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

Abstract

10511 Background: The lack of full penetrance of mutations in the BRCA genes suggests the possible existence of other modifying genes and/or environmental factors. Exposure to sex hormones is an established major risk factor for breast cancer. The polymorphisms ( rs700518 (Val80), [TTTA]n) in CYP19, a gene encoding the estrogen synthesizing enzyme P450 aromatase, may be associated with risk of breast cancer in BRCA carriers and/or non-carriers. Methods: An analysis of 922 breast cancer cases and 901 healthy controls, including 408 BRCA carriers and 1,415 non-carriers was carried out. Cases and controls of Ashkenazi origin came from a population-based case-control study of breast cancer in Northern Israel, enriched with BRCA carriers (with and without cancer) from a clinical familial cancer service. DNA samples were genotyped for Ashkenazi BRCA1,2 mutations (185delAG, 5382insC, 6174delT) and CYP19 polymorphisms by allelic discrimination using 7900HT ABI sequence detection system. Statistical analyses were performed using SPSS, SAS, and R language. Results: The Val80 G/G genotype was associated with a significantly increased risk of breast cancer as compared to the A/A genotype in BRCA1 carriers (OR=2.2; 95%CI=1.04–4.53; p=0.039) but not in BRCA2 carriers (OR=0.45, 95%CI=0.17–1.16; p=0.098). A similar magnitude association, though not statistically significant, was found between the Val80 and ER-negative status of breast tumors. A reconstructed common haplotype composed of four haplotype-tagging SNPs in Haplotype Block 4, covering the CYP19 coding region, was also significantly associated with breast cancer risk in 210 carriers of BRCA1 (OR=3.4; 95%CI=1.5–7.8; p=0.004). No significant association between CYP19 polymorphisms and breast cancer risk was found in non-carriers. Conclusions: Our data suggest that the CYP19 Val80 polymorphism and a haplotype including this polymorphism are associated with increased breast cancer risk in BRCA1 carriers. As a higher number of repeats in intron 4 ([TTTA]n polymorphism) is found in complete linkage disequilibrium with the Val80 G allele and is associated with higher estrogen levels, this mechanism could explain the phenotypic uniqueness of the carriers. No significant financial relationships to disclose.