Published OnlineFirst September 7, 2011; DOI: 10.1158/1940-6207.CAPR-11-0283 Cancer Prevention Research Article Research The Impact of Common Genetic Variations in Genes of the Sex Hormone Metabolic Pathways on Steroid Hormone Levels and Prostate Cancer Aggressiveness Tong Sun1, William K. Oh1, Susanna Jacobus2, Meredith Regan2, Mark Pomerantz1, Matthew L. Freedman1, Gwo-Shu Mary Lee1, and Philip W. Kantoff1 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 poly- morphisms (SNPs) from 30 genes that are involvedinandrogenandestrogenmetabolismwere 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 ¼ 0.005), UGT2B15 (rs2045100; P ¼ 0.007), and HSD17B12 (rs7932905; P ¼ 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. Cancer Prev Res; 4(12); 2044–50. Ó2011 AACR. Introduction principal androgen present in the blood, mostly bound to sex hormone–binding globulin (SHBG) and albumin. Sex steroid hormones influence the development, matu- Intracellularly, testosterone is enzymatically converted to ration, and maintenance of the prostate, affecting both the the more potent metabolite dihydrotestosterone (DHT). proliferation and differentiation status of the luminal epi- The complex of androgen (testosterone or DHT) and andro- thelium (1–3). Androgens are synthesized primarily in the gen receptor regulates the expression of a variety of genes testes or adrenal glands, and secondarily in peripheral that are involved in the growth, survival, and differentiation tissues including the prostate (2). Testosterone is the of prostate cells by binding to androgen response elements present in the regulatory regions of these genes (2). The relationship between androgens and the develop- Authors' Affiliations: Departments of 1Medical Oncology and 2Biostatis- ment of prostate cancer is complex. Some early studies tics and Computational Biology, Dana-Farber Cancer Institute and Harvard showed that plasma testosterone levels might be correlated Medical School, Boston, Massachusetts with Gleason grade or time to progression after orchiectomy Note: Supplementary data for this article are available at Cancer Prevention of prostate cancer (3, 4). However, other studies indicated Research Online (http://cancerprevres.aacrjournals.org/). no evidence of any association between plasma testoster- Current address for W.K. Oh: Department of Medical Oncology, Mount one, estradiol (E2), and SHBG with Gleason score at the Sinai School of Medicine, New York, NY 10029, USA. time of diagnosis (5, 6). Thus, there is insufficient evidence Corresponding Authors: Gwo-Shu Mary Lee or Philip W. Kantoff, Depart- to support the hypothesis that higher blood levels of steroid ment of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave. Binney Street, Boston, MA 02215. Phone: 617-632-1914; Fax: 617- hormones are associated with prostate cancer development 632-2165; E-mail: [email protected]; and Philip W. Kantoff, or progression. One explanation for this lack of association [email protected] is the uncertain correlation between the plasma concentra- doi: 10.1158/1940-6207.CAPR-11-0283 tions of androgens with the intraprostatic hormone levels, Ó2011 American Association for Cancer Research. an essential component in the tumor microenvironment 2044 Cancer Prev Res; 4(12) December 2011 Downloaded from cancerpreventionresearch.aacrjournals.org on September 24, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst September 7, 2011; DOI: 10.1158/1940-6207.CAPR-11-0283 Genetic Polymorphisms, Steroid Hormone, and Prostate Cancer Aggressiveness that potentially affects tumor growth (2, 7, 8). Another testosterone levels in Caucasian men in both cases and explanation is that a single determination of plasma andro- controls. They also identified relating SNPs in ESR1 and gens in middle or older age may not be representative of SRD5A2 with testosterone and 3a-androstanediol-glucu- time-averaged or maximum levels over the etiologically ronide, respectively (19). relevant time of life (9). Similarly, the relationship between We present here a