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Tumor Biology

, Volume 33, Issue 2, pp 347–361 | Cite as

Hypermethylation in bladder cancer: biological pathways and translational applications

  • Marta Sánchez-Carbayo
Research Article

Abstract

A compelling body of evidences sustains the importance of epigenetic mechanisms in the development and progression of cancer. Assessing the epigenetic component of bladder tumors is strongly improving our understanding of their biology and clinical behavior. In terms of DNA methylation, cancer cells show genome-wide hypomethylation and site-specific CpG island promoter hypermethylation. In the context of other epigenetic alterations, this review will focus on the hypermethylation of CpG islands in promoter regions, as the most widely described epigenetic modification in bladder cancer. CpG islands hypermethylation is believed to be critical in the transcriptional silencing and regulation of tumor suppressor and crucial cancer genes involved in the major molecular pathways controlling bladder cancer development and progression. In particular, several biological pathways of frequently methylated genes include cell cycle, DNA repair, apoptosis, and invasion, among others. Furthermore, translational aspects of bladder cancer methylomes described to date will be discussed towards their potential application as bladder cancer biomarkers. Several tissue methylation signatures and individual candidates have been evidenced, that could potentially stratify tumors histopathologically, and discriminate patients in terms of their clinical outcome. Tumor methylation profiles could also be detected in urinary specimens showing a promising role as non-invasive markers for cancer diagnosis towards an early detection and potentially for the surveillance of bladder cancer patients in a near future. However, the epigenomic exploration of bladder cancer has only just begun. Genome-scale DNA methylation profiling studies will further highlight the relevance of the epigenetic component to gain knowledge of bladder cancer biology and identify those profiles and candidates better correlating with clinical behavior.

Keywords

Bladder cancer Methylation 

Notes

Acknowledgments

We would like thank all members of the laboratory of M. Sánchez-Carbayo, especially Rodrigo Garcia-Baquero, Valle Montalvo, Noemi Pompas-Veganzones, and Patricia Moya, for the technical support and constructive suggestions in the preparation of this manuscript. This work is supported by grants from the Spanish Ministry of Science and Innovation grant SAF2009-13035, and Mutua Madrileña 2010 (to M. Sánchez-Carbayo).

Conflicts of interest

None.

