Skip to main content
SpringerLink
Log in

Steroid 5-alpha-reductase type 2 (SRD5A2) V89L and A49T polymorphisms and sporadic prostate cancer risk: a meta-analysis

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Steroid 5-α-reductase type 2 (SRD5A2) V89L and A49T polymorphisms are thought to play a crucial role in the androgen synthesis and metabolic pathway, but their associations with prostate cancer risk remain controversial. To provide a more precise estimation of the associations between V89L and A49T polymorphisms and prostate cancer risk, we performed a meta-analysis using all published case–control studies of prostate cancer since January 1995. We used odds ratio (OR) and its 95 % confidence interval (CI) to assess the strength of the association under various genetic models in both overall and stratified analyses. We also calculated the false-positive report probability, the power of the current study, and the observed P value for significant findings. This analysis included 45 eligible studies of a total of 15,562 cases and 15,385 controls, in which no significant associations were found for the V89L polymorphisms under all genetic models. However, small excess prostate cancer risk was associated with the 49T allele in mixed populations compared with the 49A allele (OR = 1.24, 95 % CI = 1.02–1.50), and similar results were observed in Caucasians (OR = 1.24, 95 % CI = 1.01–1.53). The sensitivity analysis further strengthened the validity of these findings without publication bias. Although there was no overall association between V89L and prostate cancer risk, A49T might play a role in the etiology of prostate cancer among Caucasians. Additional large and well-designed studies are warranted to validate these findings.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

SRD5A2:

Steroid 5-α-reductase type 2

OR:

Odds ratio

CI:

Confidence interval

FPRP:

False-positive report probability

HWE:

Hardy–Weinberg equilibrium

References

  1. Crawford ED (2009) Understanding the epidemiology, natural history, and key pathways involved in prostate cancer. Urology 73:S4–S10

    Article  PubMed  Google Scholar 

  2. Boger-Megiddo I, Weiss NS, Barnett MJ et al (2008) V89L polymorphism of the 5alpha-reductase type II gene (SRD5A2), endogenous sex hormones, and prostate cancer risk. Cancer Epidemiol Biomark Prev 17:286–291

    Article  CAS  Google Scholar 

  3. Ilic M, Vlajinac H, Marinkovic J (1996) Case–control study of risk factors for prostate cancer. Br J Cancer 74:1682–1686

    Article  PubMed  CAS  Google Scholar 

  4. Stacewicz-Sapuntzakis M, Borthakur G, Burns JL et al (2008) Correlations of dietary patterns with prostate health. Mol Nutr Food Res 52:114–130

    Article  PubMed  CAS  Google Scholar 

  5. Ferris ITJ, Berbel-Tornero O, Garcia ICJ et al (2011) Nondietetic environmental risk factors in prostate cancer. Actas Urol Esp 35:289–295

    Article  Google Scholar 

  6. Tamburrino L, Salvianti F, Marchiani S et al (2012) Androgen receptor (AR) expression in prostate cancer and progression of the tumor: lessons from cell lines, animal models and human specimens. Steroids 77:996–1001

    Article  PubMed  CAS  Google Scholar 

  7. Leav I, Lau KM, Adams JY et al (2001) Comparative studies of the estrogen receptors beta and alpha and the androgen receptor in normal human prostate glands, dysplasia, and in primary and metastatic carcinoma. Am J Pathol 159:79–92

    Article  PubMed  CAS  Google Scholar 

  8. Cicek MS, Conti DV, Curran A et al (2004) Association of prostate cancer risk and aggressiveness to androgen pathway genes: SRD5A2, CYP17, and the AR. Prostate 59:69–76

    Article  PubMed  CAS  Google Scholar 

  9. Geller J, de la Vega DJ, Albert JD et al (1984) Tissue dihydrotestosterone levels and clinical response to hormonal therapy in patients with advanced prostate cancer. J Clin Endocrinol Metab 58:36–40

