Association Between Polymorphisms in HSD3B1 and UGT2B17 and Prostate Cancer Risk

doi:10.1016/j.urology.2007.03.001

Urology

Volume 70, Issue 2, August 2007, Pages 374-379

https://doi.org/10.1016/j.urology.2007.03.001 Get rights and content

Objectives

Androgens, especially dihydrotestosterone, have been postulated to modify the risk of prostate cancer. 3-Beta-hydroxysteroid dehydrogenase1 (HSD3B1) and uridine diphosphate-glucuronosyltransferase 2B17 (UGT2B17) are enzymes that inactivate dihydrotestosterone in the prostate and may affect dihydrotestosterone concentration in prostatic tissue. The purpose of this study was to determine whether polymorphisms in HSD3B1 and UGT2B17 increase the risk of prostate cancer.

Methods

In a case-control study of 356 patients with incident primary prostate cancer and 363 age-matched controls, the frequencies of HSD3B1 N367T and UGT2B17 null polymorphisms in genomic DNA were compared between the patients and controls.

Results

No evidence was found for a main effect of the HSD3B1 codon 367 polymorphism on prostate cancer risk. However, among white men with family history of prostate cancer, the HSD3B1 367Thr allele was positively associated with prostate cancer (odds ratio 3.0, 95% confidence interval 1.0 to 9.2). A significant association was observed between the UGT2B17 null polymorphism and prostate cancer risk (odds ratio 1.7, 95% confidence interval 1.03 to 2.9). An association with the UGT2B17 null polymorphism was further elevated (odds ratio 2.7, 95% confidence interval 1.1 to 6.5) among individuals with HSD3B1 Asn/Asn genotype.

Conclusions

These results suggest that the HSD3B1 N367T and UGT2B17 null polymorphisms may modify the risk of prostate cancer, particularly among men with a family history of the disease.

Section snippets

Study Populations and Sample Processing

The appropriate institutional review board approvals were obtained for the study protocol at each institution. All study subjects provided written informed consent. A total of 356 incident patients with primary adenocarcinoma of the prostate (331 whites, 24 African Americans, and 1 other) were recruited from 2002 to 2005 at the H. Lee Moffitt Cancer Center (Tampa, Fla) and James A. Haley Veterans Affairs Hospital (Tampa, FL). Ninety-five percent of the case subjects who were asked to

Results

Table 1 provides descriptive characteristics of the patients and controls. Despite the frequency matching by age, the patients tended to be older than the controls (P <0.0001). The median age was 65 years at diagnosis for the patients and 60 years at interview for the controls. More men with prostate cancer (24%) than without (8%) reported having a first-degree family member with prostate cancer (P <0.0001). As expected, the prostate-specific antigen levels of most patients were greater than 4

Comment

In the present study, we observed that polymorphisms in HSD3B1 and UGT2B17 were associated with prostate cancer risk. These data are consistent with the hypothesis that these enzymes may play a role in the degradation of DHT²¹ and that an excessive amount of DHT may be associated with carcinogenesis in prostatic tissue.²²

The HSD3B1 codon 367 polymorphism may have an impact on HSD3B1 enzyme activity. This amino acid change from asparagine to threonine creates a new potential protein kinase C

Conclusions

Our data have suggested a potential joint effect between the HSD3B1 codon 367 and UGT2B17 deletion polymorphisms in relation to the risk of prostate cancer. These results warrant a larger study in the context of prostate cancer susceptibility, and basic research on the function of this enzyme, allelic variants, and other androgen-metabolizing enzymes.

Acknowledgment

To the Molecular Biology Core facility at H. Lee Moffitt Cancer Center for excellent technical assistance.

