BRCA1 breast cancer risk is modified by CYP19 Polymorphisms in Ashkenazi Jews

Exposure to sex hormones is a major risk factor for breast cancer andcurre nt treatments include hormone modifying drugs, among them aromatase inhibitors. We studied the association of CYP19 (Val⁸⁰ and [TTTA]_n) polymorphisms, the gene translated to aromatase, and the risk of breast cancer in BRCA carriers and noncarriers. The study consisted of 958 cancer cases and 931 healthy controls, including 474 carriers and 1,415 noncarriers. Cases and controls came from a population-based study of breast cancer in Israel, enriched with BRCA carriers from a clinical familial cancer service. Val⁸⁰ G/G genotype was associated with significantly increased risk of breast cancer compared with the Val⁸⁰ A/A genotype in BRCA1 carriers ages <50 years (odds ratio, 2.81; 95% confidence interval, 1.09-7.22; P = 0.032) but not in BRCA2 carriers or noncarriers of any age. A similar magnitude suggestive association, although nonstatistically significant, was found between Val ⁸⁰ polymorphism and estrogen receptor-negative status of the breast tumors. A common haplotype composed of the Val⁸⁰ G allele and three haplotype tagging single nucleotide polymorphisms (rs727479, rs10046, andrs4646) in the CYP19 coding region showed a trend to association with breast cancer risk in BRCA1 carriers ages <50 years. Published expression data show higher estrogen levels with higher repeats in [TTTA]_n found in linkage disequilibrium with Val⁸⁰. The present study suggests that the CYP19 Val⁸⁰ polymorphism anda haplotype that includes this polymorphism are associated with increased breast cancer risk in young women with BRCA1 mutations.