    Article  PubMed  CAS  Google Scholar 

  10. Wilbert DM, Griffin JE, Wilson JD (1983) Characterization of the cytosol androgen receptor of the human prostate. J Clin Endocrinol Metab 56:113–120

    Article  PubMed  CAS  Google Scholar 

  11. Ross RK, Bernstein L, Lobo RA et al (1992) 5-Alpha-reductase activity and risk of prostate cancer among Japanese and US White and Black males. Lancet 339:887–889

    Article  PubMed  CAS  Google Scholar 

  12. Wu AH, Whittemore AS, Kolonel LN et al (1995) Serum androgens and sex hormone-binding globulins in relation to lifestyle factors in older African-American, White, and Asian men in the United States and Canada. Cancer Epidemiol Biomark Prev 4:735–741

    CAS  Google Scholar 

  13. Hayes VM, Severi G, Padilla EJ et al (2007) 5Alpha-reductase type 2 gene variant associations with prostate cancer risk, circulating hormone levels and androgenetic alopecia. Int J Cancer 120:776–780

    Article  PubMed  CAS  Google Scholar 

  14. Makridakis NM, Ross RK, Pike MC et al (1999) Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA. Lancet 354:975–978

    Article  PubMed  CAS  Google Scholar 

  15. Makridakis NM, Ross RK, Pike MC et al (1997) A prevalent missense substitution that modulates activity of prostatic steroid 5alpha-reductase. Cancer Res 57:1020–1022

    PubMed  CAS  Google Scholar 

  16. Nam RK, Zhang WW, Trachtenberg J et al (2003) Comprehensive assessment of candidate genes and serological markers for the detection of prostate cancer. Cancer Epidemiol Biomark Prev 12:1429–1437

    CAS  Google Scholar 

  17. Febbo PG, Kantoff PW, Platz EA et al (1999) The V89L polymorphism in the 5alpha-reductase type 2 gene and risk of prostate cancer. Cancer Res 59:5878–5881

    PubMed  CAS  Google Scholar 

  18. Lunn RM, Bell DA, Mohler JL et al (1999) Prostate cancer risk and polymorphism in 17 hydroxylase (CYP17) and steroid reductase (SRD5A2). Carcinogenesis 20:1727–1731

    Article  PubMed  CAS  Google Scholar 

  19. Yamada Y, Watanabe M, Murata M et al (2001) Impact of genetic polymorphisms of 17-hydroxylase cytochrome P-450 (CYP17) and steroid 5alpha-reductase type II (SRD5A2) genes on prostate-cancer risk among the Japanese population. Int J Cancer 92:683–686

    Article  PubMed  CAS  Google Scholar 

  20. Hsing AW, Chen C, Chokkalingam AP et al (2001) Polymorphic markers in the SRD5A2 gene and prostate cancer risk: a population-based case–control study. Cancer Epidemiol Biomark Prev 10:1077–1082

    CAS  Google Scholar 

  21. Soderstrom T, Wadelius M, Andersson SO et al (2002) 5Alpha-reductase 2 polymorphisms as risk factors in prostate cancer. Pharmacogenetics 12:307–312

    Article  PubMed  Google Scholar 

  22. Latil AG, Azzouzi R, Cancel GS et al (2001) Prostate carcinoma risk and allelic variants of genes involved in androgen biosynthesis and metabolism pathways. Cancer 92:1130–1137

    Article  PubMed  CAS  Google Scholar 

  23. Pearce CL, Makridakis NM, Ross RK et al (2002) Steroid 5-alpha reductase type II V89L substitution is not associated with risk of prostate cancer in a multiethnic population study. Cancer Epidemiol Biomark Prev 11:417–418

    CAS  Google Scholar 

  24. Margiotti K, Sangiuolo F, De Luca A et al (2000) Evidence for an association between the SRD5A2 (type II steroid 5 alpha-reductase) locus and prostate cancer in Italian patients. Dis Markers 16:147–150