References

  1. 1.
    Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet. 1999;21:163–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16:6–21.PubMedCrossRefGoogle Scholar
  3. 3.
    Laird PW. The power and the promise of DNA methylation markers. Nat Rev Cancer. 2003;3:253–66.PubMedCrossRefGoogle Scholar
  4. 4.
    Eden A, Gaudet F, Waghmare A, Jaenisch R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science. 2003;300:455.PubMedCrossRefGoogle Scholar
  5. 5.
    Wang Y, Leung FC. An evaluation of new criteria for CpG islands in the human genome as gene markers. Bioinformatics. 2004;20:1170–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Feinberg AP. Cancer epigenetics is no Mickey Mouse. Cancer Cell. 2005;8:267–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Gene. 2007;8:286–98.CrossRefGoogle Scholar
  8. 8.
    Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–92.PubMedCrossRefGoogle Scholar
  9. 9.
    Esteller M. Epigenetic gene silencing in cancer: the DNA hypermethylome. Hum Mol Genet. 2007;16:50–9.CrossRefGoogle Scholar
  10. 10.
    Suzuki MM, Bird A. DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet. 2008;9:465–76.PubMedCrossRefGoogle Scholar
  11. 11.
    Meissner A, Mikkelsen TS, Gu H, Wernig M, Hanna J, Sivachenko A, et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature. 2008;454:766–70.PubMedGoogle Scholar
  12. 12.
    Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358:1148–59.PubMedCrossRefGoogle Scholar
  13. 13.
    Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462:315–22.PubMedCrossRefGoogle Scholar
  14. 14.
    Straussman R, Nejman D, Roberts D, Steinfeld I, Blum B, Benvenisty N, et al. Developmental programming of CpG island methylation profiles in the human genome. Nat Struct Mol Biol. 2009;16:564–71.PubMedCrossRefGoogle Scholar
  15. 15.
    Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462:315–22.PubMedCrossRefGoogle Scholar
  16. 16.
    Kuroda A, Rauch TA, Todorov I, Ku HT, Al-Abdullah IH, Kandeel F, et al. Insulin gene expression is regulated by DNA methylation. PLoS One. 2009;4:e6953.PubMedCrossRefGoogle Scholar
  17. 17.
    Thomson JP, Skene PJ, Selfridge J, Clouaire T, Guy J, Webb S, et al. CpG islands influence chromatin structure via the CpG-binding protein Cfp1. Nature. 2010;464:1082–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Irizarry RA, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P, et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 2009;41:178–86.PubMedCrossRefGoogle Scholar
  19. 19.
    Doi A, Park IH, Wen B, Murakami P, Aryee MJ, Irizarry R, et al. Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat Genet. 2009;41:1350–3.PubMedCrossRefGoogle Scholar
  20. 20.
    Hellman A, Chess A. Gene body-specific methylation on the active X chromosome. Science. 2007;315:1141–3.PubMedCrossRefGoogle Scholar
  21. 21.
    Futscher BW, Oshiro MM, Wozniak RJ, Holtan N, Hanigan CL, Duan H, et al. Role for DNA methylation in the control of cell type specific maspin expression. Nat Genet. 2002;31:175–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Hattori N, Nishino K, Ko YG, Hattori N, Ohgane J, Tanaka S, et al. Epigenetic control of mouse Oct-4 gene expression in embryonic stem cells and trophoblast stem cells. J Biol Chem. 2004;279:17063–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324:930–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Ito S, D'Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010;466:1129–33.PubMedCrossRefGoogle Scholar
  25. 25.
    Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, et al. The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res. 1999;27:2291–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Robert MF, Morin S, Beaulieu N, Gauthier F, Chute IC, Barsalou A, et al. DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Nat Genet. 2003;33:61–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Robertson KD, Keyomarsi K, Gonzales FA, Velicescu M, Jones PA. Differential mRNA expression of the human DNA methyltransferases (DNMTs) 1, 3a and 3b during the G(0)/G(1) to S phase transition in normal and tumor cells. Nucleic Acids Res. 2000;28:2108–13.PubMedCrossRefGoogle Scholar
  28. 28.
    Velicescu M, Weisenberger DJ, Gonzales FA, Tsai YC, Nguyen CT, Jones PA. Cell division is required for de novo methylation of CpG islands in bladder cancer cells. Cancer Res. 2002;62:2378–84.PubMedGoogle Scholar
  29. 29.
    Nakagawa T, Kanai Y, Saito Y, Kitamura T, Kakizoe T, Hirohashi S. Increased DNA methyltransferase 1 protein expression in human transitional cell carcinoma of the bladder. J Urol. 2003;170:2463–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global Cancer Statistics CA. Cancer J Clin. 2011;61:69–90.CrossRefGoogle Scholar
