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Androgen receptor GGC polymorphism and testosterone levels associated with high risk of prostate cancer and benign prostatic hyperplasia

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Abstract

Polymorphic GGC repeats in the androgen receptor (AR) gene can alter transactivation of androgen-responsive genes and increase the risk of benign prostatic hyperplasia (BPH) and prostate cancer (PCa). We investigated the association between GGC repeat length, testosterone levels and the risk of developing PCa and BPH in a population from southern Brazil. A sample comprising 130 PCa, 126 BPH and 88 control patients was evaluated. DNA was extracted from leukocytes and the AR gene was analyzed by fragment analysis. The hazard ratio (HR) was estimated. GGC mean length was not different between the three study groups. The risk of developing PCa in individuals with GGC > 19 was 3.300 (95 %CI 1.385–7.874) higher when compared to the GGC ≤ 19 group (p = 0.007). The risk of developing PCa and BPH in individuals with total testosterone levels <4 ng/mL was 2.799 (95 % CI 1.362–5.754). (p = 0.005) and 2.786 (95 % CI 1.470–5.280) (p = 0.002), respectively. Total testosterone levels in patients with GGC > 19 were significantly lower when compared to patients in the GGC ≤ 19 group. Our data suggest that the presence of a high number of polymorphic GGC repeats in the AR gene is associated with an increased risk of developing PCa and BPH, and that lower testosterone levels also increase the risk of developing these diseases.

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References

  1. American Cancer Society (2012) Cancer facts & figures 2012. reference information. http://www.cancer.org/

  2. INCA (2003) Ministério da Saúde, Brasil. Estimativa de incidência e mortalidade por câncer no Brasil para 2003. http://www2.inca.gov.br/

  3. INCA (2012) Ministério da Saúde, Brasil. Estimativa 2012: Incidência de Câncer no Brasil. http://www2.inca.gob.br/

  4. Kirby RS (2000) The natural history of benign prostatic hyperplasia: what have we learned in the last decade? Urology 56(5 Suppl 1):3–6

    Article  PubMed  CAS  Google Scholar 

  5. Platz EA, Smit E, Curhan GC, Nyberg LM, Giovannucci E (2002) Prevalence of and racial/ethnic variation in lower urinary tract symptoms and noncancer prostate surgery in U.S. men. Urology 59(6):877–883

    Article  PubMed  Google Scholar 

  6. Geck P, Maffini MV, Szelei J, Sonnenschein C, Soto AM (2000) Androgen-induced proliferative quiescence in prostate cancer cells: the role of AS3 as its mediator. Proc Natl Acad Sci USA 97(18):10185–10190

    Article  PubMed  CAS  Google Scholar 

  7. Latil A, Bieche I, Vidaud D, Lidereau R, Berthon P, Cussenot O, Vidaud M (2001) Evaluation of androgen, estrogen (ER alpha and ER beta), and progesterone receptor expression in human prostate cancer by real-time quantitative reverse transcription-polymerase chain reaction assays. Cancer Res 61(5):1919–1926

    PubMed  CAS  Google Scholar 

  8. Gobinet J, Poujol N, Sultan C (2002) Molecular action of androgens. Mol Cell Endocrinol 198(1–2):15–24

    Article  PubMed  CAS  Google Scholar 

  9. Planz B, Wang Q, Kirley SD, Marberger M, McDougal WS (2001) Regulation of keratinocyte growth factor receptor and androgen receptor in epithelial cells of the human prostate. J Urol 166(2):678–683

    Article  PubMed  CAS  Google Scholar 

  10. Chamberlain NL, Driver ED, Miesfeld RL (1994) The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 22(15):3181–3186

    Article  PubMed  CAS  Google Scholar 

  11. Sleddens HF, Oostra BA, Brinkmann AO, Trapman J (1993) Trinucleotide (GGN) repeat polymorphism in the human androgen receptor (AR) gene. Hum Mol Genet 2(4):493

    Article  PubMed  CAS  Google Scholar 

  12. Ding D, Xu L, Menon M, Reddy GP, Barrack ER (2005) Effect of GGC (glycine) repeat length polymorphism in the human androgen receptor on androgen action. Prostate 62(2):133–139

    Article  PubMed  CAS  Google Scholar 

  13. Hakimi JM, Schoenberg MP, Rondinelli RH, Piantadosi S, Barrack ER (1997) Androgen receptor variants with short glutamine or glycine repeats may identify unique subpopulations of men with prostate cancer. Clin Cancer Res 3(9):1599–1608

    PubMed  CAS  Google Scholar 

  14. Platz EA, Giovannucci E, Dahl DM, Krithivas K, Hennekens CH, Brown M, Stampfer MJ, Kantoff PW (1998) The androgen receptor gene GGN microsatellite and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 7(5):379–384

    PubMed  CAS  Google Scholar 

  15. Edwards SM, Badzioch MD, Minter R, Hamoudi R, Collins N, Ardern-Jones A, Dowe A, Osborne S, Kelly J, Shearer R, Easton DF, Saunders GF, Dearnaley DP, Eeles RA (1999) Androgen receptor polymorphisms: association with prostate cancer risk, relapse and overall survival. Int J Cancer 84(5):458–465

