Urologic Oncology: Seminars and Original Investigations
Volume 28, Issue 4 , Pages 409-428 , July 2010

Bladder cancer or bladder cancers? Genetically distinct malignant conditions of the urothelium

  • Peter J. Goebell, M.D.

      Affiliations

    • Department of Urology, University Clinic of Erlangen, Erlangen, Germany
    • Corresponding Author InformationCorresponding author. Tel.: +49-0-9131 822–3122; fax: +49-0-9131 822–3179
  • ,
  • Margaret A. Knowles, Ph.D.

      Affiliations

    • Section of Experimental Oncology, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, United Kingdom

References 

  1. Lopez-Beltran A. Bladder cancer: Clinical and pathological profile. Scand J Urol Nephrol. 2008;42(Suppl 218):95–109
  2. Knowles MA. Molecular subtypes of bladder cancer: Jekyll and Hyde or chalk and cheese?. Carcinogenesis. 2006;27:361–373
  3. Wu XR. Urothelial tumorigenesis: A tale of divergent pathways. Nat Rev Cancer. 2005;5:713–725
  4. Knowles MA. Bladder cancer subtypes defined by genomic alterations. Scand J Urol Nephrol. 2008;42(4):116–130
  5. Johnson DE, Williams LT. Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res. 1993;60:1–41
  6. Cappellen D, De Oliveira C, Ricol D, et al. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet. 1999;23:18–20
  7. Bakkar AA, Wallerand H, Radvanyi F, et al. FGFR3 and TP53 gene mutations define 2 distinct pathways in urothelial cell carcinoma of the bladder. Cancer Res. 2003;63:8108–8112
  8. Billerey C, Chopin D, Aubriot-Lorton MH, et al. Frequent FGFR3 mutations in papillary noninvasive bladder (pTa) tumors. Am J Pathol. 2001;158:1955–1959
  9. Hernandez S, Lopez-Knowles E, Lloreta J, et al. FGFR3 and Tp53 mutations in T1G3 transitional bladder carcinomas: Independent distribution and lack of association with prognosis. Clin Cancer Res. 2005;11:5444–5450
  10. Kimura T, Suzuki H, Ohashi T, et al. The incidence of thanatophoric dysplasia mutations in FGFR3 gene is higher in low-grade or superficial bladder carcinomas. Cancer. 2001;92:2555–2561
  11. Rieger-Christ KM, Mourtzinos A, Lee PJ, et al. Identification of fibroblast growth factor receptor 3 mutations in urine sediment DNA samples complements cytology in bladder tumor detection. Cancer. 2003;98:737–744
  12. Sibley K, Cuthbert-Heavens D, Knowles MA. Loss of heterozygosity at 4p16.3 and mutation of FGFR3 in transitional cell carcinoma. Oncogene. 2001;20:686–691
  13. van Rhijn BW, Lurkin I, Chopin DK, et al. Combined microsatellite and FGFR3 mutation analysis enables a highly sensitive detection of urothelial cell carcinoma in voided urine. Clin Cancer Res. 2003;9:257–263
  14. van Rhijn BW, Lurkin I, Radvanyi F, et al. The fibroblast growth factor receptor 3 (FGFR3) mutation is a strong indicator of superficial bladder cancer with low recurrence rate. Cancer Res. 2001;61:1265–1268
  15. van Rhijn BW, Montironi R, Zwarthoff EC, et al. Frequent FGFR3 mutations in urothelial papilloma. J Pathol. 2002;198:245–251
  16. van Rhijn BW, van Tilborg AA, Lurkin I, et al. Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders. Eur J Hum Genet. 2002;10:819–824
  17. van Rhijn BW, Vis AN, van der Kwast TH, et al. Molecular grading of urothelial cell carcinoma with fibroblast growth factor receptor 3 and MIB-1 is superior to pathologic grade for the prediction of clinical outcome. J Clin Oncol. 2003;21:1912–1921
  18. Wallerand H, Bakkar AA, de Medina SG, et al. Mutations in TP53, but not FGFR3, in urothelial cell carcinoma of the bladder are influenced by smoking: Contribution of exogenous versus endogenous carcinogens. Carcinogenesis. 2005;26:177–184