    PubMed  CAS  Google Scholar 

  25. Li J, Coates RJ, Gwinn M et al (2010) Steroid 5-{alpha}-reductase type 2 (SRD5a2) gene polymorphisms and risk of prostate cancer: a HuGE review. Am J Epidemiol 171:1–13

    Article  PubMed  Google Scholar 

  26. Wang C, Tao W, Chen Q et al (2010) SRD5A2 V89L polymorphism and prostate cancer risk: a meta-analysis. Prostate 70:170–178

    PubMed  CAS  Google Scholar 

  27. Li X, Huang Y, Fu X et al (2011) Meta-analysis of three polymorphisms in the steroid-5-alpha-reductase, alpha polypeptide 2 gene (SRD5A2) and risk of prostate cancer. Mutagenesis 26:371–383

    Article  PubMed  CAS  Google Scholar 

  28. Forrest MS, Edwards SM, Houlston R et al (2005) Association between hormonal genetic polymorphisms and early-onset prostate cancer. Prostate Cancer Prostatic Dis 8:95–102

    Article  PubMed  CAS  Google Scholar 

  29. Lau J, Ioannidis JP, Schmid CH (1997) Quantitative synthesis in systematic reviews. Ann Intern Med 127:820–826

    PubMed  CAS  Google Scholar 

  30. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    Article  PubMed  CAS  Google Scholar 

  31. Higgins JP, Thompson SG, Deeks JJ et al (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560

    Article  PubMed  Google Scholar 

  32. Wacholder S, Chanock S, Garcia-Closas M et al (2004) Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst 96:434–442

    Article  PubMed  Google Scholar 

  33. Egger M, Davey Smith G, Schneider M et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    Article  PubMed  CAS  Google Scholar 

  34. Cussenot O, Azzouzi AR, Nicolaiew N et al (2007) Low-activity V89L variant in SRD5A2 is associated with aggressive prostate cancer risk: an explanation for the adverse effects observed in chemoprevention trials using 5-alpha-reductase inhibitors. Eur Urol 52:1082–1087

    Article  PubMed  Google Scholar 

  35. Rajender S, Vijayalakshmi K, Pooja S et al (2009) Longer (TA)n repeat but not A49T and V89L polymorphisms in SRD5A2 gene may confer prostate cancer risk in South Indian men. J Androl 30:703–710

    Article  PubMed  CAS  Google Scholar 

  36. Li Z, Habuchi T, Mitsumori K et al (2003) Association of V89L SRD5A2 polymorphism with prostate cancer development in a Japanese population. J Urol 169:2378–2381

    Article  PubMed  CAS  Google Scholar 

  37. Salam MT, Ursin G, Skinner EC et al (2005) Associations between polymorphisms in the steroid 5-alpha reductase type II (SRD5A2) gene and benign prostatic hyperplasia and prostate cancer. Urol Oncol 23:246–253

    Article  PubMed  CAS  Google Scholar 

  38. Hsing AW (2001) Hormones and prostate cancer: what’s next? Epidemiol Rev 23:42–58

    Article  PubMed  CAS  Google Scholar 

  39. Ntais C, Polycarpou A, Ioannidis JP (2003) SRD5A2 gene polymorphisms and the risk of prostate cancer: a meta-analysis. Cancer Epidemiol Biomark Prev 12:618–624

    CAS  Google Scholar 

  40. Vatten LJ, Ursin G, Ross RK et al (1997) Androgens in serum and the risk of prostate cancer: a nested case–control study from the Janus serum bank in Norway. Cancer Epidemiol Biomark Prev 6:967–969

    CAS  Google Scholar 

  41. Heinrichs S, Look AT (2007) Identification of structural aberrations in cancer by SNP array analysis. Genome Biol 8:219

    Article  PubMed  Google Scholar 

  42. Hemminki K, Bermejo JL (2005) Relationships between familial risks of cancer and the effects of heritable genes and their SNP variants. Mutat Res 592:6–17