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Genetic variations in UGT2B28, UGT2B17, UGT2B15 genes and the risk of prostate cancer: A case-control study
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Previous findings revealed that the urine testosterone concentrations is different between subjects stratified by UGT2B17 CNV genotypes, where lower mean concentration was observed in people with two deleted UGT2B17 alleles in comparison to those who carry one copy of the gene (Jakobsson et al., 2006; Juul et al., 2009). In overall, mentioned UGT2B variants have been evaluated in relation to prostate cancer risk, with inconsistent findings (Gsur et al., 2002; Hajdinjak and Zagradišnik, 2004; MacLeod et al., 2000; Park et al., 2004; Park et al., 2007; Setlur et al., 2010; Park et al., 2006; Olsson et al., 2008; Karypidis et al., 2008). For example, some studies have shown that null genotype of UGT2B17 gene is linked to increased risk of PC in African-American and Caucasian races (Park et al., 2006; Karypidis et al., 2008).
Glucuronidation is a major pathway for elimination of exogenous and endogenous compounds such as environmental carcinogens and androgens from the body. This biochemical pathway is mediated by enzymes called uridine diphosphoglucuronosyltransferases (UGTs). Null (del/del) genes polymorphisms in UGT2B17, and UGT2B28 and D85Y single-nucleotide polymorphism (SNP) of UGT2B15 have been reported to increase the risk of prostate cancer. The goal of this study was to determine the association of mentioned genetic variants with the risk of prostate cancer.
We investigated the copy number variations (CNVs) of UGT2B17 and UGT2B28 loci and the association between rs1902023 polymorphism of UGT2B15 gene in 360 subjects consisted of 120 healthy controls, 120 prostate cancer (PC) patients and 120 benign prostatic hyperplasia (BPH) patients. No association was detected for the mentioned polymorphisms and the risk of PC. However, a significant association was detected between UGT2B17 copy number variation and BPH risk (OR = 2.189; 95% CI, 1.303–3.675; p = 0.003). Furthermore, we observed that the D85Y polymorphism increases the risk of BPH when analyzed in combination with the copy number variation of UGT2B17 gene (OR = 0.135; 95% CI, 0.036–0.512; p = 0.003).
Our findings suggest that the D85Y polymorphism of UGT2B15 and CNVs in UGT2B28 and UGT2B17 genes is not associated with prostate cancer risk in Iranian patients. To our knowledge, this is the first report that implicates the role of CNV of UGT2B17 gene in BPH.
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Thus, ranges of UGT2B17 genotypes were 41–54% and 33–64% (+/+), 33–48% and 32–52% (+/−), and 4–19% and 3–27% (−/−) in cancer patients and healthy individuals, respectively, of Caucasian descent from different geographic regions [8–14,16,21–24]. This high variability of genotype frequencies may partly explain the ambiguous data regarding the risks for individuals to develop prostate cancer [9–15], although Cai and colleagues demonstrated in a recent meta-analysis a consistent and high prostate cancer risk for men carrying the null genotype when compared to men-based controls but not in studies using population as controls [25]. Considering the heterogeneity of genotype frequencies, one limitation of our study is sample size.
Background: The enzyme uridine diphospho glucuronosyltansferase 2B17 (UGT2B17) glucuronidates several endogenous and exogenous compounds, including carcinogens from tobacco smoke like 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanl (NNAL). UGT2B17 shows a remarkable copy number variation (CNV) and an association between deletion genotype and increased risk of lung adenocarcinoma in women has been previously reported. Methods: We investigated the UGT2B17 CNV by PCR in 453 Austrian lung cancer patients and in 449 healthy donors and analyzed the impact on lung cancer susceptibility and outcome. Results: Copy numbers of UGT2B17 were 44.4% (+/+), 42.2% (+/−) and 13.5% (−/−) in lung cancer patients and 43.0% (+/+), 46.3% (+/−) and 10.7% (−/−) among healthy donors. The null genotype was not significantly more frequent among women with adenocarcinoma compared to healthy women (p = 0.59). There was no association with overall survival (p = 0.622) and no significant sex-associated (p = 0.423) or histology-related impact on development of lung cancer. Conclusion: UGT2B17 deletion genotype was not associated with a significant risk for lung cancer development or outcome in our Central European patient cohort. Our study indicates that UGT2B17 is not a crucial factor in lung carcinogenesis among Caucasians and shows the importance of investigating such markers in large cohorts from different populations.
