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CYP19A1 genetic variation in relation to prostate cancer risk and circulating sex hormone concentrations in men from the Breast and Prostate Cancer Cohort Consortium.

ABSTRACT: Sex hormones, particularly the androgens, are important for the growth of the prostate gland and have been implicated in prostate cancer carcinogenesis, yet the determinants of endogenous steroid hormone levels remain poorly understood. Twin studies suggest a heritable component for circulating concentrations of sex hormones, although epidemiologic evidence linking steroid hormone gene variants to prostate cancer is limited. Here we report on findings from a comprehensive study of genetic variation at the CYP19A1 locus in relation to prostate cancer risk and to circulating steroid hormone concentrations in men by the Breast and Prostate Cancer Cohort Consortium (BPC3), a large collaborative prospective study. The BPC3 systematically characterized variation in CYP19A1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNP) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,166 prostate cancer cases and 9,079 study-, age-, and ethnicity-matched controls. CYP19A1 htSNPs, two common missense variants and common haplotypes were not significantly associated with risk of prostate cancer. However, several htSNPs in linkage disequilibrium blocks 3 and 4 were significantly associated with a 5% to 10% difference in estradiol concentrations in men [association per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 1 x 10(-5)], and with inverse, although less marked changes, in free testosterone concentrations. These results suggest that although germline variation in CYP19A1 characterized by the htSNPs produces measurable differences in sex hormone concentrations in men, they do not substantially influence risk of prostate cancer.

SUBMITTER: Travis RC

PROVIDER: S-EPMC2812905 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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CYP19A1 genetic variation in relation to prostate cancer risk and circulating sex hormone concentrations in men from the Breast and Prostate Cancer Cohort Consortium.

Travis Ruth C RC Schumacher Fredrick F Hirschhorn Joel N JN Kraft Peter P Allen Naomi E NE Albanes Demetrius D Berglund Goran G Berndt Sonja I SI Boeing Heiner H Bueno-de-Mesquita H Bas HB Calle Eugenia E EE Chanock Stephen S Dunning Alison M AM Hayes Richard R Feigelson Heather Spencer HS Gaziano J Michael JM Giovannucci Edward E Haiman Christopher A CA Henderson Brian E BE Kaaks Rudolf R Kolonel Laurence N LN Ma Jing J Rodriguez Laudina L Riboli Elio E Stampfer Meir M Stram Daniel O DO Thun Michael J MJ Tjønneland Anne A Trichopoulos Dimitrios D Vineis Paolo P Virtamo Jarmo J Le Marchand Loïc L Hunter David J DJ

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20090929 10

Sex hormones, particularly the androgens, are important for the growth of the prostate gland and have been implicated in prostate cancer carcinogenesis, yet the determinants of endogenous steroid hormone levels remain poorly understood. Twin studies suggest a heritable component for circulating concentrations of sex hormones, although epidemiologic evidence linking steroid hormone gene variants to prostate cancer is limited. Here we report on findings from a comprehensive study of genetic variat ...[more]

PMID: 19789370

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Project description:Background: Sex hormones have been implicated in prostate carcinogenesis, yet epidemiologic studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically verified benign prostate tissue from prostate cancer cases.Methods: Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race, and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race, and age were assessed as potential effect modifiers.Results: Circulating sex steroid hormone concentrations had low-to-moderate correlations with, and explained small proportions of variations in, intraprostatic sex steroid hormone concentrations. Androstane-3α,17β-diol glucuronide (3α-diol G) explained the highest variance of tissue concentrations of 3α-diol G (linear regression r2 = 0.21), followed by serum testosterone and tissue dihydrotestosterone (r2 = 0.10), and then serum estrone and tissue estrone (r2 = 0.09). There was no effect modification by Gleason score, race, or age.Conclusions: Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu.Impact: The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating hormones with prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(11); 1660-6. ©2017 AACR.

Project description:BackgroundThe relationship between CYP19A1 genetic polymorphisms and coronary artery disease (CAD) remains unclear. Thus, the aim of the present study was to investigate the association of CYP19A1 genetic polymorphisms with CAD in Han and Uygur populations and to characterize the association between the levels of sex hormones and aromatase with single-nucleotide polymorphisms (SNPs) in CYP19A1 genes in Chinese women.ResultsThere were significant differences in the genotype distributions of rs2236722 and rs4646 between CAD patients and control subjects in the Uygur population. The rs4646 was found to be associated with CAD in the dominant model (CC vs. CA + AA) and the additive model (CA vs. CC + AA) (both P ≤ 0.001). The difference remained statistically significant after multivariate adjustment (OR = 0.483, 95% CI: 0.338-0.690, P = 0.000; and OR = 1.844, 95% CI: 1.300-2.617, P = 0.001, respectively). In normal Uygur postmenopausal women, there were significant differences in the genotype distributions of rs4646 and the circulating hormone and aromatase levels between CAD patients and control subjects. The differences in estradiol and aromatase levels remained statistically significant after multivariate adjustment (OR = 0.889, 95% CI: 0.817-0.969, P = 0.007; and OR = 0.947, 95% CI: 0.936-0.957, P = 0.000, respectively). Additionally, there were differences in sex hormone levels between the different ethnicities among the Xinjiang Chinese population.Materials and methodsAmong a total of 1,064 Han individuals (614 men and 450 women) and 790 Uygur individuals (484 men and 306 women), 498 postmenopausal women (265 Han and 233 Uygur individuals) were selected. Four SNPs (rs2236722, rs2304463, rs4646, and rs4275794) were genotyped using the improved multiplex ligation detection reaction (iMLDR) technique. The estradiol and testosterone levels were determined using a radioimmunoassay based on GC-2016γ. In addition, an enzyme-linked immunosorbent assay (ELISA) was performed to determine the serum P450 aromatase levels.ConclusionsThe results of this study indicate that the rs2236722 and rs4646 of the CYP19A1 gene are associated with CAD and circulating sex hormone levels in the Xinjiang population of China.

Dataset Information

CYP19A1 genetic variation in relation to prostate cancer risk and circulating sex hormone concentrations in men from the Breast and Prostate Cancer Cohort Consortium.

Publications

CYP19A1 genetic variation in relation to prostate cancer risk and circulating sex hormone concentrations in men from the Breast and Prostate Cancer Cohort Consortium.

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