  31. 31.
    Sánchez-Carbayo M. Use of high-throughput DNA microarrays to identify biomarkers for bladder cancer. Clin Chem. 2003;49:23–31.PubMedCrossRefGoogle Scholar
  32. 32.
    Sánchez-Carbayo M, Cordon-Cardó C. Molecular alterations associated with bladder cancer progression. Semin Oncol. 2007;34:75–84.PubMedCrossRefGoogle Scholar
  33. 33.
    Sánchez-Carbayo M, Cordon-Cardo C. Applications of array technology: identification of molecular targets in bladder cancer. Br J Cancer. 2003;89:2172–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Wolff EM, Liang G, Jones PA. Mechanisms of disease: genetic and epigenetic alterations that drive bladder cancer. Nat Clin Pract Urol. 2005;2:502–10.PubMedCrossRefGoogle Scholar
  35. 35.
    Gonzalgo ML, Datar RH, Schoenberg MP, Cote RJ. The role of deoxyribonucleic acid methylation in development, diagnosis, and prognosis of bladder cancer. Urol Oncol. 2007;25:228–35.PubMedCrossRefGoogle Scholar
  36. 36.
    Henrique R, Costa VL, Jerónimo C. Methylation-based biomarkers for early detection of urological cancer. Crit Rev Oncog. 2007;13:265–82.PubMedGoogle Scholar
  37. 37.
    Enokida H, Nakagawa M. Epigenetics in bladder cancer. Int J Clin Oncol. 2008;13:298–307.PubMedCrossRefGoogle Scholar
  38. 38.
    Kim YK, Kim WJ. Epigenetic markers as promising prognosticators for bladder cancer. Int J Urol. 2009;16:17–22.PubMedCrossRefGoogle Scholar
  39. 39.
    Kim WJ, Kim YJ. Epigenetic biomarkers in urothelial bladder cancer. Expert Rev Mol Diagn. 2009;9:259–69.PubMedCrossRefGoogle Scholar
  40. 40.
    Phé V, Cussenot O, Rouprêt M. Interest of methylated genes as biomarkers in urothelial cell carcinomas of the urinary tract. BJU Int. 2009;104:896–901.PubMedCrossRefGoogle Scholar
  41. 41.
    Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, et al. DNMT3A Mutations in acute myeloid leukemia. N Engl J Med. 2010;363:2424–2333.CrossRefGoogle Scholar
  42. 42.
    Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Massé A, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289–301.PubMedCrossRefGoogle Scholar
  43. 43.
    Bailey VJ, Easwaran H, Zhang Y, Griffiths E, Belinsky SA, Herman JG, et al. MS-qFRET: a quantum dot-based method for analysis of DNA methylation. Genome Res. 2009;19:1455–61.PubMedCrossRefGoogle Scholar
  44. 44.
    Li M, Chen WD, Papadopoulos N, Goodman SN, Bjerregaard NC, Laurberg S, et al. Sensitive digital quantification of DNA methylation in clinical samples. Nat Biotechnol. 2009;27:858–63.PubMedCrossRefGoogle Scholar
  45. 45.
    Malentacchi F, Forni G, Vinci S, Orlando C. Quantitative evaluation of DNA methylation by optimization of a differential-high resolution melt analysis protocol. Nucleic Acids Res. 2009;37:e86.PubMedCrossRefGoogle Scholar
  46. 46.
    Marsit CJ, Karagas MR, Danaee H, Liu M, Andrew A, Schned A, et al. Carcinogen exposure and gene promoter hypermethylation in bladder cancer. Carcinogenesis. 2006;27:112–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Aleman A, Adrien L, Lopez-Serra L, Cordon-Cardo C, Esteller M, Belbin TJ, et al. Identification of DNA hypermethylation of SOX9 in association with bladder cancer progression using CpG microarrays. Br J Cancer. 2008;98:466–73.PubMedCrossRefGoogle Scholar
  48. 48.
    Wilhelm-Benartzi CS, Koestler DC, Houseman EA, Christensen BC, Wiencke JK, Schned AR, et al. DNA methylation profiles delineate etiologic heterogeneity and clinically important subgroups of bladder cancer. Carcinogenesis. 2010;31:1972–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Wolff EM, Chihara Y, Pan F, Weisenberger DJ, Siegmund KD, Sugano K, et al. Unique DNA methylation patterns distinguish noninvasive and invasive urothelial cancers and establish an epigenetic field defect in premalignant tissue. Cancer Res. 2010;70:8169–78.PubMedCrossRefGoogle Scholar
  50. 50.
    Nishiyama N, Arai E, Chihara Y, Fujimoto H, Hosoda F, Shibata T, et al. Genome-wide DNA methylation profiles in urothelial carcinomas and urothelia at the precancerous stage. Cancer Sci. 2010;101:231–40.PubMedCrossRefGoogle Scholar
  51. 51.
    Marsit CJ, Houseman EA, Christensen BC, Gagne L, Wrensch MR, Nelson HH, et al. Identification of methylated genes associated with aggressive bladder cancer. PLoS One. 2010;5:e12334.PubMedCrossRefGoogle Scholar
  52. 52.