  19. Hernandez S, Lopez-Knowles E, Lloreta J, et al. Prospective study of FGFR3 mutations as a prognostic factor in non-muscle-invasive urothelial bladder carcinomas. J Clin Oncol. 2006;24:3664–3671
  20. Lamy A, Gobet F, Laurent M, et al. Molecular profiling of bladder tumors based on the detection of FGFR3 and TP53 mutations. J Urol. 2006;176:2686–2689
  21. Jebar AH, Hurst CD, Tomlinson DC, et al. FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma. Oncogene. 2005;24:5218–5225
  22. Lindgren D, Liedberg F, Andersson A, et al. Molecular characterization of early-stage bladder carcinomas by expression profiles, FGFR3 mutation status, and loss of 9q. Oncogene. 2006;25:2685–2696
  23. WHO. WHO classification tumors of the urinary system and male genital organs. Lyon: IARC Press; 2004;
  24. Tomlinson D, Baldo O, Knowles MA. FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J Pathol. 2007;213:91–98
  25. Matsumoto M, Ohtsuki Y, Ochii K, et al. Fibroblast growth factor receptor 3 protein expression in urothelial carcinoma of the urinary bladder, exhibiting no association with low-grade and/or noninvasive lesions. Oncol Rep. 2004;12:967–971
  26. Mhawech-Fauceglia P, Cheney RT, Fischer G, et al. FGFR3 and p53 protein expressions in patients with pTa and pT1 urothelial bladder cancer. Eur J Surg Oncol. 2006;32:231–237
  27. Gomez-Roman JJ, Saenz P, Molina M, et al. Fibroblast growth factor receptor 3 is overexpressed in urinary tract carcinomas and modulates the neoplastic cell growth. Clin Cancer Res. 2005;11:459–465
  28. Bernard-Pierrot I, Brams A, Dunois-Larde C, et al. Oncogenic properties of the mutated forms of fibroblast growth factor receptor 3b. Carcinogenesis. 2006;27:740–747
  29. Martinez-Torrecuadrada J, Cifuentes G, Lopez-Serra P, et al. Targeting the extracellular domain of fibroblast growth factor receptor 3 with human single-chain fv antibodies inhibits bladder carcinoma cell line proliferation. Clin Cancer Res. 2005;11:6280–6290
  30. Hart KC, Robertson SC, Kanemitsu MY, et al. Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4. Oncogene. 2000;19:3309–3320
  31. Lopez-Knowles E, Hernandez S, Malats N, et al. PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors. Cancer Res. 2006;66:7401–7404
  32. Platt FM, Hurst CD, Taylor CF, et al. Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. Clin Cancer Res. 2009;15:6008–6017
  33. Hurst CD, Zuiverloon TC, Hafner C, et al. A SNaPshot assay for the rapid and simple detection of 4 common hotspot codon mutations in the PIK3CA gene. BMC Research Notes. 2009;2:66
  34. Mozaffari M, Hoogeveen-Westerveld M, Kwiatkowski D, et al. Identification of a region required for TSC1 stability by functional analysis of TSC1 missense mutations found in individuals with tuberous sclerosis complex. BMC Medical Genetic. 2009;10:88
  35. Nellist M, van den Heuvel D, Schluep D, et al. Missense mutations to the TSC1 gene cause tuberous sclerosis complex. Eur J Human Genet. 2009;17:319–328
  36. Henske EP, Scheithauer BW, Short MP, et al. Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am J Human Genet. 1996;59:400–406
  37. Hornigold N, Devlin J, Davies AM, et al. Mutation of the 9q34 gene TSC1 in sporadic bladder cancer. Oncogene. 1999;18:2657–2661
  38. Adachi H, Igawa M, Shiina H, et al. Human bladder tumors with 2-hit mutations of tumor suppressor gene TSC1 and decreased expression of p27. J of Urol. 2003;170:601–604
