Association between hormonal genetic polymorphisms and early-onset prostate cancer

Forrest, Matthew S.; Edwards, Steven M.; Houlston, Richard S.; Kóte-Jarai, Zsofia; Key, Timothy J.; Allen, Naomi E.; Knowles, Margaret A.; Turner, Faye; Ardern‐Jones, Audrey; Murkin, A; Williams, Sue; Oram, Richard A.; Bishop, D. Timothy; Eeles, Rosalind; Cruk,

doi:10.1038/sj.pcan.4500785

Cited by 47 publications

(33 citation statements)

References 43 publications

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“…[27][28][29][30] In our study, we confirm a lack of association between V89L and risk of prostate cancer. The metaanalysis could not exclude the possibility of an association between the A49T polymorphism and risk of prostate cancer, as confirmed in our study.…”

Section: Discussionsupporting

confidence: 74%

5α‐Reductase type 2 gene variant associations with prostate cancer risk, circulating hormone levels and androgenetic alopecia

Hayes

Severi

Padilla

et al. 2006

Intl Journal of Cancer

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Controversy exists over the significance of associations between the SRD5A2 (5a-reductase type 2) polymorphisms, A49T and V89L, and risk of prostate cancer. These potentially functional polymorphisms may alter life-long exposure to androgens with subsequent effects on male health and aging. The aim of this study was to examine the association of these variants with prostate cancer risk, plasma hormone levels and androgenetic alopecia. Subjects include 827 cases and 736 controls from an Australian population-based case-control study of prostate cancer. Information on prostate cancer risk factors and patterns of balding were collected. Plasma levels of testosterone, 3a-diol glucuronide (3a-diolG), dehydroepiandrosterone sulfate, androstenedione, sex hormone-binding globulin and estradiol were measured for controls. No associations with the V89L polymorphism were found. Carriers of the rarer A49T A allele were at a 60% higher risk of prostate cancer (OR 5 1.60; 95% CI 1.09-2.36; p 5 0.02) and 50% lower risk of vertex and frontal balding (p 5 0.03) compared with men homozygous for the more common G allele. Although we found little evidence of association between this variant and plasma levels of 5 measured androgens, circulating 3a-diolG levels were 34% lower in A49T A allele carriers (p < 0.0001). Our study provides evidence that the SRD5A2 A49T A variant is associated with an increased risk of prostate cancer, lower levels of circulating 3a-diolG and decreased risk of baldness. These findings raise important questions with respect to previous assumptions concerning hormonal influences on prostate cancer risk in ageing males. ' 2006 Wiley-Liss, Inc.Key words: SRD5A2; polymorphisms; prostate cancer risk; population-based case-control study; plasma androgens; androgenetic alopecia Membrane-bound 5a-reductase type 2 (SRD5A2) is responsible for the irreversible conversion of testosterone into its more active metabolite, dihydrotestosterone (DHT) and is essential for the normal growth and development of the prostate gland.1 This hormone-regulator has been implicated in male pathophysiology, including prostate cancer and balding (androgenetic alopecia). The ratio of DHT to testosterone has been reported to be highest for African-Americans, intermediate for Europeans and lowest for Asian-Americans, which corresponds to reported ethnic-based risk of prostate cancer for these groups, suggesting an association with prostate cancer risk.2 Prostate cancer risk has been associated with vertex pattern balding.3 Increased levels of DHT have been demonstrated in the male balding scalp, 4 while lack of balding is seen in pseudohermaphrodites (men with congenital 5a reductase deficiency) with a concomitant reduced ability to convert testosterone to DHT.5 DHT in turn is metabolized to 5a-androstane-3a-17b-diol glucuronide (3a-diolG), a predictor of both cutaneous and intraprostatic serum 5a-reductase levels. 6 These observations support the ''androgen hypothesis'' that increases in active androgens (and their metabolites) are associ...

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Section: Discussionsupporting

confidence: 74%

5α‐Reductase type 2 gene variant associations with prostate cancer risk, circulating hormone levels and androgenetic alopecia

Hayes

Severi

Padilla

et al. 2006

Intl Journal of Cancer

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“…Scariano et al (20) genotyped 33 males with early onset prostate cancer and found that the expression of at least one SRD5A L allele in young males with prostate cancer was associated with a more significant disease at the time of presentation as was defined by the pretreatment PSA level, clinical staging and Gleason score when compared with affected subjects harboring the more common SRD5A2 V variant. Similar results were published by other studies (34,42). Cicek et al (34) confirmed the association between the SRD5A2 polymorphism and increased risk of prostate cancer in males diagnosed at an earlier age or with more aggressive disease (OR, 2.35; 95% CI, 1.41-3.92; P=0.001 and OR, 1.63; 95% CI, 0.98-2.72; P=0.06, respectively).…”