    Article  PubMed  CAS  Google Scholar 

  43. Bernig T, Chanock SJ (2006) Challenges of SNP genotyping and genetic variation: its future role in diagnosis and treatment of cancer. Expert Rev Mol Diagn 6:319–331

    Article  PubMed  CAS  Google Scholar 

  44. Scariano JK, Treat E, Alba F et al (2008) The SRD5A2 V89L polymorphism is associated with severity of disease in men with early onset prostate cancer. Prostate 68:1798–1805

    Article  PubMed  CAS  Google Scholar 

  45. Nam RK, Toi A, Vesprini D et al (2001) V89L polymorphism of type-2, 5-alpha reductase enzyme gene predicts prostate cancer presence and progression. Urology 57:199–204

    Article  PubMed  CAS  Google Scholar 

  46. Sobti RC, Onsory K, Al-Badran AI et al (2006) CYP17, SRD5A2, CYP1B1, and CYP2D6 gene polymorphisms with prostate cancer risk in North Indian population. DNA Cell Biol 25:287–294

    Article  PubMed  CAS  Google Scholar 

  47. Onen IH, Ekmekci A, Eroglu M et al (2007) The association of 5alpha-reductase II (SRD5A2) and 17 hydroxylase (CYP17) gene polymorphisms with prostate cancer patients in the Turkish population. DNA Cell Biol 26:100–107

    Article  PubMed  CAS  Google Scholar 

  48. Chang BL, Zheng SL, Isaacs SD et al (2003) Evaluation of SRD5A2 sequence variants in susceptibility to hereditary and sporadic prostate cancer. Prostate 56:37–44

    Article  PubMed  CAS  Google Scholar 

  49. Zenimoto M, Kita M, Arai T et al (2003) Free/total prostate specific antigen ratio (%PSA) to predict probability of prostate cancer. Rinsho Byori 51:969–973

    PubMed  Google Scholar 

  50. Tochigi T, Kawamura S, Numahata K et al (2001) Retrospective evaluation of PSA density for selection of biopsy candidates with prostate specific antigen in the gray zone. Nihon Hinyokika Gakkai Zasshi 92:609–614

    PubMed  CAS  Google Scholar 

  51. Marberger M, Barentsz J, Emberton M et al (2012) Novel approaches to improve prostate cancer diagnosis and management in early-stage disease. BJU Int 109(Suppl 2):1–7

    Article  PubMed  Google Scholar 

  52. Mononen N, Ikonen T, Syrjakoski K et al (2001) A missense substitution A49T in the steroid 5-alpha-reductase gene (SRD5A2) is not associated with prostate cancer in Finland. Br J Cancer 84:1344–1347

    Article  PubMed  CAS  Google Scholar 

  53. Lamharzi N, Johnson MM, Goodman G et al (2003) Polymorphic markers in the 5alpha-reductase type II gene and the incidence of prostate cancer. Int J Cancer 105:480–483

    Article  PubMed  CAS  Google Scholar 

  54. Giwercman YL, Abrahamsson PA, Giwercman A et al (2005) The 5alpha-reductase type II A49T and V89L high-activity allelic variants are more common in men with prostate cancer compared with the general population. Eur Urol 48:679–685

    Article  PubMed  CAS  Google Scholar 

  55. Lindstrom S, Wiklund F, Adami HO et al (2006) Germ-line genetic variation in the key androgen-regulating genes androgen receptor, cytochrome P450, and steroid-5-alpha-reductase type 2 is important for prostate cancer development. Cancer Res 66:11077–11083

    Article  PubMed  Google Scholar 

  56. Berndt SI, Chatterjee N, Huang WY et al (2007) Variant in sex hormone-binding globulin gene and the risk of prostate cancer. Cancer Epidemiol Biomark Prev 16:165–168