  39. Cairns P, Shaw ME, Knowles MA. Initiation of bladder cancer may involve deletion of a tumor-suppressor gene on chromosome 9. Oncogene. 1993;8:1083–1085
  40. Habuchi T, Devlin J, Elder PA, et al. Detailed deletion mapping of chromosome 9q in bladder cancer: Evidence for 2 tumor suppressor loci. Oncogene. 1995;11:1671–1674
  41. Simoneau M, Aboulkassim TO, LaRue H, et al. Four tumor suppressor loci on chromosome 9q in bladder cancer: Evidence for 2 novel candidate regions at 9q22.3 and 9q31. Oncogene. 1999;18:157–163
  42. van Tilborg AA, Groenfeld LE, van der Kwast TH, et al. Evidence for 2 candidate tumor suppressor loci on chromosome 9q in transitional cell carcinoma (TCC) of the bladder but no homozygous deletions in bladder tumor cell lines. Br J Cancer. 1999;80:489–494
  43. Knowles MA, Habuchi T, Kennedy W, et al. Mutation spectrum of the 9q34 tuberous sclerosis gene TSC1 in transitional cell carcinoma of the bladder. Cancer Res. 2003;63:7652–7656
  44. Pymar LS, Platt FM, Askham JM, et al. Bladder tumor derived somatic TSC1 missense mutations cause loss of function via distinct mechanisms. Human Molecular Genetics. 2008;17:2006–2017
  45. Carpten JD, Faber AL, Horn C, et al. A transforming mutation in the Pleckstrin homology domain of AKT1 in cancer. Nature. 2007;448:439–444
  46. Askham JM, Platt F, Chambers PA, et al. AKT1 mutations in bladder cancer: Identification of a novel oncogenic mutation that can cooperate with E17K. Oncogene. 2010;29:150–155
  47. Hopman AH, Kamps MA, Speel EJ, et al. 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. 2002;161:1119–1125
  48. Hartmann A, Schlake G, Zaak D, et al. Occurrence of chromosome 9 and p53 alterations in multifocal dysplasia and carcinoma in situ of human urinary bladder. Cancer Res. 2002;62:809–818
  49. Rosin MP, Cairns P, Epstein JI, et al. Partial allelotype of carcinoma in situ of the human bladder. Cancer Res. 1995;55:5213–5216
  50. Spruck CH, Ohneseit PF, Gonzalez-Zulueta M, et al. Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res. 1994;54:784–788
  51. Junker K, van Oers JM, Zwarthoff EC, et al. Fibroblast growth factor receptor 3 mutations in bladder tumors correlate with low frequency of chromosome alterations. Neoplasia. 2008;10:1–7
  52. Dyrskjot L, Kruhoffer M, Thykjaer T, et al. Gene expression in the urinary bladder: A common carcinoma in situ gene expression signature exists disregarding histopathological classification. Cancer Res. 2004;64:4040–4048
  53. Dyrskjot L, Zieger K, Kruhoffer M, et al. A molecular signature in superficial bladder carcinoma predicts clinical outcome. Clin Cancer Res. 2005;11:4029–4036
  54. Dyrskjot L, Zieger K, Real FX, et al. Gene expression signatures predict outcome in non-muscle-invasive bladder carcinoma: A multicenter validation study. Clin Cancer Res. 2007;13:3545–3551
  55. Zieger K, Dyrskjøt L, Wiuf C, et al. Role of activating fibroblast growth factor receptor 3 mutations in the development of bladder tumors. Clin Cancer Res. 2005;11:7709–7719
  56. Zieger K, Marcussen N, Borre M, et al. Consistent genomic alterations in carcinoma in situ of the urinary bladder confirm the presence of 2 major pathways in bladder cancer development. Int J Cancer. 1. 2009;125:2095–2103
  57. Fujimoto K, Yamada Y, Okajima E, et al. Frequent association of p53 gene mutation in invasive bladder cancer. Cancer Res. 1992;52:1393–1398
  58. Uchida T, Wada C, Ishida H, et al. p53 mutations and prognosis in bladder tumors. J Urol. 1995;153:1097–1104
