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Die GSTP1-CpG-Insel-Hypermethylierung als molekularer Marker des Prostatakarzinoms

GSTP1 CpG island hypermethylation as a molecular marker in the carcinogenesis of prostate cancer

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Zusammenfassung

Hintergrund

Das Prostatakarzinom (PCA) ist das häufigste Karzinom der männlichen Bevölkerung in Europa und Nordamerika. Trotz der hohen Prävalenz ist der molekulare Ablauf der Entstehung und der Progression nur teilweise bekannt. In zahlreichen Untersuchungen wurden die molekulargenetischen Alterationen in der Pathogenese des Prostatakarzinoms bearbeitet. Die CpG-Insel-Hypermethylierung des Glutathion-S-tranferase-Gens (GSTP1) ist eine dieser charakteristischen Veränderung in der Karzinogenese des Prostatakarzinoms.

Material und Methoden

Wir haben die Bedeutung der GSTP1-CpG-Insel-Hypermethylierung in der Karzinogenese des Prostatakarzinoms untersucht und auf die klinische Anwendung hin geprüft.

Ergebnisse

In den Untersuchungen konnte die GSTP1-CpG-Insel-Hypermethylierung bei mehr als 90% der Prostatakarzinome festgestellt werden. Es gelang der Nachweis in verschiedenen Körperflüssigkeiten (Blut, Urin, Ejakulat, Prostatasekret) und bei im Rahmen einer radikalen Prostatektomie entfernten Lymphknoten; eine Unterscheidung zwischen normalem Prostatagewebe, der benignen Prostatahyperplasie, Vorläuferstadien des Prostatakarzinoms und dem Prostatakarzinom ist durch die modernen, molekulargenetischen Untersuchungstechniken möglich.

Schlussfolgerungen

Mit dem Nachweis der GSTP1-CpG-Insel-Hypermethylierung steht ein molekularer Test zur Verfügung, der das Screening und die Diagnostik des Prostatakarzinoms verbessert. Ein spezifisches Methylierungsmuster des PCA könnte als molekulares Staging Aussagen über die Prognose des PCA leisten. Zur Bestätigung der vielversprechenden, aber noch experimentellen Ergebnisse sind allerdings große prospektive Studien erforderlich.

Abstract

Background

Prostate cancer is the most commonly diagnosed cancer in men in Europe and North America. Despite its high prevalence, the molecular mechanism of its underlying development and progression is poorly understood. Many studies have revealed multiple molecular alterations during prostate cancer carcinogenesis. GSTP1 CpG island hypermethylation is one of the molecular changes that occur during carcinogenesis.

Methods

We evaluated the role of GSTP1 CpG island hypermethylation in prostatic cancers and discussed its possible role as a molecular biomarker of prostate cancer.

Results

Studies haven shown that GSTP1 CpG island hypermethylation is present in about 90% of prostatic carcinomas. The DNA alteration was also detectable in body fluids such as blood, urine, ejaculate, or prostatic secretions. One study showed hypermethylation in histologically unsuspicious lymph nodes in surgical specimens in patients with biochemical PSA (prostate-specific antigen) recurrence. Additionally, it is possible to distinguish between normal prostatic tissue, benign prostatic hyperplasia, and prostate cancer.

Conclusions

The detection of GSTP1 CpG island hypermethylation serves as a molecular marker in prostate cancer screening, detection, and diagnosis. It may even provide information on prostate cancer prognosis. However, prospective trials to evaluate its predictive value are necessary.

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Literatur

  1. Adler V, Yin Z, Tew KD, Ronai Z (1999) Role of redox potential and reactive oxygen species in stress signaling. Oncogene 18: 6104–6111

    Article  CAS  PubMed  Google Scholar 

  2. Attwood JT, Yung RL, Richardson BC (2002) DNA methylation and the regulation of gene transcription. Cell Mol Life Sci 59: 241–257

    Article  Google Scholar 

  3. Bartsch G, Horninger W, Klocker H et al. (2001) Prostate cancer mortality after introduction of prostate-specific antigen mass screening in the Federal State of Tyrol, Austria. Urology 58: 417–424

    Article  CAS  PubMed  Google Scholar 

  4. Bastian PJ, Ellinger J, Wernert N, Wellmann A, Müller SC, Rücker AA von (2004) GSTPI Hypermethylation as a molecular marker in the diagnosis of prostatic cancer: Is there a correlation with clinical stage, gleason grade, PSA value or age? Onkologie (einger. zur Publikation)

