Epidemiologic Study of Genetic Variation in Hormonal Pathways in Relation to the Effect of Hormone Replacement Therapy on Breast Cancer Risk; Annual rept. 15 Mar 2007-14 Mar 2008

摘要

CHT use has been demonstrated to confer an increased risk of breast cancer. Genetic variation in hormonal pathways may modify the effect of CHT on breast cancer risk. Using 1237 cases and 1015 controls from two population- based case-control studies of breast cancer, we investigated the effect of genetic variation in 7 genes within the progesterone pathway using a tagSNP and functional SNP approach and 5 genes within the catechol estrogen pathway. Within single gene analyses we observed breast cancer risk to be modestly associated with one SNPs in each GSTP1 (rs1695: OR = 1.4 95% CI: 1.02-1.9) for carriers of A allele; CYP1B1 (rs1056827: OR = 1.7 )95% (CI:1.2-2.5) for T homozygotes; SRD5A1 (rs248793: OR=1.2 95% CI: 1.02-1.5) for G homozygotes and PGR (rs492457: OR=1.5 95% CI: 1.01-2.1) (for carriers of the A allele). We found that the breast cancer risk associated with SNPs was particularly strong in long-term CHT users. In a multi-gene model including two genes with single gene effects within the estrogen pathway (CYP1B1*2 and GSTP1), breast cancer risk was 1.6 (95% CI: 1.03-2.4) times higher for carriers of 1 high risk genotype and 2.8 (95% CI: 1.5-5.3) times higher for women with 2 high risk genotypes compared to women with 0 high risk genotypes. The impact of high risk genotypes was stronger in long-term CHT users, particularly in long-term, current CHT users (OR=5.6 95% CI: 1-5-20.6). These results suggest that breast cancer risk among CHT users is modified by variation in genes within hormonal pathways.