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Vol. 75, No. 3-4, 2008
Issue release date: October 2008
Section title: Clinical Translational Research
Oncology 2008;75:145–151
(DOI:10.1159/000158665)

Promoter Hypermethylation in Tumour Suppressor Genes Shows Association with Stage, Grade and Invasiveness of Bladder Cancer

Jarmalaite S. · Jankevicius F. · Kurgonaite K. · Suziedelis K. · Mutanen P. · Husgafvel-Pursiainen K.
aFaculty of Natural Sciences and bInstitute of Oncology, Vilnius University, Vilnius, Lithuania; cStatistical Services and dBiological Mechanisms and Prevention of Work-Related Diseases, Finnish Institute of Occupational Health, Helsinki, Finland

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Article / Publication Details

First-Page Preview
Abstract of Clinical Translational Research

Received: 11/30/2007
Accepted: 4/30/2008
Published online: 9/29/2008

Number of Print Pages: 7
Number of Figures: 2
Number of Tables: 1

ISSN: 0030-2414 (Print)
eISSN: 1423-0232 (Online)

For additional information: http://www.karger.com/OCL

Abstract

Aims: Superficial bladder cancer is a highly recurrent disease, with progression to muscle invasiveness occurring in 15–30% of cases. Promoter hypermethylation in a panel of tumour suppressor genes involved in cell cycle control, apoptosis and DNA repair was analyzed in superficial bladder tumours in order to evaluate the suitability of epigenetic biomarkers for an earlier prediction of the aggressive course of the disease. Method: Promoter hypermethylation in p16, RARβ, RASSF1A, DAPK, and MGMT genes was analyzed in 58 cases with superficial bladder cancer and 2 cases with benign urological disease using methylation-specific PCR. Results: Promoter hypermethylation was frequently detected in RARβ, RASSF1A and DAPK genes, and 62% of bladder tumours exhibited hypermethylation in at least one gene. The overall frequency of hypermethylation and the number of genes involved increased with tumour stage, grade and muscle invasiveness. Aberrant methylation of RASSF1A and RARβwas predominant (p < 0.05) in muscle-invasive tumours and high-grade tumours, respectively. Cases with concurrent hypermethylation in DAPK, p16 and RARβ genes were moresusceptible to relapse. Conclusion: The results suggest analysis of promoter hypermethylation as a valuable biomarker for prognosis of the aggressive course of disease in bladder cancer.


Article / Publication Details

First-Page Preview
Abstract of Clinical Translational Research

Received: 11/30/2007
Accepted: 4/30/2008
Published online: 9/29/2008

Number of Print Pages: 7
Number of Figures: 2
Number of Tables: 1

ISSN: 0030-2414 (Print)
eISSN: 1423-0232 (Online)

For additional information: http://www.karger.com/OCL


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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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References

  1. Kirkali Z, Chan T, Manoharan M, et al: Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology 2005;66(6 suppl 1):4–34.