    Google Scholar 

  5. Brooks JD, Weinstein M, Lin X et al. (1998) CG island methylation changes near the GSTP1 gene in prostatic intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev 7: 531–536

    CAS  PubMed  Google Scholar 

  6. Cairns P, Esteller M, Herman JG, Schoenberg M, Jeronimo C, Sanchez-Cespedes M, Chow NH, Grasso M, Wu L, Westra WB, Sidransky D. (2001) Molecular detection of prostate cancer in urine by GSTP1 hypermethylation. Clin Cancer Res 7: 2727–2730

    CAS  PubMed  Google Scholar 

  7. Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB (1999) Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 21: 103–107

    Article  PubMed  Google Scholar 

  8. Catalona WJ, Beiser JA, Smith DS (1997) Serum free prostate specific antigen and prostate specific antigen density measurements for predicting cancer in men with prior negative prostatic biopsies. J Urol 158: 2162–2167

    CAS  PubMed  Google Scholar 

  9. Cavaliere A, Bufalari A, Vitali R. (1987) 5-Azacytidine carcinogenesis in BALB/c mice. Cancer Lett 37: 51–58

    CAS  PubMed  Google Scholar 

  10. Chon CH, Lai FC, McNeal JE, Presti JC Jr. (2002) Use of extended systematic sampling in patients with a prior negative prostate needle biopsy. J Urol 167: 2457–2460

    PubMed  Google Scholar 

  11. Chu DC, Chuang CK, Fu JB et al. (2002) The use of real-time quantitative polymerase chain reaction to detect hypermethylation of the CpG islands in the promoter region flanking the GSTP1 gene to diagnose prostate carcinoma. J Urol 167: 1854–1858

    Article  CAS  PubMed  Google Scholar 

  12. Dahl C, Guldberg P (2003) DNA methylation analysis techniques. Biogerontology 4: 233–250

    Article  CAS  PubMed  Google Scholar 

  13. De Marzo AM, Marchi VL, Epstein JI, Nelson WG (1999) Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. Am J Pathol 155: 1985–1992

    PubMed  Google Scholar 

  14. Denda A, Mori Y, Yokose Y et al. (1985) 4-Hydroxyaminoquinoline 1-oxide metabolism and DNA adducts in the early stage of tumorigenesis in rats: comparison of target organ pancreas with non-target organ liver. Chem Biol Interact 56: 125–143

    Article  CAS  PubMed  Google Scholar 

  15. De Weese TL, Shipman JM, Larrier NA et al. (1998) Mouse embryonic stem cells carrying one or two defective Msh2 alleles respond abnormally to oxidative stress inflicted by low-level radiation. Proc Natl Acad Sci USA 95: 11915–11920

    Article  PubMed  Google Scholar 

  16. Esteller M, Corn PG, Urena JM et al. (1998) Inactivation of glutathione S-transferase P1 gene by promoter hypermethylation in human neoplasia. Cancer Res 58: 4515–4518

    CAS  PubMed  Google Scholar 

  17. Esteller M, Corn PG, Baylin SB, Herman JG (2001) A gene hypermethylation profile of human cancer. Cancer Res 61: 3225–3229

    CAS  PubMed  Google Scholar 

  18. Frommer M, McDonald LE, Millar DS et al.. (1992) A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci USA 89: 1827–1831

    CAS  PubMed  Google Scholar 

  19. Gattoni-Celli S, Hsiao WL, Lambert M, Kirschmeier P, Weinstein IB (1985) Genetic targets in multistage carcinogenesis. Carcinog Compr Surv 9: 29–40

    CAS  PubMed  Google Scholar 

  20. Goessl C, Krause H, Muller M et al. (2000) Fluorescent methylation-specific polymerase chain reaction for DNA-based detection of prostate cancer in bodily fluids. Cancer Res 60: 5941–5945

    CAS  PubMed  Google Scholar 

  21. Goessl C, Muller M, Heicappell R et al. (2001) DNA-based detection of prostate cancer in urine after prostatic massage. Urology 58: 335–338

    Article  CAS  PubMed  Google Scholar 

  22. Goessl C, Muller M, Heicappell R, Krause H, Miller K (2001) DNA-based detection of prostate cancer in blood, urine, and ejaculates. Ann N Y Acad Sci 945: 51–58

