|Ph.D Student||Raskin Leonid|
|Subject||The Role of Aromatase (CYP19) Polymorphisms in the Etiology|
of Breast Cancer in Ashkenazi Jews
|Department||Department of Medicine||Supervisor||Professor Gad Rennert|
The lack of full penetrance of the Jewish founder mutations in the BRCA genes suggests the possible existence of other modifying genes and/or environmental factors for breast cancer. Exposure to sex hormones is a major risk factor for breast cancer. As BRCA carriers with breast cancer manifest hormonal abnormalities, we studied the potential association of CYP19/Aromatase polymorphisms, and breast cancer risk in BRCA carriers and non-carriers. The study consisted of 625 breast cancer cases and 619 healthy controls, including 330 BRCA carriers and 914 non-carriers. In both, BRCA1 carriers and BRCA non-carriers with family history of breast cancer, the Val80 (G/G) genotype was associated with significantly increased risk of breast cancer as compared to the Val80 (A/A) genotype (OR=2.88,95%CI=1.29-6.42; OR=3.51,95%CI=1.16-10.65;respectively). In BRCA2 carriers, the Val80 (G/G) was associated with significantly decreased breast cancer risk (OR=0.27,95%CI=0.08-0.89). A similar magnitude association, though not-statistically significant, was found between the Val80 polymorphism and ER-negative status of the breast tumors. A common haplotype composed of the Val80 (G) allele and three haplotype-tagging SNPs (rs727479;rs10046;rs4646) in the CYP19 coding region was also found to be significantly associated with breast cancer risk in these groups. Published expression data suggest higher estrogen levels with higher intron 4 [TTTA]n repeats - which was found in complete linkage disequilibrium with Val80. These data suggest that a haplotype including the Val80 polymorphism is associated with increased breast cancer risk in BRCA carriers and non-carriers with family history of breast cancer, possibly through influencing circulating levels of estrogen and its metabolites.