title: The ATM missense mutation p.Ser49Cys (c.146C>G) and the risk of breast cancer.
abstract: Homozygous mutation in the ATM gene causes ataxia telangiectasia and heterozygous mutation carriers may be at increased risk of breast cancer. We studied a total of 22 ATM variants; 18 variants were analyzed in one of two large population-based studies from the U.S. and Poland, and four variants were analyzed in all 2,856 breast cancer cases and 3,344 controls from the two studies. The missense mutation Ser49Cys (c.146C>G, p.S49C), carried by approximately 2% of subjects, was more common in cases than controls in both study populations, combined odds ratio (OR) 1.69 (95% CI, 1.19-2.40; P=0.004). Another missense mutation at approximately 2% frequency, Phe858Leu (c.2572T>C, p.F858L), was associated with a significant increased risk in the U.S. study but not in Poland, and had a combined OR of 1.44 (95% CI, 0.98-2.11; P=0.06). These analyses provide the most convincing evidence thus far that missense mutations in ATM, particularly p.S49C, may be breast cancer susceptibility alleles. Because of their low frequency, even larger sample sizes are required to more firmly establish these associations.
authors.affiliation: Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5060, USA.
authors.forename: Denise L
authors.initials: DL
authors.lastname: Stredrick
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
authors.forename: Marbin A
authors.initials: MA
authors.lastname: Pineda
authors.forename: Parveen
authors.initials: P
authors.lastname: Bhatti
authors.forename: Bruce H
authors.initials: BH
authors.lastname: Alexander
authors.forename: Michele M
authors.initials: MM
authors.lastname: Doody
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.forename: Beata
authors.initials: B
authors.lastname: Peplonska
authors.forename: Louise A
authors.initials: LA
authors.lastname: Brinton
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.forename: Jeffery P
authors.initials: JP
authors.lastname: Struewing
authors.forename: Alice J
authors.initials: AJ
authors.lastname: Sigurdson
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense; D011044:Poland / Q000453:epidemiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014481:United States / Q000453:epidemiology
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