  59. Petitjean A, Achatz MIW, Borresen-Dale AL, et al. TP53 mutations in human cancers: Functional selection and impact on cancer prognosis and outcomes. Oncogene. 2007;26:2157–2165
  60. Soussi T, Beroud C. Assessing TP53 status in human tumors to evaluate clinical outcome. Nat Rev Cancer. 2001;1:233–240
  61. Olivier M, Eeles R, Hollstein M, et al. The IARC TP53 database: New online mutation analysis and recommendations to users. Hum Mutat. 2002;19:607–614
  62. Blandino G, Levine AJ, Oren M. Mutant p53 gain of function: Differential effects of different p53 mutants on resistance of cultured cells to chemotherapy. Oncogene. 1999;18:477–485
  63. Weisz L, Oren M, Rotter V. Transcription regulation by mutant p53. Oncogene. 2007;26:2202–2211
  64. Strano S, Dell'Orso S, Di Agostino S, et al. Mutant p53: An oncogenic transcription factor. Oncogene. 2007;26:2212–2219
  65. Soussi T. p53 alterations in human cancer: More questions than answers. Oncogene. 2007;26:2145–2156
  66. Malats N, Kogevinas M, Bustos A, et al. Bladder cancer and P53: An example of what should not be done in biomarker research. Int J Biol Markers. 2000;15:S30
  67. Schmitz-Dräger BJ, Goebell PJ, Ebert T, et al. P53 immunohistochemistry as a prognostic marker in bladder cancer: A new toy for urologic scientists?. Eur Urol. 2000;38:691–700
  68. Zlotta AR, Schulman CC. Biological markers in superficial bladder tumors and their prognostic significance. Urol Clin North Am. 2000;27:179–189
  69. Goebell PJ, Schmitz-Dräger BJ, Heydthausen M, et al. The International Study Initiative on Bladder Cancer (ISBC) A critical look at Antigen Retrieval and Choice of Antibodies for p53 Immunohistochemistry - Technical Aspects in the ISBC Combined Analysis. J Urol. 2002;167:453
  70. Dowell SP, Lane DP, Hall PA. The immunocytochemical detection of p53 protein in cytological specimens: Technical considerations. Cytopathology. 1994;5:76–81
  71. Malats N, Bustos A, Nascimento CM, et al. P53 as a prognostic marker for bladder cancer: A meta-analysis and review. Lancet Oncol. 2005;6:678–686
  72. Schmitz-Dräger BJ, Goebell PJ, Heydthausen M The International Study Initiative on Bladder Cancer (ISBC). P53 immunohistochemistry in bladder cancer (Combined analysis: A way to go?). Urol Oncol. 2000;5:204–215
  73. Goebell PJ, Groshen SG, Schmitz-Dräger BJ. P53 Immunohistochemistry in Bladder Cancer – a new approach to an old story. Urol Oncol. 2010;28:377–388
  74. Hall PA, Lane DP. p53 in tumor pathology: Can we trust immunohistochemistry?. Revisited! J Pathol. 1994;172:1–4
  75. George B, Datar RH, Wu L, et al. p53 gene and protein status: The role of p53 alterations in predicting outcome in patients with bladder cancer. J Clin Oncol. 2007;25:5352–5358
  76. Kelsey KT, Hirao T, Schned A, et al. A population-based study of Immunohistochemical detection of p53 alteration in bladder cancer. Br J Cancer. 2004;90:1572–1576
  77. Lopez-Knowles E, Hernandez S, Kogevinas M, et al. The p53 pathway and outcome among patients with T1G3 bladder tumors. Clin Cancer Res. 2006;12:6029–6036
  78. Simon R, Struckmann K, Schraml P, et al. Amplification pattern of 12q13 q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer. Oncogene. 2002;21:2476–2483
  79. Liang H, Atkins H, Abdel-Fattah R, et al. Genomic organization of the human MDM2 oncogene and relationship to its alternatively spliced mRNAs. Gene. 2004;338:217–223
  80. Schlott T, Quentin T, Korabiowska M, et al. Alteration of the MDM2-p73-P14ARF pathway related to tumor progression during urinary bladder carcinogenesis. Int J Mol Med. 2004;14:825–836
