title: Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry.
abstract: The ATM gene variants segregating in ataxia-telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T>G and c.1066-6T>G (IVS10-6T>G), are associated with increased risk. Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T>G allele (P=0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR]=5.5, 95% confidence interval [CI]=1.2-25.5; P=0.04) and delayed child-bearing (OR=5.1; 95% CI=1.0-25.6; P=0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI=28-80%; hazard ratio [HR]=8.6; 95% CI=3.9-18.9; P<0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066-6T>G allele (OR=0.4; 95% CI=0.2-1.0; P=0.05), and the penetrance was not increased (P=0.5). These findings suggest that although the more common c.1066-6T>G variant is not associated with breast cancer, the rare ATM c.7271T>G variant is associated with a substantially elevated risk. Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population.
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. bernstej@mskcc.org
authors.forename: J L
authors.initials: JL
authors.lastname: Bernstein
authors.forename: S
authors.initials: S
authors.lastname: Teraoka
authors.forename: M C
authors.initials: MC
authors.lastname: Southey
authors.forename: M A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: I L
authors.initials: IL
authors.lastname: Andrulis
authors.forename: J A
authors.initials: JA
authors.lastname: Knight
authors.forename: E M
authors.initials: EM
authors.lastname: John
authors.forename: R
authors.initials: R
authors.lastname: Lapinski
authors.forename: A L
authors.initials: AL
authors.lastname: Wolitzer
authors.forename: A S
authors.initials: AS
authors.lastname: Whittemore
authors.forename: D
authors.initials: D
authors.lastname: West
authors.forename: D
authors.initials: D
authors.lastname: Seminara
authors.forename: E R
authors.initials: ER
authors.lastname: Olson
authors.forename: A B
authors.initials: AB
authors.lastname: Spurdle
authors.forename: G
authors.initials: G
authors.lastname: Chenevix-Trench
authors.forename: G G
authors.initials: GG
authors.lastname: Giles
authors.forename: J L
authors.initials: JL
authors.lastname: Hopper
authors.forename: P
authors.initials: P
authors.lastname: Concannon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins; D001315:Australia / Q000453:epidemiology; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D002277:Carcinoma / Q000453:epidemiology / Q000235:genetics; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005828:Genetics, Population; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D009864:Ontario / Q000453:epidemiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012042:Registries / Q000706:statistics & numerical data*; D012307:Risk Factors; D012495:San Francisco / Q000453:epidemiology; D025521:Tumor Suppressor Proteins / 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