    Marsit CJ, Koestler DC, Christensen BC, Karagas MR, Houseman EA, Kelsey KT. DNA methylation array analysis identifies profiles of blood-derived DNA methylation associated with bladder cancer. J Clin Oncol. 2011;29:1133–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Wilhelm-Benartzi CS, Christensen BC, Koestler DC, Andres Houseman E, Schned AR, Karagas MR, et al. Association of secondhand smoke exposures with DNA methylation in bladder carcinomas. Cancer Causes Control. 2011;22:1205–13.PubMedCrossRefGoogle Scholar
  54. 54.
    Reinert T, Modin C, Castano FM, Lamy P, Wojdacz TK, Hansen LL, et al. Comprehensive genome methylation analysis in bladder cancer: identification and validation of novel methylated genes and application of these as urinary tumor markers. Clin Cancer Res. 2011;17:5582–92.PubMedCrossRefGoogle Scholar
  55. 55.
    Fernandez AF, Assenov Y, Martin-Subero JI, Balint B, Siebert R, Taniguchi H, et al. A DNA methylation fingerprint of 1628 human samples. Genome Res. 2011. doi: 10.1101/gr.119867.110.
  56. 56.
    Vallot C, Stransky N, Bernard-Pierrot I, Hérault A, Zucman-Rossi J, Chapeaublanc E, et al. A novel epigenetic phenotype associated with the most aggressive pathway of bladder tumor progression. J Natl Cancer Inst. 2011;103:47–60.PubMedCrossRefGoogle Scholar
  57. 57.
    Serizawa RR, Ralfkiaer U, Dahl C, Lam GW, Hansen AB, Steven K, et al. Custom-designed MLPA using multiple short synthetic probes: application to methylation analysis of five promoter CpG islands in tumor and urine specimens from patients with bladder cancer. J Mol Diagn. 2010;12:402–8.PubMedCrossRefGoogle Scholar
  58. 58.
    Cabello MJ, Grau L, Franco N, Orenes E, Alvarez M, Blanca A, et al. Multiplexed methylation profiles of tumor suppressor genes in bladder cancer. J Mol Diagn. 2011;13:29–40.PubMedCrossRefGoogle Scholar
  59. 59.
    Agundez M, Grau L, Palou J, Algaba F, Villavicencio H, Sanchez-Carbayo M. Evaluation of the methylation status of tumour suppressor genes for predicting bacillus Calmette-Guérin response in patients with T1G3 high-risk bladder tumours. Eur Urol. 2011;60:131–40.PubMedCrossRefGoogle Scholar
  60. 60.
    Zuiverloon TC, Beukers W, van der Keur KA, Munoz JR, Bangma CH, Lingsma HF, Eijkemans MJ, Schouten JP, Zwarthoff EC. A methylation assay for the detection of non-muscle-invasive bladder cancer (NMIBC) recurrences in voided urine. BJU Int 2011Google Scholar
  61. 61.
    Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, et al. 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nature Med. 1995;1:686–92.PubMedCrossRefGoogle Scholar
  62. 62.
    Herman JG, Graff JR, Myöhönen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA. 1996;93:9821–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Lukas J, Parry D, Aagaard L, Mann DJ, Bartkova J, Strauss M, et al. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumor suppressor p16. Nature. 1995;375:503–6.PubMedCrossRefGoogle Scholar
  64. 64.
    Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995;81:323–30.PubMedCrossRefGoogle Scholar
  65. 65.
    Florl AR, Franke KH, Niederacher D, Gerharz CD, Seifert HH, Schulz WA. DNA methylation and the mechanisms of CDKN2A inactivation in transitional cell carcinoma of the urinary bladder. Lab Invest. 2000;80:1513–22.PubMedCrossRefGoogle Scholar
  66. 66.
    Valenzuela MT, Galisteo R, Zuluaga A, Villalobos M, Núñez MI, Oliver FJ, et al. Assessing the use of p16 (INK4a) promoter gene methylation in serum for detection of bladder cancer. Eur Urol. 2002;42:622–8. discussion 628–30.PubMedCrossRefGoogle Scholar
  67. 67.
    Chan MW, Chan LW, Tang NL, Tong JH, Lo KW, Lee TL, et al. Hypermethylation of multiple genes in tumor tissues and voided urine in urinary bladder cancer patients. Clin Cancer Res. 2002;8:464–70.PubMedGoogle Scholar
  68. 68.
    Tada Y, Wada M, Taguchi K, Mochida Y, Kinugawa N, Tsuneyoshi M, et al. The association of death-associated protein kinase hypermethylation with early recurrence in superficial bladder cancers. Cancer Res. 2002;62:4048–53.PubMedGoogle Scholar
  69. 69.
    Chang LL, Yeh WT, Yang SY, Wu WJ, Huang CH. Genetic alterations of p16INK4a and p14ARF genes in human bladder cancer. J Urol. 2003;170:595–600.PubMedCrossRefGoogle Scholar
  70. 70.
    Dominguez G, Silva J, Garcia JM, Silva JM, Rodriguez R, Muñoz C, et al. Prevalence of aberrant methylation of p14ARF over p16INK4a in some human primary tumors. Mutat Res. 2003;530:9–17.PubMedGoogle Scholar
  71. 71.
    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;10:1887–93.PubMedCrossRefGoogle Scholar
  72. 72.
    Catto JW, Azzouzi AR, Rehman I, Feeley KM, Cross SS, Amira N, et al. Promoter hypermethylation is associated with tumor location, stage, and subsequent progression in transitional cell carcinoma. J Clin Oncol. 2005;23:2903–10.PubMedCrossRefGoogle Scholar
