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:

Molecular biomarkers for urothelial carcinoma of the bladder: challenges in clinical use

Nature Clinical Practice Urology volume 5, pages 676–685 (2008)Cite this article

Abstract

Conventional clinical and pathological parameters are limited in their capacity to detect patients with urothelial carcinoma of the bladder (UCB) who are at high risk for recurrence or mortality. The assessment of molecular biomarkers in surgical UCB specimens offers additional information on the biology of the disease, and might improve the prediction of oncologic end points. A wide range of candidate biomarkers, including key cell-cycle regulators, apoptotic markers and specific growth factors, have been reported to be of prognostic value. To date, however, no molecular biomarker for UCB has been introduced into clinical practice, mainly owing to insufficient validation and the absence of prospective studies. Knowledge about the value of molecular biomarkers in predicting the response to adjuvant or neoadjuvant therapies is also lacking. Prospective trials need to be initiated in high-risk patients selected on the basis of the expression patterns of molecular biomarkers that have already passed the initial steps towards clinical utility.

Key Points

  • Conventional clinical and pathological parameters are limited in their capacity to detect patients with urothelial

  • carcinoma of the bladder (UCB) at high risk for recurrence and disease-specific mortality

  • Molecular biomarkers assessed in cystectomy specimens offer additional information on the biology of UCB, and might improve the prediction of oncologic end points

  • A wide range of candidate biomarkers for UCB have been reported to provide independent prognostic value, but no marker has been introduced into clinical practice

  • Additionally, molecular biomarkers might have a role in predicting the response to adjuvant or neoadjuvant therapies

  • Prospective trials need to be initiated in high-risk patients selected on the basis of expression patterns of promising molecular biomarkers

  • Such trials should aim to determine whether adjuvant chemotherapy improves metastasis-free survival in patients at high risk for UCB recurrence, and to test whether molecular biomarker status in patients undergoing radical cystectomy predicts likelihood of UCB recurrence and survival

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: Important genetic and epigenetic defects that characterize the divergent pathways of urothelial tumorigenesis.

Similar content being viewed by others

Article 26 October 2023

Lars Dyrskjøt, Donna E. Hansel, … Dan Theodorescu

References

  1. Jemal A et al. (2008) Cancer statistics, 2008. CA Cancer J Clin 58: 71–96

    Article  PubMed  Google Scholar 

  2. Sylvester RJ et al. (2006) Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2,596 patients from seven EORTC trials. Eur Urol 49: 466–475

    Article  PubMed  Google Scholar 

  3. Shariat SF et al. (2006) Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the Bladder Cancer Research Consortium. J Urol 176: 2414–2422

    Article  PubMed  Google Scholar 

  4. Stein JP et al. (2001) Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 19: 666–675

    Article  CAS  PubMed  Google Scholar 

  5. Bochner BH et al. (2006) Postoperative nomogram predicting risk of recurrence after radical cystectomy for bladder cancer. J Clin Oncol 24: 3967–3972

    Article  PubMed  Google Scholar 

  6. Karakiewicz PI et al. (2006) Nomogram for predicting disease recurrence after radical cystectomy for transitional cell carcinoma of the bladder. J Urol 176: 1354–1361

    Article  PubMed  Google Scholar 

  7. Shariat SF et al. (2006) Nomograms provide improved accuracy for predicting survival after radical cystectomy. Clin Cancer Res 12: 6663–6676

    Article  PubMed  Google Scholar 

  8. Freiha F et al. (1996) A randomized trial of radical cystectomy versus radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer. J Urol 155: 495–499

    Article  CAS  PubMed  Google Scholar 

  9. Lehmann J et al. (2006) Complete long-term survival data from a trial of adjuvant chemotherapy vs control after radical cystectomy for locally advanced bladder cancer. BJU Int 97: 42–47