  81. Sanchez-Carbayo M, Socci ND, Kirchoff T, et al. A polymorphism in HDM2 (SNP309) associates with early onset in superficial tumors, TP53 mutations, and poor outcome in invasive bladder cancer. Clin Cancer Res. 2007;13:3215–3220
  82. Markl ID, Jones PA. Presence and location of TP53 mutation determines pattern of CDKN2A/ARF pathway inactivation in bladder cancer. Cancer Res. 1998;58:5348–5353
  83. Chang LL, Yeh WT, Yang SY, et al. Genetic alterations of p16INK4a and p14ARF genes in human bladder cancer. J Urol. 2003;170:595–600
  84. Berggren P, Kumar R, Sakano S, et al. Detecting homozygous deletions in the CDKN2A(p16(INK4a))/ARF(p14(ARF)) gene in urinary bladder cancer using real-time quantitative PCR. Clin Cancer Res. 2003;9:235–242
  85. Le Frère-Belda MA, Gil Diez de Medina S, Daher A, et al. Profiles of the 2 INK4a gene products, p16 and p14ARF, in human reference urothelium and bladder carcinomas, according to pRb and p53 protein status. Hum Pathol. 2004;35:817–824
  86. Kawamoto K, Enokida H, Gotanda T, et al. p16INK4a and p14ARF methylation as a potential biomarker for human bladder cancer. Biochem Biophys Res Commun. 2006;339:790–796
  87. Stein JP, Ginsberg DA, Grossfeld GD, et al. Effect of p21WAF1/CIP1 expression on tumor progression in bladder cancer. J Natl Cancer Inst. 1998;90:1072–1079
  88. Chatterjee SJ, Datar R, Youssefzadeh D, et al. Combined effects of p53, p21, and pRb expression in the progression of bladder transitional cell carcinoma. J Clin Oncol. 2004;22:1007–1013
  89. Shariat SF, Chade DC, Karakiewicz PI, et al. Combination of multiple molecular markers can improve prognostication in patients with locally advanced and lymph node positive bladder cancer. J Urol. 2010;183:68–75
  90. Cairns P, Proctor AJ, Knowles MA. Loss of heterozygosity at the RB locus is frequent and correlates with muscle invasion in bladder carcinoma. Oncogene. 1991;6:2305–2309
  91. Benedict WF, Lerner SP, Zhou J, et al. Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer. Oncogene. 1999;18:1197–1203
  92. Shariat SF, Tokunaga H, Zhou J. p53, p21, pRB, and p16 expression predict clinical outcome in cystectomy with bladder cancer. J Clin Oncol. 2004;22:1014–1024
  93. Cordon-Cardo C, Wartinger D, Petrylak D, et al. Altered expression of the retinoblastoma gene product: Prognostic indicator in bladder cancer. J Natl Cancer Inst. 1992;84:1251–1256
  94. Logothetis CJ, Xu H-J, Ro JY, et al. Altered expression of retinoblastoma protein and known prognostic variables in locally advanced bladder cancer. J Natl Cancer Inst. 1992;84:1256–1261
  95. Hurst CD, Tomlinson DC, Williams SV, et al. Inactivation of the Rb pathway and overexpression of both isoforms of E2F3 are obligate events in bladder tumors with 6p22 amplification. Oncogene. 2008;27:2716–2727
  96. Feber A, Clark J, Goodwin G, et al. Amplification and overexpression of E2F3 in human bladder cancer. Oncogene. 2004;23:1627–1630
  97. Oeggerli M, Tomovska S, Schraml P, et al. E2F3 amplification and overexpression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer. Oncogene. 2004;23:5616–5623
  98. Steinthorsdottir V, Thorleifsson G, Reynisdottir I, et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet. 2007;39:770–775
  99. Oeggerli M, Schraml P, Ruiz C, et al. E2F3 is the main target gene of the 6p22 amplicon with high specificity for human bladder cancer. Oncogene. 2006;25:6538–6543
  100. Olsson AY, Feber A, Edwards S, et al. Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells. Oncogene. 2007;26:1028–1037
