Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of Disease: genetic and epigenetic alterations that drive bladder cancer

Nature Clinical Practice Urology volume 2, pages 502–510 (2005)Cite this article

Abstract

There is substantial evidence for the existence of mutually exclusive molecular pathways to tumorigenesis, in the formation of papillary and invasive carcinomas, respectively. The most common genetic alterations in low grade papillary transitional-cell carcinoma (TCC) are loss of heterozygosity of part or all of chromosome 9 and activating mutations of the fibroblast growth factor receptor 3 (FGFR3). The pathway to development of invasive TCC seems to start with dysplasia, progress to carcinoma in situ, followed by invasion of the lamina propria. The most frequent genetic alteration in dysplasia and carcinoma in situ is mutation of TP53, followed by loss of heterozygosity of chromosome 9. A marker for progression in TCC is loss of chromosome 8p, which occurs in approximately 60% of bladder tumors. Global trends of increased genomic instability and aberrant methylation of cytosine residues in DNA correlate with increased tumor invasion and progression. When researching markers of bladder cancer for clinical use, it is important that biomedical pathways and their alterations are measured in the same tumor populations. This review examines the published data and proposes a model for the mechanisms behind bladder cancer development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Integration of genetic and epigenetic modifications in bladder cancer into a common pathway.
Figure 2: Model for bladder cancer progression showing the molecular pathways of tumorigenesis.

Similar content being viewed by others

References

  1. National Cancer Institute. NCI Fact Book. Bethesda, Md: National Institutes of Health; 2003.

  2. Brandau S and Bohle A (2001) Bladder cancer. I: Molecular and genetic basis of carcinogenesis. Eur Urol 39: 491–497

    CAS  PubMed  Google Scholar 

  3. Feng Z et al. (2002) 4-aminobiphenyl is a major etiological agent of human bladder cancer: evidence from its DNA binding spectrum in human p53 gene. Carcinogenesis 23: 1721–1727

    CAS  PubMed  Google Scholar 

  4. Knowles MA (2001) What we could do now: molecular pathology of bladder cancer. Mol Pathol 54: 215–221

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Williams SG and Stein JP (2004) Molecular pathways in bladder cancer. Urol Res 32: 373–385

    PubMed  Google Scholar 

  6. Tsutsumi M et al. (1998) Early acquisition of homozygous deletions of p16/p19 during squamous cell carcinogenesis and genetic mosaicism in bladder cancer. Oncogene 17: 3021–3027

    CAS  PubMed  Google Scholar 

  7. Rieger-Christ KM et al. (2003) Identification of fibroblast growth factor receptor 3 mutations in urine sediment DNA samples complements cytology in bladder tumor detection. Cancer 98: 737–744

    CAS  PubMed  Google Scholar 

  8. Dulaimi E et al. (2004) Detection of bladder cancer in urine by a tumor suppressor gene hypermethylation panel. Clin Cancer Res 10: 1887–1893

    CAS  PubMed  Google Scholar 

  9. Friedrich MG et al. (2004) Detection of methylated apoptosis-associated genes in urine sediments of bladder cancer patients. Clin Cancer Res 10: 7457–7465

    CAS  PubMed  Google Scholar 

  10. Markl ID and Jones PA (1998) Presence and location of TP53 mutation determines pattern of CDKN2A/ARF pathway inactivation in bladder cancer. Cancer Res 58: 5348–5353

    CAS  PubMed  Google Scholar 

  11. Sarkar S et al. (2000) Different combinations of genetic/epigenetic alterations inactivate the p53 and pRb pathways in invasive human bladder cancers. Cancer Res 60: 3862–3871

    CAS  PubMed  Google Scholar 

  12. Dunn KL et al. (2005) The Ras-MAPK signal transduction pathway, cancer and chromatin remodeling. Biochem Cell Biol 83: 1–14

    CAS  PubMed  Google Scholar 

  13. Hipfner DR and Cohen SM (2004) Connecting proliferation and apoptosis in development and disease. Nat Rev Mol Cell Biol 5: 805–815

    CAS  PubMed  Google Scholar 

  14. Billerey C et al. (2001) Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. Am J Pathol 158: 1955–1959

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Nicholson RI et al. (2001) EGFR and cancer prognosis. Eur J Cancer 37 (Suppl 4): S9–S15

    CAS  PubMed  Google Scholar 

  16. Oxford G and Theodorescu D (2003) The role of Ras superfamily proteins in bladder cancer progression. J Urol 170: 1987–1993

    CAS  PubMed  Google Scholar 

  17. Cappellen D et al. (1999) Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet 23: 18–20

    CAS  PubMed  Google Scholar 

  18. Munro NP and Knowles MA (2003) Fibroblast growth factors and their receptors in transitional cell carcinoma. J Urol 169: 675–682

    CAS  PubMed  Google Scholar 

  19. Jebar AH et al. (2005) FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma. Oncogene 24: 5218–5225

    CAS  PubMed  Google Scholar 

  20. van Rhijn BW et al. (2002) Frequent FGFR3 mutations in urothelial papilloma. J Pathol 198: 245–251