    CAS  PubMed  Google Scholar 

  23. Gonzalgo ML, Pavlovich CP, Lee SM, Nelson WG (2003) Prostate cancer detection by GSTP1 methylation analysis of postbiopsy urine specimens. Clin Cancer Res 9: 2673–2677

    CAS  PubMed  Google Scholar 

  24. Hankey BF, Ries LA, Edwards BK (1999) The surveillance, epidemiology, and end results program: a national resource. Cancer Epidemiol Biomarkers Prev 8: 1117–1121

    CAS  PubMed  Google Scholar 

  25. Harden SV, Guo Z, Epstein JI, Sidransky D (2003) Quantitative GSTP1 methylation clearly distinguishes benign prostatic tissue and limited prostate adenocarcinoma. J Urol 169: 1138–1142

    Article  CAS  PubMed  Google Scholar 

  26. Henderson CJ, Wolf CR, Kitteringham N et al. (2000) Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi. Proc Natl Acad Sci USA 97: 12741–12745

    Article  CAS  PubMed  Google Scholar 

  27. Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349: 2042–2054

    Article  CAS  PubMed  Google Scholar 

  28. Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93: 9821–9826

    CAS  PubMed  Google Scholar 

  29. Hsiao WL, Gattoni-Celli S, Weinstein IB (1985) Effects of 5-azacytidine on the progressive nature of cell transformation. Mol Cell Biol 5: 1800–1803

    CAS  PubMed  Google Scholar 

  30. Jackson-Grusby L, Laird PW, Magge SN, Moeller BJ, Jaenisch R (1997) Mutagenicity of 5-aza-2’-deoxycytidine is mediated by the mammalian DNA methyltransferase. Proc Natl Acad Sci USA 94: 4681–4685

    Article  CAS  PubMed  Google Scholar 

  31. Jemal A, Murray T, Samuels A et al. (2003) Cancer statistics, 2003. CA Cancer J Clin 53: 5-26

    Google Scholar 

  32. Jones PA (2002) DNA methylation and cancer. Oncogene 21: 5358–5360

    Article  CAS  PubMed  Google Scholar 

  33. Jones PA, Taylor SM (1980) Cellular differentiation, cytidine analogs and DNA methylation. Cell 20: 85–93

    CAS  PubMed  Google Scholar 

  34. Jeronimo C, Usadel H, Henrique R et al. (2001) Quantitation of GSTP1 methylation in non-neoplastic prostatic tissue and organ-confined prostate adenocarcinoma. J Natl Cancer Inst 93: 1747–1752

    Article  CAS  PubMed  Google Scholar 

  35. Jeronimo C, Usadel H, Henrique R et al. (2002) Quantitative GSTP1 hypermethylation in bodily fluids of patients with prostate cancer. Urology 60: 1131–1135

    Article  PubMed  Google Scholar 

  36. Lee WH, Morton RA, Epstein JI et al. (1994) Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. Proc Natl Acad Sci USA 91: 11733–11737

    CAS  PubMed  Google Scholar 

  37. Lee WH, Isaacs WB, Bova GS, Nelson WG (1997) CG island methylation changes near the GSTP1 gene in prostatic carcinoma cells detected using the polymerase chain reaction: a new prostate cancer biomarker. Cancer Epidemiol Biomarkers Prev 6: 443–450

    CAS  PubMed  Google Scholar 

  38. Lin X, Tascilar M, Lee WH et al. (2001) GSTP1 CpG island hypermethylation is responsible for the absence of GSTP1 expression in human prostate cancer cells. Am J Pathol 159: 1815–1826

    CAS  PubMed  Google Scholar 

  39. Kallakury BV, Sheehan CE, Winn-Deen E et al. (2001) Decreased expression of catenins (alpha and beta), p120 CTN, and E-cadherin cell adhesion proteins and E-cadherin gene promoter methylation in prostatic adenocarcinomas. Cancer 92: 2786–2795

    Article  CAS  PubMed  Google Scholar 

  40. Kollermann J, Muller M, Goessl C et al. (2003) Methylation-specific PCR for DNA-based detection of occult tumor cells in lymph nodes of prostate cancer patients. Eur Urol 44: 533–538

    Article  PubMed  Google Scholar 

  41. Maruyama R, Toyooka S, Toyooka KO et al. (2002) Aberrant promoter methylation profile of prostate cancers and its relationship to clinicopathological features. Clin Cancer Res 8: 514–519