    Article  CAS  Google Scholar 

  57. Cunningham JM, Hebbring SJ, McDonnell SK et al (2007) Evaluation of genetic variations in the androgen and estrogen metabolic pathways as risk factors for sporadic and familial prostate cancer. Cancer Epidemiol Biomark Prev 16:969–978

    Article  CAS  Google Scholar 

  58. Neslund-Dudas C, Bock CH, Monaghan K et al (2007) SRD5A2 and HSD3B2 polymorphisms are associated with prostate cancer risk and aggressiveness. Prostate 67:1654–1663

    Article  PubMed  CAS  Google Scholar 

  59. Lindstrom S, Zheng SL, Wiklund F et al (2006) Systematic replication study of reported genetic associations in prostate cancer: strong support for genetic variation in the androgen pathway. Prostate 66:1729–1743

    Article  PubMed  Google Scholar 

  60. Sarma AV, Dunn RL, Lange LA et al (2008) Genetic polymorphisms in CYP17, CYP3A4, CYP19A1, SRD5A2, IGF-1, and IGFBP-3 and prostate cancer risk in African-American men: the Flint Men’s Health Study. Prostate 68:296–305

    Article  PubMed  CAS  Google Scholar 

  61. Torkko KC, van Bokhoven A, Mai P et al (2008) VDR and SRD5A2 polymorphisms combine to increase risk for prostate cancer in both non-Hispanic White and Hispanic White men. Clin Cancer Res 14:3223–3229

    Article  PubMed  CAS  Google Scholar 

  62. Kantoff PW, Febbo PG, Giovannucci E et al (1997) A polymorphism of the 5 alpha-reductase gene and its association with prostate cancer: a case–control analysis. Cancer Epidemiol Biomark Prev 6:189–192

    CAS  Google Scholar 

  63. Pearce CL, Van Den Berg DJ, Makridakis NM et al (2008) No association between the SRD5A2 gene A49T missense variant and prostate cancer risk: lessons learned. Hum Mol Genet 17:2456–2461

    Article  PubMed  CAS  Google Scholar 

  64. Sobti RC, Gupta L, Singh SK et al (2008) Role of hormonal genes and risk of prostate cancer: gene–gene interactions in a North Indian population. Cancer Genet Cytogenet 185:78–85

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the grant from “China’s Thousand Talents Program” Recruitment at Fudan University.

Conflict of interests

The authors have declared that no competing interests exist.

Author information

Authors and Affiliations

  1. Cancer Research Laboratory, Fudan University Shanghai Cancer Institute, Shanghai, China

    Qiaoxin Li, Jing He, Mengyun Wang, Meiling Zhu, Tingyan Shi & Qingyi Wei

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Qiaoxin Li, Yao Zhu, Jing He, Mengyun Wang, Meiling Zhu, Tingyan Shi, Lixin Qiu & Dingwei Ye

  3. Department of Urology Oncology, Fudan University Shanghai Cancer Institute, 270 Dong An Road, Shanghai, 200032, China

    Yao Zhu & Dingwei Ye

  4. Department of Medical Oncology, Fudan University Shanghai Cancer Institute, Shanghai, China

    Lixin Qiu

  5. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Qingyi Wei

Authors
  1. Qiaoxin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yao Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jing He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mengyun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Meiling Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tingyan Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lixin Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dingwei Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Qingyi Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Dingwei Ye or Qingyi Wei.

Additional information

Qiaoxin Li and Yao Zhu contributed equally to this work and should be considered co-first authors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 63 kb)

Supplementary material 2 (DOCX 12 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, Q., Zhu, Y., He, J. et al. Steroid 5-alpha-reductase type 2 (SRD5A2) V89L and A49T polymorphisms and sporadic prostate cancer risk: a meta-analysis. Mol Biol Rep 40, 3597–3608 (2013). https://doi.org/10.1007/s11033-012-2434-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-012-2434-x

Keywords

Search

Navigation