    External Resources

  2. Kurtinaitis J, Aleknaviciene B, Smailyte G: The main results of cancer control in Lithuania; in Transitional Report 2005. Vilnius, Lithuanian Cancer Registry, 2006.
  3. Chopin DK, Gattegno B: Superficial bladder tumors. Eur Urol 2002;42:533–541.
  4. Knowles MA: Molecular subtypes of bladder cancer: Jekyll and Hyde or chalk and cheese? Carcinogenesis 2006;27:361–373.
  5. Josephson DY, Pasin E, Stein JP: Superficial bladder cancer. 1. Update on etiology, classification and natural history. Expert Rev Anticancer Ther 2006;6:1723–1734.
  6. Wu X-R: Urothelial tumorigenesis: a tale of divergent pathways. Nature 2005;5:713–726.
  7. Schulz WA: Understanding urothelial carcinoma through cancer pathways. Int J Cancer 2006;119:1513–1518.
  8. Herman JG, Baylin SB: Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 2003;349:2042–2054.
  9. Veltri RW, Makarov DV: Nucleic acid-based marker approaches to urological cancers. Urol Oncol 2006;24:510–527.
  10. Goessl C, Muller M, Straub B, Miller K: DNA alterations in body fluids as molecular tumor markers for urological malignancies. Eur Urol 2002;41:668–676.
  11. Kawamoto K, Enokida H, Gotanda T, Kubo H, Nishiyama K, Kawahara M, Nakagawa M: p16INK4aand p14ARF and methylation as a potential biomarker for human bladder cancer. Biochem Biophys Res Commun 2006;339:790–796.
  12. Friedrich MG, Chandrasoma S, Siegmund KD, et al: Prognostic relevance of methylation markers in patients with non-muscle invasive bladder carcinoma. Eur J Cancer 2005;41:2769–2778.
  13. Catto JW, Azzouzi AR, Rehman I, et al: Promoter hypermethylation is associated with tumor location, stage and subsequent progression in transitional cell carcinoma. J Clin Oncol 2005;23:2903–2910.
  14. Tada Y, Wada M, Taguchi K, et al: The association of death-associated protein kinase hypermethylation with early recurrence in superficial bladder cancers. Cancer Res 2002;62:4048–4053.
  15. Maruyama R, Toyooka S, Toyooka KO, et al: Aberrant promoter methylation profile of bladder cancer and its relationship to clinicopathological features. Cancer Res 2001;61:8659–8663.
  16. Cairns P: Gene methylation and early detection of genitourinary cancer: the road ahead. Nat Rev Cancer 2007;7:531–543.
  17. Sobin LH, Wittekind C: TNM Classification of Malignant Tumors, ed 5. New York, Wiley, 1997.
  18. Mostofi FK, Sobin LH, Torlini H: Histological typing of urinary bladder tumors; in International Histological Classification of Tumors, No 10. Geneva, World Health Organization, 1973.
  19. Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB: Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996;93:9821–9826.
  20. Jarmalaite S, Kannio A, Anttila S, Lazutka JR, Husgafvel-Pursiainen K: Aberrant p16 promoter methylation in smokers and former smokers with nonsmall cell lung cancer. Int J Cancer 2003;106:913–918.
  21. Lemeta S, Jarmalaite S, Pylkkanen L, Bohling T, Husgafvel-Pursiainen K: Preferential loss of the noninprinted allele for the ZAC1 tumor suppressor gene in human capillary hemangioblastoma. J Neuropathol Exp Neurol 2007;66:860–867.
  22. Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB: Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996;93:9821–9826.
  23. Virmani AK, Rathi A, Zöchbauer-Müller S, et al: Promoter methylation and silencing of the retinoic acid receptor-beta gene in lung carcinomas. J Natl Cancer Inst 2000;92:1303–1307.
  24. Burbee DG, Forgacs E, Zöchbauer-Müller S: Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst 2001;93:691–699.
  25. Katzenellenbogen RA, Baylin SB, Herman JG: Hypermethylation of the DAP-kinase CpG island is a common alteration in B-cell malignancies. Blood 1999;93:4347–4353.
  26. Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG: Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 1999;59:793–797.
  27. Hoque MO, Begum S, Topalogu O, et al: Quantitation of promoter methylation of multiple genes in urine DNA and bladder cancer detection. J Natl Cancer Inst 2006;98:996–1004.
  28. Marsit CJ, Karagas MR, Danaee H, et al: Carcinogen exposure and gene promoter hypermethylation in bladder cancer. Carcinogenesis 2006;27:112–116.
  29. Dulaimi E, Uzzo RG, Greenberg RE, Al- Saleem T, Cairns P: Detection of bladder cancer in urine by a tumor suppressor gene hypermethylation panel. Clin Cancer Res 2004;10:1887–1893.
  30. Chan MWY, Chan LW, Tang NLS, et al: Frequent hypermethylation of promoter region of RASSF1A in tumor tissues and voided urine of urinary bladder cancer patients. Int J Cancer 2003;104:611–616.
  31. Chan MWY, Chan LW, Tang NLS, et al: Hypermethylation of multiple genes in tumor tissues and voided urine in urinary bladder cancer patients. Clin Cancer Res 2002;8:464–470.
  32. Dhawan D, Hamdy FC, Rehman I, et al: Evidence for the early onset of aberrant promoter methylation in urothelial carcinoma. J Pathol 2006;209:336–343.
  33. Nakagawa T, Kanai Y, Ushijima S, Kitamura T, Kakizoe T, Hirohashi S: DNA hypermethylation on multiple CpG islands associated with increased DNA methyltransferase DNMT1 protein expression during multistage urothelial carcinogenesis. J Urol 2005;173:1767–1771.
  34. Marsit CJ, Houseman EA, Schned AR, Karagas MR, Kelsey KT: Promoter hypermethylation is associated with current smoking, age, gender and survival in bladder cancer. Carcinogenesis 2007;28:1745–1751.
  35. Baylin SB, Ohm JE: Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 2006;6:107–116.
  36. Friedrich MG, Weisenberger DJ, Cheng JC, et al: Detection of methylated apoptosis-associated genes in urine sediments of bladder cancer patients. Clin Cancer Res 2004;10:7457–7465.
  37. Yates DR, Rehman I, Meuth M, Cross SS, Hamdy FC, Catto JWF: Methylation urinalysis: a prospective study of bladder cancer patients and age stratified benign controls. Oncogene 2006;25:1984–1988.