| Note | |
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| Entity | Prostate cancer |
| Note | Various genetic studies from multiple ethnic populations have shown genetic variations in the SRD5A2 gene are associated with prostate cancer. Polymorphisms V89L, A29T, and the (TA)n repeat are some of well-known SRD5A2 variation that have been liked to prostate cancer risk. However, these associations are not always consistent. For example, the V89L (rs523349) variant is a missense single nucleotide polymorphism resulting in a valine to leucine substitution at condon 89 that reduced SRD5A2 enzyme activity. More than couple dozen of studies performed genetic association studies between V89L polymorphism and prostate cancer risk since 1997. Although the association has been found significant repeatedly, the results were inconsistent and conflicting (Nam et al., 2001; Salam et al., 2005, Hsing et al., 2001). Recently, a meta-analysis review (Wang et al., 2010) was conducted on 25 genetic studies of SRD5A2 V89L polymorphism and prostate cancer, which included additional subgroup analysis in Asian, African, European and age ≤ 65 group. In overall analysis, no significant association was found between V89L and prostate cancer risk. Subgroup analysis revealed a slight but significant increased risk in European men with at least one L-allele (LL+LV vs VV, OR=1.11; 95%CI=1.03-1.19; P<0.01), and in men younger than 65 with LL genotype when compared to those with VV genotype (OR=1.70; 95%CI=1.14-2.68; P=0.02). The interethnic discrepancy of the effect of V89L may have arisen from a variable influence of the risk allele due to the significantly varied allelic distribution of V89L between the ethnic groups (Zeigler-Johnson et al., 2002). It was concluded that the V89L polymorphism plays a low-penetrant role in the risk of prostate cancer among European and men younger than 65 years of age. |
| Oncogenesis | Androgen levels have been suggested to play an important role in the etiology of prostate cancer. The same SRD5A2 genetic variations linked to prostate cancer has also been repeatedly shown to be associated with various circulating androgen level in the blood, including testosterone, dihydrotestosterone and various forms of their metabolites (Makridakis et al., 2000; Allen et al., 2001; Hsing et al., 2001). Therefore, it is possible that these risk-predisposing polymorphisms may cause changes in the SRD5A2 enzyme functional activity that results in the variation of circulating androgens, and ultimately leads to the development of prostate cancer. |
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| The association between polymorphisms in the CYP17 and 5alpha-reductase (SRD5A2) genes and serum androgen concentrations in men. |
| Allen NE, Forrest MS, Key TJ. |
| Cancer Epidemiol Biomarkers Prev. 2001 Mar;10(3):185-9. |
| PMID 11303586 |
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| Polymorphic markers in the SRD5A2 gene and prostate cancer risk: a population-based case-control study. |
| Hsing AW, Chen C, Chokkalingam AP, Gao YT, Dightman DA, Nguyen HT, Deng J, Cheng J, Sesterhenn IA, Mostofi FK, Stanczyk FZ, Reichardt JK. |
| Cancer Epidemiol Biomarkers Prev. 2001 Oct;10(10):1077-82. |
| PMID 11588134 |
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| International trends and patterns of prostate cancer incidence and mortality. |
| Hsing AW, Tsao L, Devesa SS. |
| Int J Cancer. 2000 Jan 1;85(1):60-7. |
| PMID 10585584 |
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| Association of SRD5A2 variants and serum androstane-3alpha,17beta-diol glucuronide concentration in Chinese elderly men. |
| Jiang J, Tang NL, Ohlsson C, Eriksson AL, Vandenput L, Liao C, Wang X, Chan FW, Kwok A, Orwoll E, Kwok TC, Woo J, Leung PC. |
| Clin Chem. 2010 Nov;56(11):1742-9. doi: 10.1373/clinchem.2010.150607. Epub 2010 Sep 20. |
| PMID 20855474 |
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| Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II. |
| Makridakis NM, di Salle E, Reichardt JK. |
| Pharmacogenetics. 2000 Jul;10(5):407-13. |
| PMID 10898110 |
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| V89L polymorphism of type-2, 5-alpha reductase enzyme gene predicts prostate cancer presence and progression. |
| Nam RK, Toi A, Vesprini D, Ho M, Chu W, Harvie S, Sweet J, Trachtenberg J, Jewett MA, Narod SA. |
| Urology. 2001 Jan;57(1):199-204. |
| PMID 11164181 |
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| Five novel mutations of SRD5A2 found in eight Chinese patients with 46,XY disorders of sex development. |
| Nie M, Zhou Q, Mao J, Lu S, Wu X. |
| Mol Hum Reprod. 2011 Jan;17(1):57-62. doi: 10.1093/molehr/gaq072. Epub 2010 Aug 24. |
| PMID 20736251 |
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| Associations between polymorphisms in the steroid 5-alpha reductase type II (SRD5A2) gene and benign prostatic hyperplasia and prostate cancer. |
| Salam MT, Ursin G, Skinner EC, Dessissa T, Reichardt JK. |
| Urol Oncol. 2005 Jul-Aug;23(4):246-53. |
| PMID 16018939 |
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| Novel compound heterozygous mutations in the SRD5A2 gene from 46,XY infants with ambiguous external genitalia. |
| Vilchis F, Valdez E, Ramos L, Garcia R, Gomez R, Chavez B. |
| J Hum Genet. 2008;53(5):401-6. doi: 10.1007/s10038-008-0274-2. Epub 2008 Mar 19. |
| PMID 18350250 |
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| SRD5A2 V89L polymorphism and prostate cancer risk: a meta-analysis. |
| Wang C, Tao W, Chen Q, Hu H, Wen XY, Han R. |
| Prostate. 2010 Feb 1;70(2):170-8. doi: 10.1002/pros.21050. |
| PMID 19760631 |
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| Ethnic differences in the frequency of prostate cancer susceptibility alleles at SRD5A2 and CYP3A4. |
| Zeigler-Johnson CM, Walker AH, Mancke B, Spangler E, Jalloh M, McBride S, Deitz A, Malkowicz SB, Ofori-Adjei D, Gueye SM, Rebbeck TR. |
| Hum Hered. 2002;54(1):13-21. |
| PMID 12446983 |
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