  73. 73.
    Dhawan D, Hamdy FC, Rehman I, Patterson J, Cross SS, Feeley KM, et al. Evidence for the early onset of aberrant promoter methylation in urothelial carcinoma. J Pathol. 2006;209:336–43.PubMedCrossRefGoogle Scholar
  74. 74.
    Friedrich MG, Weisenberger DJ, Cheng JC, Chandrasoma S, Siegmund KD, Gonzalgo ML, et al. Detection of methylated apoptosis-associated genes in urine sediments of bladder cancer patients. Clin Cancer Res. 2004;10:7457–65.PubMedCrossRefGoogle Scholar
  75. 75.
    Kawamoto K, Enokida H, Gotanda T, Kubo H, Nishiyama K, Kawahara M, et al. p16INK4a and p14ARF methylation as a potential biomarker for human bladder cancer. Biochem Biophys Res Commun. 2006;339:790–6.PubMedCrossRefGoogle Scholar
  76. 76.
    Jarmalaite S, Jankevicius F, Kurgonaite K, Suziedelis K, Mutanen P, Husgafvel-Pursiainen K. Promoter hypermethylation in tumour suppressor genes shows association with stage, grade and invasiveness of bladder cancer. Oncology. 2008;75:145–51.PubMedCrossRefGoogle Scholar
  77. 77.
    Khin SS, Kitazawa R, Win N, Aye TT, Mori K, Kondo T, et al. BAMBI gene is epigenetically silenced in subset of high-grade bladder cancer. Int J Cancer. 2009;125:328–38.PubMedCrossRefGoogle Scholar
  78. 78.
    Jarmalaite S, Andrekute R, Scesnaite A, Suziedelis K, Husgafvel-Pursiainen K, Jankevicius F. Promoter hypermethylation in tumour suppressor genes and response to interleukin-2 treatment in bladder cancer: a pilot study. J Cancer Res Clin Oncol. 2010;136:847–54.PubMedCrossRefGoogle Scholar
  79. 79.
    Lin HH, Ke HL, Huang SP, Wu WJ, Chen YK, Chang LL. Increase sensitivity in detecting superficial, low grade bladder cancer by combination analysis of hypermethylation of E-cadherin, p16, p14, RASSF1A genes in urine. Urol Oncol. 2010;28:597–602.PubMedCrossRefGoogle Scholar
  80. 80.
    Lin HH, Ke HL, Wu WJ, Lee YH, Chang LL. Hypermethylation of E-cadherin, p16,p14, and RASSF1A genes in pathologically normal urothelium predict bladder recurrence of bladder cancer after transurethral resection. Urol Oncol 2010.Google Scholar
  81. 81.
    Schlott T, Quentin T, Korabiowska M, Budd B, Kunze E. Alteration of the MDM2-p73-P14ARF pathway related to tumour progression during urinary bladder carcinogenesis. Int J Mol Med. 2004;14:825–36.PubMedGoogle Scholar
  82. 82.
    Yurakh AO, Ramos D, Calabuig-Fariñas S, López-Guerrero JA, Rubio J, Solsona E, et al. Molecular and immunohistochemical analysis of the prognostic value of cell-cycle regulators in urothelial neoplasms of the bladder. Eur Urol. 2006;50:506–15.PubMedCrossRefGoogle Scholar
  83. 83.
    Pu RT, Laitala LE, Clark DP. Methylation profiling of urothelial carcinoma in bladder biopsy and urine. Acta Cytol. 2006;50:499–506.PubMedCrossRefGoogle Scholar
  84. 84.
    Hoque MO, Begum S, Topaloglu O, Chatterjee A, Rosenbaum E, Van Criekinge W, et al. Quantitation of promoter methylation of multiple genes in urine DNA and bladder cancer detection. J Natl Cancer Inst. 2006;98:996–1004.PubMedCrossRefGoogle Scholar
  85. 85.
    Yates DR, Rehman I, Meuth M, Cross SS, Hamdy FC, Catto JW. Methylational urinalysis: a prospective study of bladder cancer patients and age stratified benign controls. Oncogene. 2006;25:1984–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Yates DR, Rehman I, Abbod MF, Meuth M, Cross SS, Linkens DA, et al. Promoter hypermethylation identifies progression risk in bladder cancer. Clin Cancer Res. 2007;13:2046–53.PubMedCrossRefGoogle Scholar
  87. 87.
    Brait M, Begum S, Carvalho AL, Dasgupta S, Vettore AL, Czerniak B, et al. Aberrant promoter methylation of multiple genes during pathogenesis of bladder cancer. Cancer Epidemiol Biomarkers Prev. 2008;17:2786–94.PubMedCrossRefGoogle Scholar
  88. 88.
    Hoffmann MJ, Florl AR, Seifert HH, Schulz WA. Multiple mechanisms down regulate CDKN1C in human bladder cancer. Int J Cancer. 2005;114:406–13.PubMedCrossRefGoogle Scholar
  89. 89.
    Chapman EJ, Harnden P, Chambers P, Johnston C, Knowles MA. Comprehensive analysis of CDKN2A status in microdissected urothelial cell carcinoma reveals potential haploinsufficiency, a high frequency of homozygous co-deletion and associations with clinical phenotype. Clin Cancer Res. 2005;11:5740–7.PubMedCrossRefGoogle Scholar
  90. 90.
    Salem CE, Markl ID, Bender CM, Gonzales FA, Jones PA, Liang G. PAX6 methylation and ectopic expression in human tumor cells. Int J Cancer. 2000;87:179–85.PubMedCrossRefGoogle Scholar
  91. 91.
    Hellwinkel OJ, Kedia M, Isbarn H, Budäus L, Friedrich MG. Methylation of the TPEF- and PAX6-promoters is increased in early bladder cancer and in normal mucosa adjacent to pTa tumours. BJU Int. 2008;101:753–7.PubMedCrossRefGoogle Scholar