  101. Xu HJ, Cairns P, Hu SX, et al. Loss of RB protein expression in primary bladder cancer correlates with loss of heterozygosity at the RB locus and tumor progression. Int J Cancer. 1993;53:781–784
  102. Adams J, Williams SV, Aveyard JS, et al. Loss of heterozygosity analysis and DNA copy number measurement on 8p in bladder cancer reveals 2 mechanisms of allelic loss. Cancer Res. 2005;65:66–75
  103. Choi C, Kim MH, Juhng SW, et al. Loss of heterozygosity at chromosome segments 8p22 and 8p11.2 21.1 in transitional-cell carcinoma of the urinary bladder. Int J Cancer. 2000;86:501–505
  104. Stoehr R, Wissmann C, Suzuki H, et al. Deletions of chromosome 8p and loss of sFRP1 expression are progression markers of papillary bladder cancer. Lab Invest. 2004;16:465–478
  105. Takle LA, Knowles MA. Deletion mapping implicates 2 tumor suppressor genes on chromosome 8p in the development of bladder cancer. Oncogene. 1996;12:1083–1087
  106. Thompson TE, Rogan PK, Risinger JI, et al. Splice variants but not mutations of DNA polymerase beta are common in bladder cancer. Cancer Res. 2002;62:3251–3256
  107. Adams J, Cuthbert-Heavens D, Bass S, et al. Infrequent mutation of TRAIL receptor 2 (TRAIL-R2/DR5) in transitional cell carcinoma of the bladder with 8p21 loss of heterozygosity. Cancer Lett. 2005;220:137–144
  108. Eydmann ME, Knowles MA. Mutation analysis of 8p genes POLB and PPP2CB in bladder cancer. Cancer Genet Cytogenet. 1997;93:167–171
  109. Knowles MA, Aveyard JS, Taylor CF, et al. Mutation analysis of the 8p candidate tumor suppressor genes DBC2 (RHOBTB2) and LZTS1 in bladder cancer. Cancer Lett. 2005;225:121–130
  110. Blaveri E, Brewer JL, Roydasgupta R, et al. Bladder cancer stage and outcome by array-based comparative genomic hybridization. Clin Cancer Res. 2005;11:7012–7022
  111. Richter J, Beffa L, Wagner U, et al. Patterns of chromosomal imbalances in advanced urinary bladder cancer detected by comparative genomic hybridization. Am J Pathol. 1998;153:1615–1621
  112. Aveyard JS, Skilleter A, Habuchi T, et al. Somatic mutation of PTEN in bladder carcinoma. Br J Cancer. 1999;80:904–908
  113. Cappellen D, Gil Diez de Medina S, Chopin D, et al. Frequent loss of heterozygosity on chromosome 10q in muscle-invasive transitional cell carcinomas of the bladder. Oncogene. 1997;14:3059–3066
  114. Kagan J, Liu J, Stein JD, et al. Cluster of allele losses within a 2.5 cM region of chromosome 10 in high-grade invasive bladder cancer. Oncogene. 1998;16:909–913
  115. Wang DS, Rieger-Christ K, Latini JM, et al. Molecular analysis of PTEN and MXI1 in primary bladder carcinoma. Int J Cancer. 2000;88:620–625
  116. Liu J, Babaian DC, Liebert M, et al. Inactivation of MMAC1 in bladder transitional-cell carcinoma cell lines and specimens. Mol Carcinog. 2000;29:143–150
  117. Kwabi-Addo B, Giri D, Schmidt K, et al. Haploinsufficiency of the PTEN tumor suppressor gene promotes prostate cancer progression. Proc Natl Acad Sci U S A. 2001;98:11563–11568
  118. Kwon CH, Zhao D, Chen J, et al. PTEN haploinsufficiency accelerates formation of high-grade astrocytomas. Cancer Res. 2008;68:3286–3294
  119. Gildea JJ, Herlevsen M, Harding MA, et al. PTEN can inhibit in vitro organotypic and in vivo orthotopic invasion of human bladder cancer cells even in the absence of its lipid phosphatide activity. Oncogene. 2004;23:6788–6797
  120. Tsuruta H, Kishimoto H, Sasaki T, et al. Hyperplasia and carcinomas in PTEN-deficient mice and reduced PTEN protein in human bladder cancer patients. Cancer Res. 2006;66:8389–8396