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Androgen receptor (AR) signaling is essential for the initial development and progression of prostate cancer (PCa) as well as the growth and survival of castration-resistant tumors. However, AR action may be opposed by estrogen receptor beta (ERß) that responds to androgen metabolites produced in the prostate. The balance between the activity of these two receptors is not only influenced by the steroidogenic capacity of the prostatic microenvironment but also by its redox status and local paracrine signals such as transforming growth factor-beta (TGF-ß). In this review, we highlight the studies that revealed select roles for AR and ERß in distinct compartments of the prostate cancer microenvironment. We also discuss new work that identified stromal-epithelial crosstalk through TGF-ß1 signaling that drives the production of reactive oxygen species in stromal cells thereby selectively limiting the anti-tumor activity of ERß in cancer cells. Therefore, any new therapeutic approaches that seek to limit AR but enhance ERß activity in PCa, must take into account potential adaptive changes in the tumor microenvironment that utilize paracrine signals and altered redox balance to divert local androgen metabolites towards AR at the expense of ERß.
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In a case-control study of 356 PCa cases and 363 age-matched controls the UGT2B17 null polymorphism was associated with overall PCa risk. Risk for PCa associated with UGT2B17 null polymorphisms was further elevated among individuals with HSD3B1 variant (Park et al., 2007). In another study by Karypidis et al. (2008) a deletion polymorphism of UGT2B17 was found to be significantly associated with increased risk of PCa but no association was detected between the UTG2B17 del allele and metastatic disease or high-grade tumor differentiation.
Prostate cancer is the most frequent male malignancy diagnosed in western countries and androgens are known to mediate key physiological processes in prostate tissue. Since endogenous androgens have long been considered to be risk factors for prostate cancer, genes involved in androgen biosynthesis and metabolism have been extensively studied. In this review, association of androgen pathway genes, their polymorphic sites and risk of prostate cancer in different ethnic backgrounds is addressed together with their use to predict susceptibility and clinical outcomes of prostate cancer patients. The effect of the polymorphisms seems vary in different patients, populations and ethnic backgrounds. To date it is evident that the association between androgen pathway gene polymorphisms and prostate cancer risk is complex and many of the results are characterized by irreproducibility, which can be attributed to a variety of biological, statistical and technical reasons. In the future, with increasing knowledge, developing technologies and new genomic biomarkers it likely becomes possible to better estimate the risk of prostate cancer, and distinguish indolent disease from aggressive based on molecular profiling, and the analysis of gene–gene and gene–environment interactions.

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Basic scienceAssociation Between Polymorphisms in HSD3B1 and UGT2B17 and Prostate Cancer Risk

Objectives

Methods

Results

Conclusions

Section snippets

Study Populations and Sample Processing

Results

Comment

Conclusions

Acknowledgment

Lancet

Mol Cell Endocrinol

J Urol

Gen Pharmacol

Urology

J Urol

Genomics

Cancer Facts & Figures 2006

Prostate cancer epidemiology

Front Biosci

Serum testosterone levels in healthy young black and white men

J Natl Cancer Inst

Prostate cancer and polymorphism D85Y in gene for dihydrotestosterone degrading enzyme UGT2B15: frequency of DD homozygotes increases with Gleason Score

Prostate

A polymorphism in the UDP-glucuronosyltransferase 2B15 gene (D85Y) is not associated with prostate cancer risk

Cancer Epidemiol Biomarkers Prev

Deletion polymorphism of UDP-glucuronosyltransferase 2B17 and risk of prostate cancer in African American and Caucasian men

Cancer Epidemiol Biomarkers Prev

Basic science
Association Between Polymorphisms in HSD3B1 and UGT2B17 and Prostate Cancer Risk