    CAS  PubMed  Google Scholar 

  21. Wallerand H et al. (2005) Mutations in TP53, but not FGFR3, in urothelial cell carcinoma of the bladder are influenced by smoking: contribution of exogenous versus endogenous carcinogens. Carcinogenesis 26: 177–184

    CAS  PubMed  Google Scholar 

  22. Bakkar AA et al. (2003) FGFR3 and TP53 gene mutations define two distinct pathways in urothelial cell carcinoma of the bladder. Cancer Res 63: 8108–8112

    CAS  PubMed  Google Scholar 

  23. Cheng J et al. (2002) Overexpression of epidermal growth factor receptor in urothelium elicits urothelial hyperplasia and promotes bladder tumor growth. Cancer Res 62: 4157–4163

    CAS  PubMed  Google Scholar 

  24. Zhang ZT et al. (2001) Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation. Oncogene 20: 1973–1980

    CAS  PubMed  Google Scholar 

  25. Garcia-Espana A et al. (2005) Differential expression of cell cycle regulators in phenotypic variants of transgenically induced bladder tumors: implications for tumor behavior. Cancer Res 65: 1150–1157

    CAS  PubMed  Google Scholar 

  26. Gao J et al. (2004) p53 deficiency provokes urothelial proliferation and synergizes with activated Ha-ras in promoting urothelial tumorigenesis. Oncogene 23: 687–696

    CAS  PubMed  Google Scholar 

  27. Dimova DK and Dyson NJ (2005) The E2F transcriptional network: old acquaintances with new faces. Oncogene 24: 2810–2826

    CAS  PubMed  Google Scholar 

  28. Oeggerli M et al. (2004) E2F3 amplification and overexpression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer. Oncogene 23: 5616–5623

    CAS  PubMed  Google Scholar 

  29. Chen CH et al. (2005) Bidirectional signals transduced by DAPK-ERK interaction promote the apoptotic effect of DAPK. Embo J 24: 294–304

    CAS  PubMed  Google Scholar 

  30. Tada Y et al. (2002) The association of death-associated protein kinase hypermethylation with early recurrence in superficial bladder cancers. Cancer Res 62: 4048–4053

    CAS  PubMed  Google Scholar 

  31. Robertson KD et al. (2000) DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet 25: 338–342

    CAS  PubMed  Google Scholar 

  32. Chatterjee SJ et al. (2004) Hyperphosphorylation of pRb: a mechanism for RB tumour suppressor pathway inactivation in bladder cancer. J Pathol 203: 762–770

    CAS  PubMed  Google Scholar 

  33. Cote RJ et al. (1998) Elevated and absent pRb expression is associated with bladder cancer progression and has cooperative effects with p53. Cancer Res 58: 1090–1094

    CAS  PubMed  Google Scholar 

  34. Batsche E et al. (1998) RB and c-Myc activate expression of the E-cadherin gene in epithelial cells through interaction with transcription factor AP-2. Mol Cell Biol 18: 3647–3658

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Decesse JT et al. (2001) RB regulates transcription of the p21/WAF1/CIP1 gene. Oncogene 20: 962–971

    CAS  PubMed  Google Scholar 

  36. Stein JP et al. (1998) Effect of p21WAF1/CIP1 expression on tumor progression in bladder cancer. J Natl Cancer Inst 90: 1072–1079

    CAS  Google Scholar 

  37. Wada T et al. (2000) Bladder cancer: allelic deletions at and around the retinoblastoma tumor suppressor gene in relation to stage and grade. Clin Cancer Res 6: 610–615

    CAS  PubMed  Google Scholar 

  38. Eymin B et al. (2001) Human ARF binds E2F1 and inhibits its transcriptional activity. Oncogene 20: 1033–1041

    CAS  PubMed  Google Scholar 

  39. Robertson KD and Jones PA (1998) The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53. Mol Cell Biol 18: 6457–6473

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Hartmann A et al. (2002) Occurrence of chromosome 9 and p53 alterations in multifocal dysplasia and carcinoma in situ of human urinary bladder. Cancer Res 62: 809–818

    CAS  PubMed  Google Scholar 

  41. Cheng J et al. (2003) Allelic loss of p53 gene is associated with genesis and maintenance, but not invasion, of mouse carcinoma in situ of the bladder. Cancer Res 63: 179–185

    CAS  PubMed  Google Scholar 

  42. Swaminathan S et al. (2002) Human urinary bladder epithelial cells lacking wild-type p53 function are deficient in the repair of 4-aminobiphenyl-DNA adducts in genomic DNA. Mutat Res 499: 103–117

    CAS  PubMed  Google Scholar 

  43. Spruck CH Jr et al. (1993) Distinct pattern of p53 mutations in bladder cancer: relationship to tobacco usage. Cancer Res 53: 1162–1166

    CAS  PubMed  Google Scholar 

  44. Orlow I et al. (1999) Deletions of the INK4A gene in superficial bladder tumors. Association with recurrence. Am J Pathol 155: 105–113

