Modification of BRCA1- and BRCA2-associated breast cancer risk by AIB1 genotype and reproductive history

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 interindiv idual variability in the occurrence of breast cancer among BRCA1/2 mutation carriers. We hypothesize that genes involved in endocrine signaling may mo dify the BRCA1/2-associated age-specific breast cancer penetrance, We studi ed the effect of alleles at the A1B1 gene using a matched case-control samp le 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 wi th at least 28 or 29 polyglutamine repeats at A1B1, compared with women who carried alleles with fewer polyglutamine repeats [odds ratio (OR), 1.59; 9 5% confidence interval (CI), 1.03-2.47 and OR, 2.85; 95% CI, 1.64-4.96, res pectively]. Late age at first live birth and nulliparity have been associat ed with increased breast cancer risk. We observed increases in BRCA1/2-asso ciated 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 A1B1 alleles no shorter than 28 or 29 or more A1B 1 polyglutamine repeats (OR, 1.62; 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 A1B1 genotype and reproductive history, may have a sub stantial effect on BRCA1/2-associated breast cancer risk.