    Article  PubMed  Google Scholar 

  10. Skinner DG et al. (1991) The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. J Urol 145: 459–464

    Article  CAS  PubMed  Google Scholar 

  11. Stöckle M et al. (1992) Advanced bladder cancer (stages pT3b, pT4a, pN1 and pN2): improved survival after radical cystectomy and 3 adjuvant cycles of chemotherapy. Results of a controlled prospective study. J Urol 148: 302–306

    Article  PubMed  Google Scholar 

  12. Ilyin SE et al. (2004) Biomarker discovery and validation: technologies and integrative approaches. Trends Biotechnol 22: 411–416

    Article  CAS  PubMed  Google Scholar 

  13. Egawa S and Kuruma H (2006) Search for biomarkers of aggressiveness in bladder cancer. Eur Urol 50: 20–22

    Article  CAS  PubMed  Google Scholar 

  14. Karam JA et al. (2007) Use of combined apoptosis biomarkers for prediction of bladder cancer recurrence and mortality after radical cystectomy. Lancet Oncol 8: 128–136

    Article  CAS  PubMed  Google Scholar 

  15. Shariat SF et al. (2007) Predictive value of cell cycle biomarkers in nonmuscle invasive bladder transitional cell carcinoma. J Urol 177: 481–487

    Article  PubMed  Google Scholar 

  16. Shariat SF et al. (2008) Multiple biomarkers improve prediction of bladder cancer recurrence and mortality in patients undergoing cystectomy. Cancer 112: 315–325

    Article  PubMed  Google Scholar 

  17. Shariat SF et al. (2004) p53, p21, pRB, and p16 expression predict clinical outcome in cystectomy with bladder cancer. J Clin Oncol 22: 1014–1024

    Article  CAS  PubMed  Google Scholar 

  18. Shariat SF et al. (2007) Cooperative effect of cell-cycle regulators expression on bladder cancer development and biologic aggressiveness. Mod Pathol 20: 445–459

    Article  CAS  PubMed  Google Scholar 

  19. Wu XR (2005) Urothelial tumorigenesis: a tale of divergent pathways. Nat Rev Cancer 5: 713–725

    Article  CAS  PubMed  Google Scholar 

  20. Kim WJ and Bae SC (2008) Molecular biomarkers in urothelial bladder cancer. Cancer Sci 99: 646–652

    Article  CAS  PubMed  Google Scholar 

  21. Schulz WA (2006) Understanding urothelial carcinoma through cancer pathways. Int J Cancer 119: 1513–1518

    Article  CAS  PubMed  Google Scholar 

  22. Chatterjee et al. (2004) Combined effects of p53, p21, and pRb expression in the progression of bladder transitional cell carcinoma. J Clin Oncol 22: 1007–1013

    Article  CAS  PubMed  Google Scholar 

  23. Cote RJ et al. (1997) p53 and treatment of bladder cancer. Nature 385: 123–125

    Article  CAS  PubMed  Google Scholar 

  24. Esrig D et al. (1993) p53 nuclear protein accumulation correlates with mutations in the p53 gene, tumor grade, and stage in bladder cancer. Am J Pathol 143: 1389–1397

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Grossman HB et al. (1998) p53 and RB expression predict progression in T1 bladder cancer. Clin Cancer Res 4: 829–834

    CAS  PubMed  Google Scholar 

  26. Malats N et al. (2005) P53 as a prognostic marker for bladder cancer: a meta-analysis and review. Lancet Oncol 6: 678–686

    Article  CAS  PubMed  Google Scholar 

  27. George B et al. (2007) p53 gene and protein status: the role of p53 alterations in predicting outcome in patients with bladder cancer. J Clin Oncol 25: 5352–5358

    Article  CAS  PubMed  Google Scholar 

  28. Mitra AP et al. (2006) Molecular pathways in invasive bladder cancer: new insights into mechanisms, progression, and target identification. J Clin Oncol 24: 5552–5564