  92. 92.
    Scolnick DM, Halazonetis TD. Chfr defines a mitotic stress checkpoint that delays entry into metaphase. Nature. 2000;406:430–5.PubMedCrossRefGoogle Scholar
  93. 93.
    Maruyama R, Toyooka S, Toyooka Ko, Harada K, Virmani AK, Zochbauer-Muller S, et al. Aberrant promoter methylation profile of bladder cancer and its relationship to clinicopathological features. Cancer Res. 2001;61:8659–63.PubMedGoogle Scholar
  94. 94.
    Cohen O, Inbal B, Kissil JL, Raveh T, Berissi H, Spivak-Kroizaman T, et al. DAP-kinase participates in TNF-α and Fas-induced apoptosis and its function requires the death domain. J Cell Biol. 1999;146:141–8.PubMedGoogle Scholar
  95. 95.
    Friedrich MG, Chandrasoma S, Siegmund KD, Weisenberger DJ, Cheng JC, Toma MI, et al. Prognostic relevance of methylation markers in patients with non-muscle invasive bladder carcinoma. Eur J Cancer. 2005;41:2769–78.PubMedCrossRefGoogle Scholar
  96. 96.
    Christoph F, Kempkensteffen C, Weikert S, Köllermann J, Krause H, Miller K, et al. Methylation of tumour suppressor genes APAF-1 and DAPK-1 and in vitro effects of demethylating agents in bladder and kidney cancer. Br J Cancer. 2006;95:1701–7.PubMedCrossRefGoogle Scholar
  97. 97.
    Christoph F, Weikert S, Kempkensteffen C, Krause H, Schostak M, Miller K, et al. Regularly methylated novel pro-apoptotic genes associated with recurrence in transitional cell carcinoma of the bladder. Int J Cancer. 2006;119:1396–402.PubMedCrossRefGoogle Scholar
  98. 98.
    Chen WT, Hung WC, Kang WY, Huang YC, Chai CY. Urothelial carcinomas arising in arsenic-contaminated areas are associated with hypermethylation of the gene promoter of the death-associated protein kinase. Histopathology. 2007;51:785–92.PubMedCrossRefGoogle Scholar
  99. 99.
    Christoph F, Hinz S, Weikert S, Kempkensteffen C, Schostak M, Miller K, et al. Comparative promoter methylation analysis of p53 target genes in urogenital cancers. Urol Int. 2008;80:398–404.PubMedCrossRefGoogle Scholar
  100. 100.
    Wolff EM, Liang G, Cortez CC, Tsai YC, Castelao JE, Cortessis VK, et al. RUNX3 methylation reveals that bladder tumors are older in patients with a history of smoking. Cancer Res. 2008;68:6208–14.PubMedCrossRefGoogle Scholar
  101. 101.
    Vinci S, Giannarini G, Selli C, Kuncova J, Villari D, Valent F, et al. Quantitative methylation analysis of BCL2, hTERT, and DAPK promoters in urine sediment for the detection of non-muscle-invasive urothelial carcinoma of the bladder: a prospective, two-center validation study. Urol Oncol. 2011;29:150–6.PubMedCrossRefGoogle Scholar
  102. 102.
    Shivapurkar N, Toyooka S, Toyooka KO, Reddy J, Miyajima K, Suzuki M, et al. Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types. Int J Cancer. 2004;109:786–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T, Zhang XF, et al. Identification of a novel Ras-regulated proapoptotic pathway. Curr Biol. 2002;12:253–65.PubMedCrossRefGoogle Scholar
  104. 104.
    Lee MG, Kim HY, Byun DS, Lee SJ, Lee CH, Kim JI, et al. Frequent epigenetic inactivation of RASSF1A in human bladder carcinoma. Cancer Res. 2001;61:6688–92.PubMedGoogle Scholar
  105. 105.
    Negraes PD, Favaro FP, Camargo JL, Oliveira ML, Goldberg J, Rainho CA, et al. DNA methylation patterns in bladder cancer and washing cell sediments: a perspective for tumor recurrence detection. BMC Cancer. 2008;8:238.PubMedCrossRefGoogle Scholar
  106. 106.
    Takeichi M. Cadherin cell adhesion receptors as a morphogenetic regulator. Science. 1991;251:1451–5.PubMedCrossRefGoogle Scholar
  107. 107.
    Chambers AF, Matrisian LM. Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst. 1997;89:1260–70.PubMedCrossRefGoogle Scholar
  108. 108.
    Hoque MO, Begum S, Brait M, Jeronimo C, Zahurak M, Ostrow KL, et al. Tissue inhibitor of metalloproteinases-3 promoter methylation is an independent prognostic factor for bladder cancer. J Urol. 2008;179:743–7.PubMedCrossRefGoogle Scholar
  109. 109.
    Colognato H, Yurchenco PD. Form and function: the laminin family of heterotrimers. Dev Dyn. 2000;218:213–34.PubMedCrossRefGoogle Scholar
  110. 110.
    Sathyanarayana UG, Maruyama R, Padar A, Suzuki M, Bondaruk J, Sagalowsky A, et al. Molecular detection of noninvasive and invasive bladder tumor tissues and exfoliated cells by aberrant promoter methylation of laminin-5 encoding genes. Cancer Res. 2004;64:1425–30.PubMedCrossRefGoogle Scholar
  111. 111.
    Bornman DM, Mathew S, Alsruhe J, Herman JG, Gabrielson E. Methylation of the E-cadherin gene in bladder neoplasia and in normal urothelial epithelium from elderly individuals. Am J Pathol. 2001;159:831–5.PubMedCrossRefGoogle Scholar