    CAS  PubMed  Google Scholar 

  42. Millar DS, Ow KK, Paul CL, Russell PJ, Molloy PL, Clark SJ. (1999) Detailed methylation analysis of the glutathione S-transferase pi (GSTP1) gene in prostate cancer. Oncogene 18: 1313–1324

    PubMed  Google Scholar 

  43. Nakayama M, Bennett CJ, Hicks JL et al. (2003) Hypermethylation of the human glutathione S-transferase-pi gene (GSTP1) CpG island is present in a subset of proliferative inflammatory atrophy lesions but not in normal or hyperplastic epithelium of the prostate: a detailed study using laser-capture microdissection. Am J Pathol 163: 923–933

    CAS  PubMed  Google Scholar 

  44. Nelson CP, Kidd LC, Sauvageot J et al. (2001) Protection against 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine cytotoxicity and DNA adduct formation in human prostate by glutathione S-transferase P1. Cancer Res 61: 103–109

    CAS  PubMed  Google Scholar 

  45. Nelson WG, De Marzo AM, Isaacs WB (2003) Prostate cancer. N Engl J Med 349: 366–381

    Article  CAS  PubMed  Google Scholar 

  46. Nuovo GJ, Plaia TW, Belinsky SA, Baylin SB, Herman JG (1999) In situ detection of the hypermethylation-induced inactivation of the p16 gene as an early event in oncogenesis. Proc Natl Acad Sci USA 96: 12754–12759

    Article  CAS  PubMed  Google Scholar 

  47. Ruscoe JE, Rosario LA, Wang T et al. (2001) Pharmacologic or genetic manipulation of glutathione S-transferase P1–1 (GSTpi) influences cell proliferation pathways. J Pharmacol Exp Ther 298: 339–345

    CAS  PubMed  Google Scholar 

  48. Santini V, Kantarjian HM, Issa JP. (2001) Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann Intern Med 134: 573–586

    CAS  PubMed  Google Scholar 

  49. Santourlidis S, Florl A, Ackermann R, Wirtz HC, Schulz WA (1999) High frequency of alterations in DNA methylation in adenocarcinoma of the prostate. Prostate 39: 166–174

    CAS  PubMed  Google Scholar 

  50. Shirai T, Sano M, Tamano S et al. (1997) The prostate: a target for carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) derived from cooked foods. Cancer Res 57: 195–198

    CAS  PubMed  Google Scholar 

  51. Stuart GR, Holcroft J, de Boer JG, Glickman BW (2000) Prostate mutations in rats induced by the suspected human carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Cancer Res 60: 266–268

    CAS  PubMed  Google Scholar 

  52. Suh CI, Shanafelt T, May DJ et al. (2000) Comparison of telomerase activity and GSTP1 promoter methylation in ejaculate as potential screening tests for prostate cancer. Mol Cell Probes 14: 211–217

    Article  CAS  PubMed  Google Scholar 

  53. Suzuki H, Gabrielson E, Chen W et al. (2002) A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet 31: 141–149

    Article  CAS  PubMed  Google Scholar 

  54. Tchou JC, Lin X, Freije D et al. (2000) GSTP1 CpG island DNA hypermethylation in hepatocellular carcinomas. Int J Oncol 16: 663–676

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    P. J. Bastian, A. M. De Marzo & W. G. Nelson

  2. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    M. Nakayama, A. M. De Marzo & W. G. Nelson

  3. The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    A. M. De Marzo & W. G. Nelson

  4. The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Bunting Blaustein Cancer Research Building, CRB 152, 1650 Orleans Street, Baltimore, MD 21231, USA

    P. J. Bastian

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  1. P. J. Bastian
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  2. M. Nakayama
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  3. A. M. De Marzo
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  4. W. G. Nelson
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Correspondence to P. J. Bastian.

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Das Projekt wurde gefördert durch NIH/NCI grant R01 CA70196 und NIH/NCI SPORE grant P50 CA58236.

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Bastian, P.J., Nakayama, M., De Marzo, A.M. et al. Die GSTP1-CpG-Insel-Hypermethylierung als molekularer Marker des Prostatakarzinoms. Urologe [A] 43, 573–579 (2004). https://doi.org/10.1007/s00120-004-0540-7

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