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The impact of common genetic variations in genes of the sex hormone metabolic pathways on steroid hormone levels and prostate cancer aggressiveness.

ABSTRACT: Our previous work suggested that there was no significant association between plasma steroid hormone levels and prostate cancer tumor grade at diagnosis. In this study, we systematically tested the hypothesis that inherited variations in the androgen and estrogen metabolic pathways may be associated with plasma levels of steroid hormones, or prostate cancer aggressiveness at diagnosis. Plasma hormone levels including total testosterone, total estradiol, and sex hormone-binding globulin were measured in a cohort of 508 patients identified with localized prostate cancer. D'Amico risk classification at diagnosis was also determined. A total of 143 single-nucleotide polymorphisms (SNPs) from 30 genes that are involved in androgen and estrogen metabolism were selected for analysis. The global association of genotypes with plasma hormone levels and prostate cancer aggressiveness (D'Amico risk classification) was statistically analyzed. Q values were estimated to account for multiple testing. We observed significant associations between plasma testosterone level and SNPs in HSD17B2 (rs1424151), HSD17B3 (rs9409407), and HSD17B1 (rs12602084), with P values of 0.002, 0.006, and 0.006, respectively. We also observed borderline significant associations between prostate aggressiveness at diagnosis and SNPs in AKR1C1 (rs11252845; P = 0.005), UGT2B15 (rs2045100; P = 0.007), and HSD17B12 (rs7932905; P = 0.008). No individual SNP was associated with both clinical variables. Genetic variants of genes in hormone metabolic pathways may influence plasma androgen levels or prostate cancer aggressiveness. However, it seems that the inherited variations affecting plasma hormone levels differ from those affecting disease aggressiveness.

SUBMITTER: Sun T

PROVIDER: S-EPMC3773969 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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The impact of common genetic variations in genes of the sex hormone metabolic pathways on steroid hormone levels and prostate cancer aggressiveness.

Sun Tong T Oh William K WK Jacobus Susanna S Regan Meredith M Pomerantz Mark M Freedman Matthew L ML Lee Gwo-Shu Mary GS Kantoff Philip W PW

Cancer prevention research (Philadelphia, Pa.) 20110907 12

Our previous work suggested that there was no significant association between plasma steroid hormone levels and prostate cancer tumor grade at diagnosis. In this study, we systematically tested the hypothesis that inherited variations in the androgen and estrogen metabolic pathways may be associated with plasma levels of steroid hormones, or prostate cancer aggressiveness at diagnosis. Plasma hormone levels including total testosterone, total estradiol, and sex hormone-binding globulin were meas ...[more]

PMID: 21900597

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Project description:Essentials Endogenous hormone levels' influence on hemostatic factor levels is not fully characterized. We tested for associations of endogenous hormone with hemostatic factor levels in postmenopause. Estrone levels were inversely associated with the natural anticoagulant, protein S antigen. Dehydroepiandrosterone sulfate levels were inversely associated with thrombin generation.SummaryBackground Oral use of exogenous estrogen/progestin alters hemostatic factor levels. The influence of endogenous hormones on these levels is incompletely characterized. Objectives Our study aimed to test whether, among postmenopausal women, high levels of estradiol (E2), estrone (E1), testosterone (T), dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), and androstenedione, and low levels of sex hormone-binding globulin (SHBG), are positively associated with measures of thrombin generation (TG), a normalized activated protein C sensitivity ratio (nAPCsr), and factor VII activity (FVIIc), and negatively associated with antithrombin activity (ATc) and total protein S antigen (PSAg). Methods This Heart and Vascular Health study cross-sectional analysis included 131 postmenopausal women without a prior venous thrombosis who were not currently using hormone therapy. Adjusted mean differences in TG, nAPCsr, FVIIc, ATc and PSAg levels associated with differences in hormone levels were estimated using multiple linear regression. We measured E2, E1, total T, DHEAS, DHEA and androstenedione levels by mass spectrometry, SHBG levels by immunoassay, and calculated the level of free T. Results One picogram per milliliter higher E1 levels were associated with 0.24% lower PSAg levels (95% Confidence Interval [CI]: -0.35, -0.12) and 1 μg mL-1 higher DHEAS levels were associated with 40.8 nm lower TG peak values (95% CI: -59.5, -22.2) and 140.7 nm×min lower TG endogenous thrombin potential (ETP) (95% CI: -212.1, -69.4). After multiple comparisons correction, there was no evidence for other associations. Conclusions As hypothesized, higher E1 levels were associated with lower levels of the natural anticoagulant PSAg. Contrary to hypotheses, higher DHEAS levels were associated with differences in TG peak and ETP that suggest less generation of thrombin.

Project description:BACKGROUND:Genetic variations in some of the selenoprotein genes, alone or together with an individual's selenium status, may influence risk or progression of prostate cancer. We investigated the impact of genetic variants of selenoproteins on plasma selenium levels and cancer aggressiveness at diagnosis in men with localized prostate cancer (PCa). METHODS:The study cohort comprised 722 patients seen at Dana-Farber Cancer Institute who had localized/locally advanced PCa (i.e., stage T3 or less, N0, and M0) from 1994 to 2001. Fifty-five tagging single nucleotide polymorphisms (SNPs) from six selenoprotein genes (TXNRD1, TXNRD2, SEP15, GPX3, SELENBP1, and SEPP1) were analyzed. Logistic regression is used to examine associations of genotypes and plasma selenium levels with risk of aggressive disease, defined as D'Amico intermediate/high risk categories. Step down permutation was applied to adjust for multiple comparisons. RESULTS:Three hundred and forty-eight patients (48%) had aggressive disease at diagnosis. Two SNPs were associated with cancer aggressiveness at diagnosis (unadjusted P?=?0.017 and 0.018, respectively). The odds ratio for aggressive disease in patients carrying TXNRD2 rs1005873-AG/GG genotypes or SELENBP1 rs10788804-AG/AA genotypes was 1.54 (95% CI?=?1.08, 2.20) and 1.45 (95% CI?=?1.07, 1.98), respectively, compared to TXNRD2 rs1005873-AA or SELENBP1 rs10788804-GG carriers. Four SNPs in TXNRD2 (rs1005873, rs13054371, rs3788310, and rs9606174) and the rs230820 in SEPP1 were associated with plasma selenium levels (unadjusted P?<?0.05). Permutation adjusted P-values were not statistically significant for all these comparisons at the cut-off point of 0.05. CONCLUSION:We identified polymorphisms in selenoproteins that may influence the plasma selenium levels and may be associated with the risk of presenting with aggressive PCa in men with localized or locally advanced PCa. These results should be validated in other independent datasets.

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.

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The impact of common genetic variations in genes of the sex hormone metabolic pathways on steroid hormone levels and prostate cancer aggressiveness.

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The impact of common genetic variations in genes of the sex hormone metabolic pathways on steroid hormone levels and prostate cancer aggressiveness.

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