    Article  CAS  PubMed  Google Scholar 

  29. Benedict WF et al. (1999) Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer. Oncogene 18: 1197–1203

    Article  CAS  PubMed  Google Scholar 

  30. Cordon-Cardo C et al. (1992) Altered expression of the retinoblastoma gene product: prognostic indicator in bladder cancer. J Natl Cancer Inst 84: 1251–1256

    Article  CAS  PubMed  Google Scholar 

  31. 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 

  32. Esrig D et al. (1994) Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 331: 1259–1264

    Article  CAS  PubMed  Google Scholar 

  33. Sarkis AS et al. (1993) Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression. J Natl Cancer Inst 85: 53–59

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Margulis V et al. (2006) Ki-67 is an independent predictor of bladder cancer outcome in patients treated with radical cystectomy for organ-confined disease. Clin Cancer Res 12: 7369–7373

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lipponen P and Eskelinen M (1994) Expression of epidermal growth factor receptor in bladder cancer as related to established prognostic factors, oncoprotein (c-erbB-2, p53) expression and long-term prognosis. Br J Cancer 69: 1120–1125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mhawech-Fauceglia P et al. (2007) Predicting outcome in minimally invasive (T1a and T1b) urothelial bladder carcinoma using a panel of biomarkers: a high throughput tissue microarray analysis. BJU Int 100: 1182–1187

    PubMed  Google Scholar 

  39. Yamana K et al. (2005) Prognostic impact of FAS/CD95/APO-1 in urothelial cancers: decreased expression of Fas is associated with disease progression. Br J Cancer 93: 544–551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Akhtar M et al. (2006) Survivin: role in diagnosis, prognosis, and treatment of bladder cancer. Adv Anat Pathol 13: 122–126

    Article  CAS  PubMed  Google Scholar 

  41. Shariat SF et al. (2007) Survivin expression is associated with bladder cancer presence, stage, progression, and mortality. Cancer 109: 1106–1113

    Article  CAS  PubMed  Google Scholar 

  42. Crew JP et al. (1997) Vascular endothelial growth factor is a predictor of relapse and stage progression in superficial bladder cancer. Cancer Res 57: 5281–5285

    CAS  PubMed  Google Scholar 

  43. Elkin M et al. (1999) Inhibition of bladder carcinoma angiogenesis, stromal support, and tumor growth by halofuginone. Cancer Res 59: 4111–4118

    CAS  PubMed  Google Scholar 

  44. Papathoma AS et al. (2000) Prognostic significance of matrix metalloproteinases 2 and 9 in bladder cancer. Anticancer Res 20: 2009–2013

    CAS  PubMed  Google Scholar 

  45. Bochner BH et al. (1995) Angiogenesis in bladder cancer: relationship between microvessel density and tumor prognosis. J Natl Cancer Inst 87: 1603–1612

    Article  CAS  PubMed  Google Scholar 

  46. Fernandez MI et al. (2008) Prognostic implications of lymphangiogenesis in muscle-invasive transitional cell carcinoma of the bladder. Eur Urol 53: 571–578

    Article  PubMed  Google Scholar 

  47. Harrell FE et al. (1982) Evaluating the yield of medical tests. JAMA 247: 2543–2546

    Article  PubMed  Google Scholar 

  48. Harrell FE et al. (1996) Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med 15: 361–387

    Article  PubMed  Google Scholar 

  49. Bensalah K et al. (2007) Challenges of cancer biomarker profiling. Eur Urol 52: 1601–1609

    Article  PubMed  Google Scholar 

  50. Lamy A et al. (2006) Molecular profiling of bladder tumors based on the detection of FGFR3 and TP53 mutations. J Urol 176: 2686–2689

    Article  CAS  PubMed  Google Scholar 

  51. Yurakh AO et al. (2006) Molecular and immunohistochemical analysis of the prognostic value of cell-cycle regulators in urothelial neoplasms of the bladder. Eur Urol 50: 506–515