  112. 112.
    Ribeiro-Filho LA, Franks J, Sasaki M, Shiina H, Li LC, Nojima D, et al. CpG hypermethylation of promoter region and inactivation of E-cadherin gene in human bladder cancer. Mol Carcinog. 2002;34:187–98.PubMedCrossRefGoogle Scholar
  113. 113.
    Horikawa Y, Sugano K, Shigyo M, Yamamoto H, Nakazono M, Fujimoto H, et al. Hypermethylation of an E-cadherin (CDH1) promoter region in high grade transitional cell carcinoma of the bladder comprising carcinoma in situ. J Urol. 2003;169:1541–5.PubMedCrossRefGoogle Scholar
  114. 114.
    Owen HC, Giedl J, Wild PJ, Fine SW, Humphrey PA, Dehner LP, et al. Low frequency of epigenetic events in urothelial tumors in young patients. J Urol. 2010;184:459–63.PubMedCrossRefGoogle Scholar
  115. 115.
    Chen PC, Tsai MH, Yip SK, Jou YC, Ng CF, Chen Y, et al. Distinct DNA methylation epigenotypes in bladder cancer from different Chinese sub-populations and its implication in cancer detection using voided urine. BMC Med Genomics. 2011;4:45.PubMedCrossRefGoogle Scholar
  116. 116.
    Dumache R, David D, Kaycsa A, Minciu R, Negru S, Puiu M. Genetic and epigenetic biomarkers for early detection, therapeutic effectiveness and relapse monitoring in bladder cancer. Rev Med Chir Soc Med Nat Iasi. 2011;115:163–7.PubMedGoogle Scholar
  117. 117.
    Mori K, Enokida H, Kagara I, Kawakami K, Chiyomaru T, Tatarano S, et al. CpG hypermethylation of collagen type I alpha 2 contributes to proliferation and migration activity of human bladder cancer. Int J Oncol. 2009;34:1593–602.PubMedCrossRefGoogle Scholar
  118. 118.
    Toki K, Enokida H, Kawakami K, Chiyomaru T, Tatarano S, Yoshino H, et al. CpG hypermethylation of cellular retinol-binding protein 1 contributes to cell proliferation and migration in bladder cancer. Int J Oncol. 2010;37:1379–88.PubMedGoogle Scholar
  119. 119.
    Costa VL, Henrique R, Danielsen SA, Duarte-Pereira S, Eknaes M, Skotheim RI, et al. Three epigenetic biomarkers, GDF15, TMEFF2, and VIM, accurately predict bladder cancer from DNA-based analyses of urine samples. Clin Cancer Res. 2010;16:5842–51.PubMedCrossRefGoogle Scholar
  120. 120.
    Xuan Y, Kim S, Lin Z. Protein expression and gene promoter hypermethylation of CD99 in transitional cell carcinoma of urinary bladder. J Cancer Res Clin Oncol. 2011;137:49–54.PubMedCrossRefGoogle Scholar
  121. 121.
    Ruppen I, Grau L, Orenes-Piñero E, Ashman K, Gil M, Algaba F, et al. Differential protein expression profiling by iTRAQ-two-dimensional LC-MS/MS of human bladder cancer EJ138 cells transfected with the metastasis suppressor KiSS-1 gene. Mol Cell Proteomics. 2010;10:2276–91.Google Scholar
  122. 122.
    Cebrian V, Fierro M, Orenes-Piñero E, Grau L, Moya P, Ecke T, et al. KISS1 methylation and expression as tumor stratification biomarkers and clinical outcome prognosticators for bladder cancer patients. Am J Pathol. 2011;179:540–6.PubMedCrossRefGoogle Scholar
  123. 123.
    Marsit CJ, Karagas MR, Andrew A, Liu M, Danaee H, Schned AR, et al. Epigenetic inactivation of SFRP genes and TP53 alteration act jointly as markers of invasive bladder cancer. Cancer Res. 2005;65:7081–5.PubMedCrossRefGoogle Scholar
  124. 124.
    Urakami S, Shiina H, Enokida H, Kawakami T, Kawamoto K, Hirata H, et al. Combination analysis of hypermethylated Wnt-antagonist family genes as a novel epigenetic biomarker panel for bladder cancer detection. Clin Cancer Res. 2006;12:2109–16.PubMedCrossRefGoogle Scholar
  125. 125.
    Urakami S, Shiina H, Enokida H, Kawakami T, Tokizane T, Ogishima T, et al. Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt/beta-catenin signaling pathway. Clin Cancer Res. 2006;12:383–91.PubMedCrossRefGoogle Scholar
  126. 126.
    Sun J, Chen Z, Zhu T, Yu J, Ma K, Zhang H, et al. Hypermethylated SFRP1, but none of other nine genes “informative” for western countries, is valuable for bladder cancer detection in Mainland China. J Cancer Res Clin Oncol. 2009;135:1717–27.PubMedCrossRefGoogle Scholar
  127. 127.
    Costa VL, Henrique R, Ribeiro FR, Carvalho JR, Oliveira J, Lobo F, et al. Epigenetic regulation of Wnt signaling pathway in urological cancer. Epigenetics. 2010;4:343–5.CrossRefGoogle Scholar
  128. 128.
    Habuchi T, Takahashi T, Kakinuma H, Wang L, Tsuchiya N, Satoh S, et al. Hypermethylation at 9q32-33 tumour suppressor region is age-related in normal urothelium and an early and frequent alteration in bladder cancer. Oncogene. 2001;20:531–7.PubMedCrossRefGoogle Scholar
  129. 129.
    Kim WJ, Kim EJ, Jeong P, Quan C, Kim J, Li QL, et al. RUNX3 inactivation by point mutations and aberrant DNA methylation in bladder tumors. Cancer Res. 2005;65:9347–54.PubMedCrossRefGoogle Scholar