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Hartmann A et al. (1999) Frequent genetic alterations in simple urothelial hyperplasias of the bladder in patients with papillary urothelial carcinoma. Am J Pathol 154: 721–727

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Chow NH et al. (2000) Papillary urothelial hyperplasia is a clonal precursor to papillary transitional cell bladder cancer. Int J Cancer 89: 514–518

    CAS  PubMed  Google Scholar 

  47. Habuchi T et al. (1998) Structure and methylation-based silencing of a gene (DBCCR1) within a candidate bladder cancer tumor suppressor region at 9q32-q33. Genomics 48: 277–288

    CAS  PubMed  Google Scholar 

  48. Nishiyama H et al. (2001) Negative regulation of G(1)/S transition by the candidate bladder tumour suppressor gene DBCCR1. Oncogene 20: 2956–2964

    CAS  PubMed  Google Scholar 

  49. Wright KO et al. (2004) DBCCR1 mediates death in cultured bladder tumor cells. Oncogene 23: 82–90

    CAS  PubMed  Google Scholar 

  50. Gonzalez-Zulueta M et al. (1995) Methylation of the 5' CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. Cancer Res 55: 4531–4535

    CAS  PubMed  Google Scholar 

  51. Jones PA and Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3: 415–428

    CAS  PubMed  Google Scholar 

  52. Salem C et al. (2000) Progressive increases in de novo methylation of CpG islands in bladder cancer. Cancer Res 60: 2473–2476

    CAS  PubMed  Google Scholar 

  53. Peterson EJ et al. (2003) p53-mediated repression of DNA methyltransferase 1 expression by specific DNA binding. Cancer Res 63: 6579–6582

    CAS  PubMed  Google Scholar 

  54. McCabe MT et al. (2005) Regulation of DNA methyltransferase 1 by the pRb/E2F1 pathway. Cancer Res 65: 3624–3632

    CAS  PubMed  Google Scholar 

  55. Ordway JM et al. (2004) Transcription repression in oncogenic transformation: common targets of epigenetic repression in cells transformed by Fos, Ras or Dnmt1. Oncogene 23: 3737–3748

    CAS  PubMed  Google Scholar 

  56. Nakagawa T et al. (2005) DNA hypomethylation on pericentromeric satellite regions significantly correlates with loss of heterozygosity on chromosome 9 in urothelial carcinomas. J Urol 173: 243–246

    CAS  PubMed  Google Scholar 

  57. Gonzalo S et al. (2005) Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nat Cell Biol 7: 420–428

    CAS  PubMed  Google Scholar 

  58. Kawamura K et al. (2004) Induction of centrosome amplification and chromosome instability in human bladder cancer cells by p53 mutation and cyclin E overexpression. Cancer Res 64: 4800–4809

    CAS  PubMed  Google Scholar 

  59. van Tilborg AA et al. (2000) Molecular evolution of multiple recurrent cancers of the bladder. Hum Mol Genet 9: 2973–2980

    CAS  PubMed  Google Scholar 

  60. Hopman AH et al. (2002) Identification of chromosome 9 alterations and p53 accumulation in isolated carcinoma in situ of the urinary bladder versus carcinoma in situ associated with carcinoma. Am J Pathol 161: 1119–1125

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Stoehr R et al. (2004) Deletions of chromosome 8p and loss of sFRP1 expression are progression markers of papillary bladder cancer. Lab Invest 84: 465–478

    CAS  PubMed  Google Scholar 

  62. Dyrskjot L et al. (2004) Gene expression in the urinary bladder: a common carcinoma in situ gene expression signature exists disregarding histopathological classification. Cancer Res 64: 4040–4048

    CAS  PubMed  Google Scholar 

  63. Dyrskjot L et al. (2003) Identifying distinct classes of bladder carcinoma using microarrays. Nat Genet 33: 90–96

    CAS  PubMed  Google Scholar 

  64. Knowles MA (1999) The genetics of transitional cell carcinoma: progress and potential clinical application. BJU Int 84: 412–427

    CAS  PubMed  Google Scholar 

  65. Bartkova J et al. (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434: 864–87055

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Funding support from National Cancer Institute grants 1PO1 CA 86871-01A2 and ROI CA 83867.

Author information

Authors and Affiliations

  1. Department of Biochemistry,

    Erika M Wolff, Gangning Liang & Peter A Jones

  2. Department of Urology, at the University of Southern California, Los Angeles, CA, USA

    Erika M Wolff, Gangning Liang & Peter A Jones

  3. Professor in the Department of Urology at the University of Southern California and Director of the Norris Comprehensive Cancer Center and Hospital, CA, USA

    Gangning Liang

Authors
  1. Erika M Wolff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gangning Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter A Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter A Jones.

Ethics declarations

Competing interests

Peter A Jones is a shareholder and consultant for Epigenomics AG, Seattle, USA.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wolff, E., Liang, G. & Jones, P. Mechanisms of Disease: genetic and epigenetic alterations that drive bladder cancer. Nat Rev Urol 2, 502–510 (2005). https://doi.org/10.1038/ncpuro0318

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpuro0318

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing