title: Modification of BRCA1- and BRCA2-associated breast cancer risk by AIB1 genotype and reproductive history.
abstract: Women who have inherited a germ-line mutation in the BRCA1 or BRCA2 (BRCA1/2) genes have a greatly increased risk of developing breast cancer compared with the general population. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1/2 mutation carriers. We hypothesize that genes involved in endocrine signaling may modify the BRCA1/2-associated age-specific breast cancer penetrance. We studied the effect of alleles at the AIB1 gene using a matched case-control sample of 448 women with germ-line BRCA1/2 mutations. We found that these women were at significantly higher breast cancer risk if they carried alleles with at least 28 or 29 polyglutamine repeats at AIB1, compared with women who carried alleles with fewer polyglutamine repeats [odds ratio (OR), 1.59; 95% confidence interval (CI), 1.03-2.47 and OR, 2.85; 95% CI, 1.64-4.96, respectively]. Late age at first live birth and nulliparity have been associated with increased breast cancer risk. We observed increases in BRCA1/2-associated breast cancer risk in women who were either nulliparous or had their first live birth after age 30 (OR, 3.06; 95% CI, 1.52-6.16). Women were at significantly increased risk if they were nulliparous or had a late age at first live birth and had AIB1 alleles no shorter than 28 or 29 or more AIB1 polyglutamine repeats (OR, 4.62; 95% CI, 2.02-10.56 and OR, 6.97; 95% CI, 1.71-28.43, respectively) than women with none of these risk factors. Our results support the hypothesis that pathways involving endocrine signaling, as measured through AIB1 genotype and reproductive history, may have a substantial effect on BRCA1/2-associated breast cancer risk.
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. trebbeck@cceb.med.upenn.edu
authors.forename: T R
authors.initials: TR
authors.lastname: Rebbeck
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: P W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: K
authors.initials: K
authors.lastname: Krithivas
authors.forename: S L
authors.initials: SL
authors.lastname: Neuhausen
authors.forename: A K
authors.initials: AK
authors.lastname: Godwin
authors.forename: M B
authors.initials: MB
authors.lastname: Daly
authors.forename: S A
authors.initials: SA
authors.lastname: Narod
authors.forename: J S
authors.initials: JS
authors.lastname: Brunet
authors.forename: D
authors.initials: D
authors.lastname: Vesprini
authors.forename: J E
authors.initials: JE
authors.lastname: Garber
authors.forename: H T
authors.initials: HT
authors.lastname: Lynch
authors.forename: B L
authors.initials: BL
authors.lastname: Weber
authors.forename: M
authors.initials: M
authors.lastname: Brown
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D056921:Nuclear Receptor Coactivator 3; D017584:Reproductive History; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics*; D018911:Trinucleotide Repeats / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D009363:Neoplasm Proteins; D014157:Transcription Factors; D056921:Nuclear Receptor Coactivator 3