  130. 130.
    Kunze E, Wendt M, Schlott T. Promoter hypermethylation of the 14-3-3 sigma, SYK and CAGE-1 genes is related to the various phenotypes of urinary bladder carcinomas and associated with progression of transitional cell carcinomas. Int J Mol Med. 2006;18:547–57.PubMedGoogle Scholar
  131. 131.
    Yu J, Zhu T, Wang Z, Zhang H, Qian Z, Xu H, et al. A novel set of DNA methylation markers in urine sediments for sensitive-specific detection of bladder cancer. Clin Cancer Res. 2007;13:7296–304.PubMedCrossRefGoogle Scholar
  132. 132.
    Kim EJ, Kim YJ, Jeong P, Ha YS, Bae SC, Kim WJ. Methylation of the RUNX3 promoter as a potential prognostic marker for bladder tumor. J Urol. 2008;180:1141–5.PubMedCrossRefGoogle Scholar
  133. 133.
    Sanchez-Carbayo M, Schwarz K, Charytonowicz E, Cordon-Cardo C, Mundel P. Tumor suppressor role for myopodin in bladder cancer: loss of nuclear expression of myopodin is cell-cycle dependent and predicts clinical outcome. Oncogene. 2003;22:5298–305.PubMedCrossRefGoogle Scholar
  134. 134.
    Cebrian V, Alvarez M, Aleman A, Palou J, Bellmunt J, Gonzalez-Peramato P, et al. Discovery of myopodin methylation in bladder cancer. J Pathol. 2008;216:111–9.PubMedCrossRefGoogle Scholar
  135. 135.
    Alvarez-Mugica M, Cebrian V, Fernandez-Gomez JM, Fresno F, Escaf S, Sanchez-Carbayo M. Myopodin methylation is associated with clinical outcome in patients with T1G3 bladder cancer. J Urol. 2010;4:1507–13.CrossRefGoogle Scholar
  136. 136.
    Dokun OY, Florl AR, Seifert HH, Wolff I, Schulz WA. Relationship of SNCG, S100A4, S100A9 and LCN2 gene expression and DNA methylation in bladder cancer. Int J Cancer. 2008;123:2798–807.PubMedCrossRefGoogle Scholar
  137. 137.
    Aleman A, Cebrian V, Alvarez M, Lopez V, Orenes E, Lopez-Serra L, et al. Identification of PMF1 methylation in association with bladder cancer progression. Clin Cancer Res. 2008;14:8236–43.PubMedCrossRefGoogle Scholar
  138. 138.
    Kunze E, Schlott T. High frequency of promoter methylation of the 14-3-3 sigma and CAGE-1 genes, but lack of hypermethylation of the caveolin-1 gene, in primary adenocarcinomas and signet ring cell carcinomas of the urinary bladder. Int J Mol Med. 2007;20:557–63.PubMedGoogle Scholar
  139. 139.
    Eissa S, Swellam M, El-Khouly IM, Kassim SK, Shehata H, Mansour A, et al. Aberrant methylation of RAR{beta}2 and APC genes in voided urine as molecular markers for early detection of bilharzial and nonbilharzial bladder cancer. Cancer Epidemiol Biomarkers Prev. 2011;20:1657–64.PubMedCrossRefGoogle Scholar
  140. 140.
    Serizawa RR, Ralfkiaer U, Steven K, Lam GW, Schmiedel S, Schüz J, et al. Integrated genetic and epigenetic analysis of bladder cancer reveals an additive diagnostic value of FGFR3 mutations and hypermethylation events. Int J Cancer. 2011;129:78–87.PubMedCrossRefGoogle Scholar
  141. 141.
    Abbosh PH, Wang M, Eble JN, Lopez-Beltran A, Maclennan GT, Montironi R, et al. Hypermethylation of tumor-suppressor gene CpG islands in small-cell carcinoma of the urinary bladder. Mod Pathol. 2008;21:355–62.PubMedCrossRefGoogle Scholar
  142. 142.
    Rouprêt M, Hupertan V, Yates DR, Comperat E, Catto JW, Meuth M, et al. A comparison of the performance of microsatellite and methylation urine analysis for predicting the recurrence of urothelial cell carcinoma, and definition of a set of markers by Bayesian network analysis. BJU Int. 2008;101:1448–53.PubMedCrossRefGoogle Scholar
  143. 143.
    Renard I, Joniau S, van Cleynenbreugel B, Collette C, Naômé C, Vlassenbroeck I, et al. Identification and validation of the methylated TWIST1 and NID2 genes through real-time methylation-specific polymerase chain reaction assays for the noninvasive detection of primary bladder cancer in urine samples. Eur Urol. 2010;58:96–104.PubMedCrossRefGoogle Scholar
  144. 144.
    Nishiyama N, Arai E, Nagashio R, Fujimoto H, Hosoda F, Shibata T, et al. Copy number alterations in urothelial carcinomas: their clinicopathological significance and correlation with DNA methylation alterations. `Carcinogenesis. 2011;32:462–9.PubMedCrossRefGoogle Scholar
  145. 145.
    Chung W, Bondaruk J, Jelinek J, Lotan Y, Liang S, Czerniak B, et al. Detection of bladder cancer using novel DNA methylation biomarkers in urine sediments. Cancer Epidemiol Biomarkers Prev. 2011;20:1483–91.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2012

Authors and Affiliations

  1. 1.Tumor Markers Group, 308ASpanish National Cancer Research CenterMadridSpain

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