title: The relationship between twenty missense ATM variants and breast cancer risk: the Multiethnic Cohort.
abstract: Deficiencies in tasks of detecting and repairing DNA damage lead to mutations and chromosomal abnormalities, a hallmark of cancer. The gene mutated in ataxia-telangiectasia (A-T), ATM, is a proximal component in performing such tasks. Studies of A-T families have suggested an increased risk of breast cancer among obligate female heterozygous carriers of ATM mutations. Paradoxically, studies of sporadic and familial breast cancer have failed to demonstrate an elevated prevalence of mutations among breast cancer cases. We characterized the prevalence and distribution of 20 ATM missense mutations/polymorphisms in a population-based case-control study of 854 African-American, Latina, Japanese, and Caucasian women aged >/==" BORDER="0">45 years participating in the Multiethnic Cohort Study. The study population included 428 incident breast cancer cases and 426 controls. The prevalence of variants ranged from 0% to 13.6% among controls and varied by ethnicity (0-32.5%). Overall, these data provide little support for an association of ATM missense mutations with breast cancer among older women. We observed only one sequence variation (L546V), common among African-American women, to be overrepresented among all high-stage breast cancer cases (odds ratio, 3.35; 95% confidence interval, 1.27-8.84). After correction for multiple comparisons, this observed risk modification did not attain statistical significance. The distribution of ATM missense mutations and polymorphisms varied widely across the four ethnic groups studied. Although a single missense variant (L546V) appeared to act as a modest predictor of risk, the remaining variants were no more common in breast cancer cases as compared with controls.
authors.affiliation: University of Southern California/Norris Comprehensive Cancer Center, Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA. bretsky@usc.edu
authors.forename: Philip
authors.initials: P
authors.lastname: Bretsky
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.forename: Shlomit
authors.initials: S
authors.lastname: Gilad
authors.forename: Joachim
authors.initials: J
authors.lastname: Yahalom
authors.forename: Avital
authors.initials: A
authors.lastname: Grossman
authors.forename: Shoshana
authors.initials: S
authors.lastname: Paglin
authors.forename: David
authors.initials: D
authors.lastname: Van Den Berg
authors.forename: Laurence N
authors.initials: LN
authors.lastname: Kolonel
authors.forename: Rami
authors.initials: R
authors.lastname: Skaliter
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
mesh_terms: D001741:Black or African American / Q000235:genetics; D000368:Aged; D001213:Asian / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins; D015331:Cohort Studies; D004268:DNA-Binding Proteins; D005006:Ethnicity; D005260:Female; D014644:Genetic Variation; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007564:Japan; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins; D044465:White People / Q000235:genetics
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