    Article  CAS  PubMed  Google Scholar 

  52. Shariat SF et al. (2000) Prognostic value of P53 nuclear accumulation and histopathologic features in T1 transitional cell carcinoma of the urinary bladder. Urology 56: 735–740

    Article  CAS  PubMed  Google Scholar 

  53. Fleshner N et al. (2000) p53 nuclear accumulation is not associated with decreased disease-free survival in patients with node positive transitional cell carcinoma of the bladder. J Urol 164: 1177–1182

    Article  CAS  PubMed  Google Scholar 

  54. Frank I et al. (2004) Prognostic value of p53 and MIB-1 in transitional cell carcinoma of the urinary bladder with regional lymph node involvement. Cancer 101: 1803–1808

    Article  PubMed  Google Scholar 

  55. Dalbagni G et al. (2007) Prospective evaluation of p53 as a prognostic marker in T1 transitional cell carcinoma of the bladder. BJU Int 99: 281–285

    Article  CAS  PubMed  Google Scholar 

  56. Lopez-Knowles E et al. (2006) The p53 pathway and outcome among patients with T1G3 bladder tumors. Clin Cancer Res 12: 6029–6036

    Article  CAS  PubMed  Google Scholar 

  57. Moonen PM et al. (2007) Prognostic value of p53 for high risk superficial bladder cancer with long-term followup. J Urol 177: 80–83

    Article  CAS  PubMed  Google Scholar 

  58. Hernandez S et al. (2005) FGFR3 and Tp53 mutations in T1G3 transitional bladder carcinomas: independent distribution and lack of association with prognosis. Clin Cancer Res 11: 5444–5450

    Article  CAS  PubMed  Google Scholar 

  59. Lerner SP (2005) Bladder cancer clinical trials. Urol Oncol 23: 275–279

    Article  PubMed  Google Scholar 

  60. p53 Targeted-Therapy Trial in Bladder Cancer [https://www.uscnorris.com/p53/]

  61. Lopez-Beltran A et al. (2006) Cyclin D3 expression in primary Ta/T1 bladder cancer. J Pathol 209: 106–113

    Article  CAS  PubMed  Google Scholar 

  62. Shariat SF et al. (2007) Association of cyclin D1 and E1 expression with disease progression and biomarkers in patients with nonmuscle-invasive urothelial cell carcinoma of the bladder. Urol Oncol 25: 468–475

    Article  CAS  PubMed  Google Scholar 

  63. Grossfeld GD et al. (1997) Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression. J Natl Cancer Inst 89: 219–227

    Article  CAS  PubMed  Google Scholar 

  64. Cordon-Cardo C et al. (1997) Cooperative effects of p53 and pRB alterations in primary superficial bladder tumors. Cancer Res 57: 1217–1221

    CAS  PubMed  Google Scholar 

  65. Shariat SF et al. (2003) Association of p53 and p21 expression with clinical outcome in patients with carcinoma in situ of the urinary bladder. Urology 61: 1140–1145

    Article  PubMed  Google Scholar 

  66. Shariat SF et al. (2006) Correlation of cyclin D1 and E1 expression with bladder cancer presence, invasion, progression, and metastasis. Hum Pathol 37: 1568–1576

    Article  CAS  PubMed  Google Scholar 

  67. Shariat SF et al. (2005) Nomograms including nuclear matrix protein 22 for prediction of disease recurrence and progression in patients with Ta, T1 or CIS transitional cell carcinoma of the bladder. J Urol 173: 1518–1525

    Article  CAS  PubMed  Google Scholar 

  68. Catto JW et al. (2003) Artificial intelligence in predicting bladder cancer outcome: a comparison of neuro-fuzzy modeling and artificial neural networks. Clin Cancer Res 9: 4172–4177

    PubMed  Google Scholar 

  69. Qureshi KN et al. (2000) Neural network analysis of clinicopathological and molecular markers in bladder cancer. J Urol 163: 630–633