    Article  PubMed  CAS  Google Scholar 

  16. Rodriguez-Gonzalez G, Cabrera S, Ramirez-Moreno R, Bilbao C, Diaz-Chico JC, Serra L, Chesa N, Cabrera JJ, Diaz-Chico BN (2009) Short alleles of both GGN and CAG repeats at the exon-1 of the androgen receptor gene are associated to increased PSA staining and a higher Gleason score in human prostatic cancer. J Steroid Biochem Mol Biol 113(1–2):85–91

    Article  PubMed  CAS  Google Scholar 

  17. Silva Neto B, Koff WJ, Biolchi V, Brenner C, Biolo KD, Spritzer PM, Brum IS (2008) Polymorphic CAG and GGC repeat lengths in the androgen receptor gene and prostate cancer risk: analysis of a Brazilian population. Cancer Invest 26(1):74–80

    Article  PubMed  CAS  Google Scholar 

  18. Jenster G, de Ruiter PE, van der Korput HA, Kuiper GG, Trapman J, Brinkmann AO (1994) Changes in the abundance of androgen receptor isotypes: effects of ligand treatment, glutamine-stretch variation, and mutation of putative phosphorylation sites. Biochemistry 33(47):14064–14072

    Article  PubMed  CAS  Google Scholar 

  19. Gao T, Marcelli M, McPhaul MJ (1996) Transcriptional activation and transient expression of the human androgen receptor. J Steroid Biochem Mol Biol 59(1):9–20

    Article  PubMed  CAS  Google Scholar 

  20. Esteban E, Rodon N, Via M, Gonzalez-Perez E, Santamaria J, Dugoujon JM, Chennawi FE, Melhaoui M, Cherkaoui M, Vona G, Harich N, Moral P (2006) Androgen receptor CAG and GGC polymorphisms in Mediterraneans: repeat dynamics and population relationships. J Hum Genet 51(2):129–136

    Article  PubMed  CAS  Google Scholar 

  21. Kittles RA, Young D, Weinrich S, Hudson J, Argyropoulos G, Ukoli F, Adams-Campbell L, Dunston GM (2001) Extent of linkage disequilibrium between the androgen receptor gene CAG and GGC repeats in human populations: implications for prostate cancer risk. Hum Genet 109(3):253–261

    Article  PubMed  CAS  Google Scholar 

  22. Marrero AR, Das Neves Leite FP, De Almeida Carvalho B, Peres LM, Kommers TC, Da Cruz IM, Salzano FM, Ruiz-Linares A, Da Silva Junior WA, Bortolini MC (2005) Heterogeneity of the genome ancestry of individuals classified as White in the state of Rio Grande do Sul, Brazil. Am J Hum Biol 17(4):496–506

    Article  PubMed  Google Scholar 

  23. Parra FC, Amado RC, Lambertucci JR, Rocha J, Antunes CM, Pena SD (2003) Color and genomic ancestry in Brazilians. Proc Natl Acad Sci USA 100(1):177–182

    Article  PubMed  CAS  Google Scholar 

  24. Pena SD, Bastos-Rodrigues L, Pimenta JR, Bydlowski SP (2009) DNA tests probe the genomic ancestry of Brazilians. Braz J Med Biol Res 42(10):870–876

    Article  PubMed  CAS  Google Scholar 

  25. Pena SD, Di Pietro G, Fuchshuber-Moraes M, Genro JP, Hutz MH, Kehdy Fde S, Kohlrausch F, Magno LA, Montenegro RC, Moraes MO, de Moraes ME, de Moraes MR, Ojopi EB, Perini JA, Racciopi C, Ribeiro-Dos-Santos AK, Rios-Santos F, Romano-Silva MA, Sortica VA, Suarez-Kurtz G (2011) The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected. PLoS ONE 6(2):e17063

    Article  PubMed  CAS  Google Scholar 

  26. Silva IS, Morsch DM, Urnauer L, Spritzer PM (2001) Androgen-induced cell growth and c-myc expression in human non-transformed epithelial prostatic cells in primary culture. Endocr Res 27(1–2):153–169

    Article  PubMed  CAS  Google Scholar 

  27. Giwercman YL, Abrahamsson PA, Giwercman A, Gadaleanu V, Ahlgren G (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(4):679–685

    Article  PubMed  CAS  Google Scholar 

  28. Lundin KB, Giwercman YL, Rylander L, Hagmar L, Giwercman A (2006) Androgen receptor gene GGN repeat length and reproductive characteristics in young Swedish men. Eur J Endocrinol 155(2):347–354

    Article  PubMed  CAS  Google Scholar 

  29. Bogaert V, Vanbillemont G, Taes Y, De Bacquer D, Deschepper E, Van Steen K, Kaufman JM (2009) Small effect of the androgen receptor gene GGN repeat polymorphism on serum testosterone levels in healthy men. Eur J Endocrinol 161(1):171–177

    Article  PubMed  CAS  Google Scholar 

  30. Parsons JK, Carter HB, Platz EA, Wright EJ, Landis P, Metter EJ (2005) Serum testosterone and the risk of prostate cancer: potential implications for testosterone therapy. Cancer Epidemiol Biomarkers Prev 14(9):2257–2260

    Article  PubMed  CAS  Google Scholar 

  31. Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ (1996) Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst 88(16):1118–1126

    Article  PubMed  CAS  Google Scholar 

  32. Heikkila R, Aho K, Heliovaara M, Hakama M, Marniemi J, Reunanen A, Knekt P (1999) Serum testosterone and sex hormone-binding globulin concentrations and the risk of prostate carcinoma: a longitudinal study. Cancer 86(2):312–315

    Article  PubMed  CAS  Google Scholar 

  33. Hsing AW, Comstock GW (1993) Serological precursors of cancer: serum hormones and risk of subsequent prostate cancer. Cancer Epidemiol Biomarkers Prev 2(1):27–32

    PubMed  CAS  Google Scholar 

  34. Dorgan JF, Albanes D, Virtamo J, Heinonen OP, Chandler DW, Galmarini M, McShane LM, Barrett MJ, Tangrea J, Taylor PR (1998) Relationships of serum androgens and estrogens to prostate cancer risk: results from a prospective study in Finland. Cancer Epidemiol Biomarkers Prev 7(12):1069–1074

    PubMed  CAS  Google Scholar 

  35. Vatten LJ, Ursin G, Ross RK, Stanczyk FZ, Lobo RA, Harvei S, Jellum E (1997) Androgens in serum and the risk of prostate cancer: a nested case-control study from the Janus serum bank in Norway. Cancer Epidemiol Biomarkers Prev 6(11):967–969

    PubMed  CAS  Google Scholar 

  36. Imamoto T, Suzuki H, Fukasawa S, Shimbo M, Inahara M, Komiya A, Ueda T, Shiraishi T, Ichikawa T (2005) Pretreatment serum testosterone level as a predictive factor of pathological stage in localized prostate cancer patients treated with radical prostatectomy. Eur Urol 47(3):308–312

    Article  PubMed  CAS  Google Scholar 

  37. Isom-Batz G, Bianco FJ Jr, Kattan MW, Mulhall JP, Lilja H, Eastham JA (2005) Testosterone as a predictor of pathological stage in clinically localized prostate cancer. J Urol 173(6):1935–1937

    Article  PubMed  CAS  Google Scholar 

  38. Massengill JC, Sun L, Moul JW, Wu H, McLeod DG, Amling C, Lance R, Foley J, Sexton W, Kusuda L, Chung A, Soderdahl D, Donahue T (2003) Pretreatment total testosterone level predicts pathological stage in patients with localized prostate cancer treated with radical prostatectomy. J Urol 169(5):1670–1675

    Article  PubMed  Google Scholar 

  39. Morgentaler A (2007) Testosterone deficiency and prostate cancer: emerging recognition of an important and troubling relationship. Eur Urol 52(3):623–625

    Article  PubMed  CAS  Google Scholar 

  40. Schatzl G, Madersbacher S, Thurridl T, Waldmuller J, Kramer G, Haitel A, Marberger M (2001) High-grade prostate cancer is associated with low serum testosterone levels. Prostate 47(1):52–58

    Article  PubMed  CAS  Google Scholar 

  41. Kristal AR, Schenk JM, Song Y, Arnold KB, Neuhouser ML, Goodman PJ, Lin DW, Stanczyk FZ, Thompson IM (2008) Serum steroid and sex hormone-binding globulin concentrations and the risk of incident benign prostatic hyperplasia: results from the prostate cancer prevention trial. Am J Epidemiol 168(12):1416–1424

    Article  PubMed  Google Scholar 

  42. Teloken C, Da Ros CT, Caraver F, Weber FA, Cavalheiro AP, Graziottin TM (2005) Low serum testosterone levels are associated with positive surgical margins in radical retropubic prostatectomy: hypogonadism represents bad prognosis in prostate cancer. J Urol 174(6):2178–2180

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by Fundação de Amparo à Pesquisa do Rio Grande do Sul—FAPERGS (Grant No. 0413137), Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre—FIPE/HCPA (Grant No. 04243), Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq and Programa de Apoio a Projetos Institucionais com a Participação de Recém-Doutores/Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—PRODOC/CAPES (Grant No. 2937-32/2010).

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Authors and Affiliations

  1. Department of Physiology, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite 500, CEP 90050-170, Porto Alegre/RS, Brazil

    Vanderlei Biolchi, Diego Bromfman Pianta & Ilma Simoni Brum

  2. Division of Urology, Hospital de Clínicas de Porto Alegre and Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Brasil Silva Neto, Walter José Koff & Milton Berger

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  1. Vanderlei Biolchi
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Correspondence to Vanderlei Biolchi.

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Biolchi, V., Neto, B.S., Pianta, D.B. et al. Androgen receptor GGC polymorphism and testosterone levels associated with high risk of prostate cancer and benign prostatic hyperplasia. Mol Biol Rep 40, 2749–2756 (2013). https://doi.org/10.1007/s11033-012-2293-5

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