P1-09-02: HDL-Cholesterol and Low-Penetrance Gene CYP17 rs2486758 Influence Daily Estrogen Levels. The EBBA-I Study.
Authors: A Iversen, I Thune, A McTiernan, KW Makar, T Wilsgaard, PT Ellison, G Jasienska, V Flote, E Poole, A-S Furberg
Journal: Cancer Research (2011)

Abstract Objectives: The low-penetrance gene CYP17 encodes cytochrome P450 enzymes, catalysts in the endogenous estrogen biosynthesis. Low levels of high-density lipoprotein cholesterol (HDL-C) have been associated with increased estrogen level1, increased breast cancer risk and poor breast cancer prognosis2. However, the relationship between CYP17 and metabolic profile including HDL-C levels, and estradiol levels remains unclear. Thus, we hypothesize that gene-environment interactions between eight SNPs on CYP17 and metabolic profile including HDL-cholesterol, may influence the levels of biologically active 17β-estradiol of importance of breast cancer development. Material and methods: The Norwegian Energy Balance and Breast cancer Aspects Study (EBBA-I) includes 203 healthy women (25-35 years) that underwent clinical examinations, blood sampling for metabolic profiling in serum and DNA extraction from whole blood, and daily saliva sampling throughout an entire menstrual cycle. Daily salivary levels of 17b-estradiol were measured by radioimmunoassay at the Reproductive Ecology Laboratory, Harvard University, USA. Tagging SNPs (rs1004467, rs743575, rs4919687, rs3781286, rs3824755, rs10786712, rs743572, rs2486758) representing CYP17 variability in the Caucasian population were selected using MAF &amp;gt; 5% and r2 = 0.80. The polymorphisms were genotyped at the Molecular Epidemiology Laboratory, Fred Hutchinson Cancer Research Center, USA. A clustered metabolic risk score was defined based on WHO criteria for the metabolic syndrome. Multivariable linear and generalized estimating equation regression models were used to study the associations. Result: Women with at least one variant allele of the CYP17 rs2486758 combined with the highest metabolic risk score (i.e. upper tertile), had 53% higher levels of daily salivary 17β-estradiol throughout the entire menstrual cycle compared with all other women (P &amp;lt; 0.001). Among women in the upper tertile of metabolic risk score, those with the variant allele had 43% higher levels of daily salivary 17β-estradiol (P =0.002). Similarly, the combination of having the variant allele and serum total cholesterol/HDL-C ratio in the upper tertile was associated with 43% higher levels of daily salivary 17β-estradiol, compared with all other women (P= 0.005), and 34% higher levels of daily salivary 17β-estradiol, compared with the women with common allele in the upper tertile (P= 0.038). Conclusion: Our results suggest that a polymorphism in CYP17 (rs2486758) may represent a strong genetic predisposition to increased endogenous estrogen levels in women with an unfavourable metabolic profile and a high total cholesterol/HDL-C ratio. Thus, total cholesterol/HDL-C ratio may be a clinical biomarker for breast cancer development in these subsets of women. References 1Furberg A-S et al. Metabolic and Hormonal Profiles: HDL Cholesterol as a Plausible Biomarker of Breast Cancer Risk. The Norwegian EBBA Study. Cancer Epidemiol Biomarkers Prev 2005;14:33–40. 2Emaus A et al. Metabolic profile, physical activity, and mortality in breast cancer patients. Breast Cancer Research and Treatment 2010;121: 651–660. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-09-02.