    Article  CAS  PubMed  Google Scholar 

  70. Shariat SF et al. (2008) Combination of cell cycle regulating bio-markers improves prognosis in patients with organ confined urothelial cancer at radical cystectomy [abstract #1690]. J Urol 179 (4 Suppl): 578

    Article  Google Scholar 

  71. Grossman HB et al. (2006) Evaluation of Ki67, p53 and angiogenesis in patients enrolled in a randomized study of neoadjuvant chemotherapy with or without cystectomy: a Southwest Oncology Group Study. Oncol Rep 16: 807–810

    CAS  PubMed  Google Scholar 

  72. Therasse P et al. (2006) Clinical trials design and treatment tailoring: general principles applied to breast cancer research. Crit Rev Oncol Hematol 59: 98–105

    Article  CAS  PubMed  Google Scholar 

  73. Bellmunt J et al. (2008) Optimizing therapeutic strategies in advanced bladder cancer: Update on chemotherapy and the role of targeted agents. Crit Rev Oncol Hematol [10.1016/j.critrevonc.2008.06.002]

  74. Als AB et al. (2007) Emmprin and survivin predict response and survival following cisplatin-containing chemotherapy in patients with advanced bladder cancer. Clin Cancer Res 13: 4407–4414

    Article  CAS  PubMed  Google Scholar 

  75. Sternberg CN et al. (2001) Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol 19: 2638–2646

    Article  CAS  PubMed  Google Scholar 

  76. Escudier B et al. (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356: 125–134

    Article  CAS  PubMed  Google Scholar 

  77. Motzer RJ et al. (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356: 115–124

    Article  CAS  PubMed  Google Scholar 

  78. Mellon K et al. (1995) Long-term outcome related to epidermal growth factor receptor status in bladder cancer. J Urol 153: 919–925

    Article  CAS  PubMed  Google Scholar 

  79. Kassouf W et al. (2006) Schedule dependent efficacy of gefitinib and docetaxel for bladder cancer. J Urol 176: 787–792

    Article  CAS  PubMed  Google Scholar 

  80. Philips GK et al. (2008) A phase II trial of cisplatin, fixed dose-rate gemcitabine and gefitinib for advanced urothelial tract carcinoma: results of the Cancer and Leukaemia Group B 90102. BJU Int 101: 20–25

    CAS  PubMed  Google Scholar 

  81. Gandour-Edwards R et al. (2002) Does HER2/neu expression provide prognostic information in patients with advanced urothelial carcinoma. Cancer 95: 1009–1015

    Article  CAS  PubMed  Google Scholar 

  82. Hussain MH et al. (2007) Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. J Clin Oncol 25: 2218–2224

    Article  CAS  PubMed  Google Scholar 

  83. Sonpavde G et al. (2008) Sunitinib malate is active against human urothelial carcinoma and enhances the activity of cisplatin in a preclinical model. Urol Oncol [10.1016/j.urolonc.2008.03.017]

  84. Bradley DA et al. (2007) Randomized, double-blind, placebo-controlled phase II trial of maintenance sunitinib versus placebo after chemotherapy for patients with advanced urothelial carcinoma: scientific rationale and study design. Clin Genitourin Cancer 5: 460–463

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. and a Research Fellow at the Department of Urology, C Bolenz is a Urology Resident at Mannheim Medical Center, University of Heidelberg, Mannheim, Germany, University of Texas Southwestern Medical Center,

    Christian Bolenz

  2. Y Lotan is an Associate Professor at the Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.,

    Yair Lotan

Authors
  1. Christian Bolenz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yair Lotan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yair Lotan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bolenz, C., Lotan, Y. Molecular biomarkers for urothelial carcinoma of the bladder: challenges in clinical use. Nat Rev Urol 5, 676–685 (2008). https://doi.org/10.1038/ncpuro1259

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpuro1259

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