Association of missense substitution of A49T and V89L in the SRD5A2 gene with prostate cancer in Turkish patients

Sebnem Tekin Neijmann 1 , Alev Kural 1 , Ilker Tinay 2 , Ayten Livaoglu 3 , Tulay Cevlik 4  and Levent Turkeri 2
  • 1 Department of Biochemistry, Bakirkoy Dr. Sadi Konuk Research and Training Hospital, Istanbul, Turkey
  • 2 Department of Urology, Marmara University Pendik Research and Training Hospital Istanbul, Turkey
  • 3 Trabzon Kanuni Research and Training Hospital, Trabzon, Turkey
  • 4 Department of Biochemistry, Marmara University Pendik Research and Training Hospital, Istanbul, Turkey
Sebnem Tekin Neijmann, Alev Kural, Ilker Tinay, Ayten Livaoglu, Tulay Cevlik and Levent Turkeri

Abstract

Objective:

To determine the association of missense substitution of alanine 49 threonine (A49T) and valine 89 leucine (V89L) in the steroid-5-alpha-reductase type II (SRD5A2) gene with prostate cancer in Turkish patients.

Methods:

Eighty patients with prostate cancer and 76 healthy control subjects were evaluated for A49T and V89L polymorphisms in the SRD5A2 gene mutations via real time fluorescence PCR and melting curve analysis.

Results:

Patients and controls were similar in terms of allele frequencies for polymorphic markers A49T and V89L in the SRD5A2 gene. Most patients had T2b (51.3%), N0 (96.3%) stage tumors with Gleason Score of ≥6 (82.7%) and surgical margin in 28.8%. While 81.3% had no seminal vesicle invasion, 36.3% had capsular invasion. Carrying the 49T allele was associated with higher likelihood of positive surgical margin status (27.5% in 49A vs. 75.0% in 49T, p=0.038) and Gleason Scores of ≥7 (47.5% in 49A vs. 100.0% in 49T, p=0.032) than 49A allele.

Conclusion:

Our findings revealed no significant difference between patient and control groups in terms of allele frequencies of polymorphic markers in the SRD5A2 gene. T allele was only shown in the patient group. Carrying the 49T allele was associated with higher tumor aggressiveness in A49T polymorphism.

  • 1.

    Hsing AW, Chokkalingam AP. Prostate cancer epidemiology. Front Biosci 2006;11:1388–413.

    • Crossref
    • PubMed
    • Export Citation
  • 2.

    Lindström S, Zheng SL, Wiklund F, Jonsson BA, Adami HO, Bälter KA, et al. Systematic replication study of reported genetic associations in prostate cancer: strong support for genetic variation in the androgen pathway. Prostate 2006;66:1729–43.

    • Crossref
    • PubMed
    • Export Citation
  • 3.

    Crawford ED. Epidemiology of prostate cancer. Urology 2003;62:3–12.

    • PubMed
    • Export Citation
  • 4.

    Giwercman YL, Abrahamsson PA, Giwercman A, Gadaleanu V, Ahlgren G. 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 2005;48:679–85.

    • Crossref
    • PubMed
    • Export Citation
  • 5.

    Rittmaster RS. 5α-Reductase inhibitors in benign prostatic hyperplasia and prostate cancer risk reduction. Best Pract Res Clin Endocrinol Metab 2008;22:389–402.

    • Crossref
    • PubMed
    • Export Citation
  • 6.

    Singh AS, Chau CH, Price DK, Figg WD. Mechanisms of disease. Polymorphisms of androgen regulatory genes in the development of prostate cancer. Nat Clin Pract Urol 2005;2:101–7.

    • Crossref
    • PubMed
    • Export Citation
  • 7.

    Paz-y-Miño C, Witte T, Robles P, LIumipanta W, Diaz M, Arévalo M. Association among polymorphisms in the steroid 5α-reductase type II (SRD5A2) gene, prostate cancer risk, and pathologic characteristics of prostate tumors in an Ecuadorian population. Cancer Genet Cytogenet 2009;189:71–6.

    • Crossref
    • Export Citation
  • 8.

    Makridakis NM, Ross RK, Pike MC, Crocitto LE, Kolonel LN, Pearce CL, et al. Association of mis- sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA. Lancet 1999;354:975–8.

    • Crossref
    • PubMed
    • Export Citation
  • 9.

    Scariano JK, Treat E, Alba F, Nelson H, Ness SA, Smith AY. The SRD5A2 V89L polymorphism is associated with severity of disease in men with early onset prostate cancer. Prostate 2008;68:1798–805.

    • Crossref
    • PubMed
    • Export Citation
  • 10.

    Wang C, Tao W, Chen Q, Hu H, Wen XY, Han R. SRD5A2 V89L polymorphism and prostate cancer risk: a meta-analysis. Prostate 2010;70:170–8.

  • 11.

    Labrie F, Sugimoto Y, Luu-The V, Simard J, Lachance Y, Bachvarov D, et al. Structure of human type II 5 alpha-reductase gene. Endocrinology 1992;131:1571–3.

    • Crossref
    • PubMed
    • Export Citation
  • 12.

    Neslund-Dudas C, Bock CH, Monaghan K, Nock NL, Yang JJ, Rundle A, et al. SRD5A2 and HSD3B2 polymorphisms are associated with prostate cancer risk and aggressiveness. Prostate 2007;67:1654–63.