systematic analysis of 143 common estrogen levels and prostate cancer is unclear. There is some polymorphisms in 30 genes that are involved in the sex evidence that estrogen metabolites functioning as genotox- steroid hormones metabolic pathways for their potential ins can increase risk for prostate cancer (10). It also has been associations with plasma total testosterone, total estradiol, suggested that a decrease in the androgen/estrogen ratio and SHBG, or with prostate cancer aggressiveness in an with aging could be responsible in part for prostate carci- established cohort of 508 patients with newly diagnosed nogenesis (10). localized prostate cancer. Therapeutically, blocking androgen production has been one of the most commonly used treatments of advanced Materials and Methods prostate cancer and is often successful until castration resistant growth is acquired (2, 11, 12). In addition, estro- Study population and laboratory assays gens are recognized therapies for prostate cancer. Oral E2 The study cohort and the measurement of hormone levels administration may be useful for treatment of advanced have been previously described in detail (5, 20). Briefly, a castration-resistant prostate cancer (10). This therapy also total of 539 patients with localized prostate cancer evalu- has side effects and that the effects of estrogens are mediated ated at the Dana-Farber Cancer Institute from 2001 to 2005, by 2 different receptors, estrogen receptor a (ERa) and ERb who were enrolled in a prospective sample banking proto- (10). col, were eligible for this study. Most clinical data were Genetic polymorphisms of genes involved in metabolic abstracted from the Current Research Information System pathways of sex steroid hormones have been investigated database, as described (21). Because mixed ethnicity could as candidates for prostate cancer risk in many association confound the association results, we removed 31 patients of studies (13–16). Data from these case–control studies non-Caucasian race or with indeterminate ancestry from suggest that interindividual variation in genes involved this study. A total of 508 individuals were analyzed. These in sex hormone metabolic pathway could be related to the individuals either self-reported as European American or risk of prostate cancer incidence (13–16). However, few were determined to be of European ancestry, based on studies have examined the association of these poly- genotyping of ancestry informative markers. Using the morphisms with blood hormone levels in prostate cancer D’Amico risk classification criteria, newly diagnosed (17–19). In the National Cancer Institute (NCI)-Breast patients with prostate cancer were classified as at low, and Prostate Cancer Cohort Consortium (BPC3) study, intermediate, or high risk of clinical recurrence after pri- single-nucleotide polymorphisms (SNP) in SHBG gene mary therapy (22). Briefly, 3 risk groups were established on werefoundtobeassociatedwithcirculatingSHBGand the basis of serum prostate-specific antigen (PSA) level, HSD17B1, HSD17B7 Cholesterol DHEA-S HSD17B2 Androstenediol-S CYP11A1 SULT2A1 STS SULT1E1 STS AKR1C3 3β-Androstanediol CYP17A1 Pregnenolone DHEA Androstenediol HSD17B2 HSD3B1, HSD3B2 HSD3B1, HSD3B2 HSD3B1, HSD3B2 AKR1C1 AKR1C3, HSD17B1 AKR1C1, AKR1C2 CYP17A1 HSD17B3, HSD17B7 SRD5A1, SRD5A2 AKR1C3, AKR1C4 Progesterone Androstenedione Testosterone DHT 3α-Androstanediol AKR1C3, HSD17B2 HSD17B HSD17B4 UGT2B15 UGT2B15 CYP19A1 CYP19A1 UGT2B17 UGT2B17 AKR1C3, HSD17B1 UGT2B4 UGT2B4 HSD17B7, HSD17B12 β Estrone 17 -Estradiol DHT-17-glucuronide 3α-Androstanediol- HSD17B2 17-glucuronide CYP3A4, CYP1A1 UGT2B28 SULT1A1 UGT2B4 SULT1E1, SULT2A1 UGT2B7 4-Hydroxyestron 17β-Estra-1,3,5-trien 3,17-diol Estradiol 3-glucuronide 3-sulfate COMT CYP3A4, CYP1A1, CYP1B1 Methoxyestrone Hydroxyestradiol COMT Methoxyestradiol Figure 1. Candidate genes involved in androgen and estrogen biosynthesis and metabolism process. This diagram shows how the 30 metabolic genes analyzed in this study are involved in different steps of androgen