Associations between the CYP17, CYPIB1, COMT and SHBG polymorphisms and serum sex hormones in post-menopausal breast cancer survivors

Abstract

Several polymorphisms have been identified in genes that code for enzymes involved with estrogen biosynthesis and metabolism. Little is known about the functional relevance of these polymorphisms on sex hormones in vivo. We examined the association between CYP17, CYP1B1, COMT or SHBG genotypes and serum concentrations of estrone, estradiol, free estradiol, sex hormone binding globulin (SHBG), testosterone, free testosterone and dehyroepiandrosterone in 366 post-menopausal breast cancer survivors in New Mexico, California and Washington. Hormone levels were determined by high performance liquid chromatography and radioimmunoassay in blood drawn approximately 2 years post-diagnosis. We used generalized linear regression to calculate mean hormone levels by genotype, adjusting for age, race/ethnicity, stage, study site, tamoxifen use, number of remaining ovaries, hormone therapy use, marital status and BMI. No associations were observed between any of the genotypes and sex hormones when analyzing the main effects. In subgroup analyses, androgen levels of Hispanic women with the variant (A2) CYP17 genotype were 46-87% higher than those of women with the wildtype; androgen levels were 13-20% lower in non-Hispanic whites with the variant genotype; no difference by genotype was observed for African-American women. Current tamoxifen users with the variant asn 327 SHBG genotype had 81% higher serum SHBG and 39% lower free testosterone concentrations than women with the wildtype genotype. Non-tamoxifen users with the variant NIH Public Access

Reproductive Steroid Hormones and Recurrence-Free Survival in Women with a History of Breast Cancer

“…Serum SHBG was measured using the Immulite 2000 analyzer and a two-site chemiluminometric sandwich assay (Siemens Medical Solutions Diagnostics); the sensitivity was 0.2 nmol/L; intraassay and interassay coefficients of variation were 6.5% and 8.7%, respectively. Bioavailable and free testosterone and estradiol were calculated using law of mass action equations (27). Total estradiol (or testosterone) includes SHBG-bound, albumin-bound and free hormone; bioavailable estrogen (or testosterone) includes albumin-bound and free hormone; and free estrogen (or testosterone) is free or unbound hormone.…”

“…In the Health, Eating, Activity and Lifestyle Study, associations between the CYP17, COMT, and SHBG polymorphisms and serum sex hormone concentrations were examined in 366 postmenopausal breast cancer survivors (27). In that study, no associations between any of the genotypes examined and sex hormone concentrations were observed when analyzing for main effects, although CYP17 and SHBG variants were associated with a few differences in androgen, estradiol, and SHBG levels in small subsets of those participants.…”

Associations between null mutations in GSTT1 and GSTM1, the GSTP1 Ile105Val polymorphism, and mortality in breast cancer survivors

“…DNA was extracted from peripheral blood leukocytes, which was processed within 3 hours of collection, and stored at -80° C until analysis (Abrahamson et al 2007). …”

Polymorphisms in the promoter region of ESR2 gene and breast cancer susceptibility

“…SNPs located in exon regions may alter protein function, whereas SNPs in the gene promoter can modify gene expression levels [16][17][18][19][20][21][22]. Polymorphisms in genes involved in estrogen biosynthesis, metabolism and signal transduction have been suggested to play a role in breast cancer risk [23][24][25][26][27][28][29][30][31]. In the last years, a multitude of SNPs both in ESR1 and ESR2 gene have been identified and different genotype-phenotype association studies have been published examining the significance of randomly chosen SNPs in different hormone-dependent diseases [18,[32][33][34][35].…”