Section: No Of Cases (%) -------------------------------------------supporting

confidence: 80%

Polymorphism of the SRD5A2 gene and the risk of prostate cancer

Dusenka

Tomaskin

Kliment

et al. 2014

Molecular Medicine Reports

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Abstract. Androgens are actively involved in the development of the prostate gland and appear to be essential for prostate carcinogenesis. The product of the SRD5A2 gene, membrane-bound steroid 5-α-reductase, type II enzyme, is key in testosterone metabolism. The present study explored the association between the SRD5A2 V89L gene polymorphism and the risk of developing prostate cancer. The study cohort consisted of 456 male Slovak patients, including 260 cases with histologically confirmed prostate cancer and 196 age-matched controls without any clinically suspected infections of the prostate. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to detect the SRD5A2 polymorphism on codon 89. Odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) for different allele variants were calculated in order to determine the association between the SRD5A2 V89L gene polymorphism and prostate cancer. The distribution of V89L variants in the control group was consistent with the Hardy-Weinberg equilibrium (χ 2 test, P=0.266) with a significant deviation in the case group (χ 2 test, P=0.04). However, no association between the SRD5A2 polymorphism and an increased risk of developing prostate cancer was identified. When the wild type VV variant was used as a reference, the ORs for different allele variants ranged from 1.11 (95% CI 0.66-1.87, P=0.70) for the LL genotype to 0.99 (95% CI 0.68-1.46, P=0.99) for the LL + VL genotypes. No particular allele variant was identified to exhibit an increased capacity to promote the development of highly aggressive prostate cancer (Gleason ≥7) or induce carcinogenesis at an earlier onset (<65 years of age). It was confirmed that in the population studied, the SRD5A2 V89L polymorphism was not associated with the risk of prostate cancer and SRD5A2 was not shown to be a key gene involved in prostate cancer development. Published data indicate that a combination of multiple genetic changes are required for prostate cancer development, rather than a single gene change. Therefore, it was hypothesized that high-throughput genotyping may be more effective than single nucleotide polymorphism detection.

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“…The differences in androgen levels may be due to variation in activity or expression of the enzymes responsible for metabolism of androgens. Most epidemiologic studies have focused on enzymes involved in production of androgens, such as CYP3A4 (10)(11)(12)(13), CYP17 (14)(15)(16)(17)(18)(19)(20)(21)(22), CYP3A43 (23), and SRD5A2 (22,24). Although differences in androgen levels may reflect variation in catabolism, fewer studies (25)(26)(27)(28) have evaluated this hypothesis.…”

Section: Introductionmentioning

confidence: 99%

Deletion Polymorphism of UDP-Glucuronosyltransferase 2B17 and Risk of Prostate Cancer in African American and Caucasian Men

Park

Chen

Ratnashinge

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Purpose: UDP-glucuronosyltransferases (UGT) are a family of enzymes that glucuronidate many endogenous chemicals, including androgens. This makes them more hydrophilic, alters biological activity, and facilitates their excretion. A deletion polymorphism in the UGT2B17 gene was recently described that was associated with a reduced rate of glucuronidation in vivo. The purpose of this study was to determine if the deletion polymorphism is associated with susceptibility to prostate cancer. Materials and Methods: UGT2B17 expression was determined by reverse transcription-PCR of pathologically normal prostate tissues (n = 5). In a case-control study with 420 patients with incident primary prostate cancer (127 African Americans and 293 Caucasians) and 487 controls (120 African Americans and 367 Caucasians), the frequency of UGT2B17 deletion polymorphism in genomic DNA was compared between cases and controls with PCR analysis.Results: UGT2B17 mRNA was detected only in individuals with at least one UGT2B17 allele. The frequency of the null genotype was present in 0.11 and 0.12 of Caucasian and African American controls, respectively. When all subjects were considered, a significant association was found between the UGT2B17 deletion polymorphism and prostate cancer risk [odds ratio (OR), 1.7; 95% confidence interval (95% CI), 1.2-2.6]. There was an increase in prostate cancer risk among individuals with UGT2B17 deletion polymorphism in Caucasians (OR, 1.9; 95% CI, 1.2-3.0) but not in African Americans (OR, 1.3; 95% CI, 0.6-2.7). Conclusions: These results suggest that the UGT2B17 enzyme may play a role in the metabolism of androgens in prostate tissue and that the UGT2B17 deletion polymorphism is associated with prostate cancer risk. (Cancer Epidemiol Biomarkers Prev 2006;15(8):1473 -8)

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Association between hormonal genetic polymorphisms and early-onset prostate cancer

Cited by 47 publications

References 43 publications

5α‐Reductase type 2 gene variant associations with prostate cancer risk, circulating hormone levels and androgenetic alopecia

5α‐Reductase type 2 gene variant associations with prostate cancer risk, circulating hormone levels and androgenetic alopecia

Polymorphism of the SRD5A2 gene and the risk of prostate cancer

Deletion Polymorphism of UDP-Glucuronosyltransferase 2B17 and Risk of Prostate Cancer in African American and Caucasian Men

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