    • Crossref
    • PubMed
    • Export Citation
  • 13.

    Makridakis NM, di Salle E, Reichardt JK. Biochemical and pharmacogenetic dissection of human steroid 5 [alpha]-reductase type II. Pharmacogenetics 2000;10:407–13.

    • Crossref
    • PubMed
    • Export Citation
  • 14.

    Andriole G, Bostwick D, Civantos F, Epstein J, Lucia MS, McConnell J, et al. The effects of 5alpha- reductase inhibitors on the natural history, detection and grading of prostate cancer: Current state of knowledge. J Urol 2005;174:2098–104.

    • Crossref
    • PubMed
    • Export Citation
  • 15.

    Cussenot O, Azzouzi AR, Nicolaiew N, Mangin P, Cormier L, Fournier G, et al. 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 2007;52:1082–9.

    • Crossref
    • PubMed
    • Export Citation
  • 16.

    Nauck M, März W, Wieland H. Rapid detection of missense mutations in the prostatic steroid 5α-reductase gene using real-time fluorescence PCR and melting curve analysis. In: Dietmaier W, Wittwer C, Sivasubramanian N, editors. Rapid cycle real-time PCR: methods and applications: genetic and oncology, 1st ed. Berlin: Springer, 2002:129–35.

  • 17.

    Makridakis N, Akalu A, Reichardt JK. Identification and characterization of somatic steroid 5α-reductase (SRD5A2) mutations in human prostate cancer tissue. Oncogene 2004;23:7399–405.

    • Crossref
    • PubMed
    • Export Citation
  • 18.

    Hoffman MA, DeWolf WC, Morgentaler A. Is low serum free testosterone a marker for high grade prostate cancer? J Urol 2000;163:824–7.

    • Crossref
    • PubMed
    • Export Citation
  • 19.

    Jaffe JM, Malkowicz SB, Walker AH, MacBride S, Peschel R, Tomaszewski J, et al. Association of SRD5A2 genotype and pathological characteristics of prostate tumors. Cancer Res 2000;60:1626–30.

    • PubMed
    • Export Citation
  • 20.

    Söderström T, Wadelius M, Andersson SO, Johansson JE, Johansson S, Granath F, et al. 5Alpha-reductase 2 polymorphisms as risk factors in prostate. Pharmacogenetics 2002;12:307–12.

    • Crossref
    • PubMed
    • Export Citation
  • 21.

    Mononen N, Ikonen T, Syrjakoski K, Matikainen M, Schleutker J, Tammela TL, et al. A missense substitution A49T in the steroid 5-alpha-reductase gene (SRD5A2) is not associated with prostate cancer in Finland. Brit J Cancer 2001;84:1344–7.

    • Crossref
    • Export Citation
  • 22.

    Ntais C, Polycarpou A, Ioannidis JP. SRD5A2 gene polymorphisms and the risk of prostate cancer: a meta-analysis. Cancer Epidem Biomar 2003;12:618–24.

  • 23.

    Ribeiro ML, Santos A, Carvalho-Sales AB, Hackel C. Allelic frequencies of six polymorphic markers for risk of prostate cancer. Braz J Med Biol Res 2002;35:205–13.

    • Crossref
    • PubMed
    • Export Citation
  • 24.

    Chang B, Zheng SL, Isaacs SD, Turner AR, Bleecker ER, Walsh PC, et al. Evaluation of SRD5A2 sequence variants in susceptibility to hereditary and sporadic prostate cancer Prostate 2003;56:37–44.

    • Crossref
    • PubMed
    • Export Citation
  • 25.

    Cicek MS, Conti DV, Curran A, Neville PJ, Paris PL, Casey G, et al. Association of prostate cancer risk and aggressiveness to androgen pathway genes: SRD5A2, CYP17 and the AR. Prostate 2004;59:69–76.

    • Crossref
    • PubMed
    • Export Citation
  • 26.

    Makridakis NM, Ross RK, Pike MC, Chang L, Stanczyk FZ, Kolonel LN, et al. A prevalent missense substitution that modulates activity of prostatic steroid 5alpha-reductase. Cancer Res 1997;57:1020–2.

    • PubMed
    • Export Citation
  • 27.

    Lunn RM, Bell DA, Mohler JL, Taylor JA. Prostate cancer risk and polymorphism in 17 hydroxylase (CYP17) and steroid reductase (SRD5A2). Carcinogenesis 1999;20:1727–31.

    • Crossref
    • PubMed
    • Export Citation
  • 28.

    Gu X, Na R, Huang T, Wang L, Tao S, Tian L, et al. SRD5A1 and SRD5A2 are associated with the treatment for benign prostatic hyperplasia with the combination of 5alpha- reductase inhibitors and alpha-adrenergic-receptor antagonist. J Urol 2013;190:615–9.

    • Crossref
    • PubMed
    • Export Citation
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Turkish Journal of Biochemistry (TJB), official journal of Turkish Biochemical Society, is issued electronically every 2 months. The main aim of the journal is to support the research and publishing culture by ensuring that every published manuscript has an added value and thus providing international acceptance of the “readability” of the manuscripts published in the journal.

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