Ph.D Thesis

Ph.D StudentRaskin Leonid
SubjectThe Role of Aromatase (CYP19) Polymorphisms in the Etiology
of Breast Cancer in Ashkenazi Jews
DepartmentDepartment of Medicine
Supervisor PROF. 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.