  121. Coombs LM, Pigott DA, Sweeney E, et al. Amplification and over-expression of c-erbB-2 in transitional cell carcinoma of the urinary bladder. Br J Cancer. 1991;63:601–608
  122. Lonn U, Lonn S, Friberg S, et al. Prognostic value of amplification of c-erb-B2 in bladder carcinoma. Clin Cancer Res. 1995;1:1189–1194
  123. Miyamoto H, Kubota Y, Noguchi S, et al. C-ERBB-2 gene amplification as a prognostic marker in human bladder cancer. Urology. 2000;55:679–683
  124. Sauter G, Moch H, Moore D, et al. Heterogeneity of erbB-2 gene amplification in bladder cancer. Cancer Res. 1993;53:2199–2203
  125. Simon R, Atefy R, Wagner U, et al. HER-2 and TOP2A coamplification in urinary bladder cancer. Int J Cancer. 2003;107:764–772
  126. Hovey RM, Chu L, Balazs M, et al. Genetic alterations in primary bladder cancers and their metastases. Cancer Res. 1998;58:3555–3560
  127. Simon R, Burger H, Semjonow A, et al. Patterns of chromosomal imbalances in muscle invasive bladder cancer. Int J Oncol. 2000;17:1025–1029
  128. Veltman JA, Fridlyand J, Pejavar S, et al. Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors. Cancer Res. 2003;63:2872–2880
  129. Simon R, Eltze E, Schafer KL, et al. Cytogenetic analysis of multifocal bladder cancer supports a monoclonal origin and intraepithelial spread of tumor cells. Cancer Res. 2001;61:355–362
  130. Blaveri E, Simko JP, Korkola JE, et al. Bladder cancer outcome and subtype classification by gene expression. Clin Cancer Res. 2005;11:4044–4055
  131. Schaffer AA, Simon R, Desper R, et al. Tree models for dependent copy number changes in bladder cancer. Int J Oncol. 2001;18:349–354
  132. Kulkarni GS, Hakenberg OW, Gschwend JE, et al. An updated critical analysis of the treatment strategy for newly diagnosed high-grade T1 (previously T1G3) bladder cancer. Eur Urol. 2010;57:60–70
  133. Fritsche HM, Burger M, Svatek RS, et al. Characteristics and outcomes of patients with clinical T1 grade 3 urothelial carcinoma treated with radical cystectomy: Results from an international cohort. Eur Urol. 2010;57:300–309
  134. Inci K, Guliyev F, Bilen CY, et al. Incidental diagnosis of transitional cell carcinoma during percutaneous nephrolithotomy. Urol Int. 2009;83:291–294
  135. Emiliozzi P, Pansadoro A, Pansadoro V. The optimal management of T1G3 bladder cancer. BJU Int. 2008;102:1265–1273
  136. Soloway MS, Lee CT, Steinberg GD, et al. Difficult decisions in urologic oncology: Management of high-grade T1 transitional cell carcinoma of the bladder. Urol Oncol. 2007;25:338–340
  137. Metwalli AR, Kamat AM. Controversial issues and optimal management of stage T1G3 bladder cancer. Expert Rev Anticancer Ther. 2006;6:1283–1294
  138. Witjes JA. Management of the first recurrence of T1G3 bladder cancer: Does intravesical chemotherapy deserve a chance?. Urol Oncol. 2009;27:322–324
  139. Halachmi S, Moskovitz B, Maffezzini M, et al. Intravesical mitomycin c combined with hyperthermia for patients with T1G3 transitional cell carcinoma of the bladder. Urol Oncol. 2009;322–324Epub ahead of print
  140. Kulkarni GS, Alibhai SM, Finelli A, et al. Cost-effectiveness analysis of immediate radical cystectomy versus intravesical bacillus Calmette-Guerin therapy for high-risk, high-grade (T1G3) bladder cancer. Cancer. 2009;115:5450–5459
  141. Herr HW. High-risk, high-grade (T1G3) bladder cancer: Models versus reality. Cancer. 2009;115:5366–5367
  142. Park J, Song C, Hong JH, et al. Prognostic significance of nonpapillary tumor morphology as a predictor of cancer progression and survival in patients with primary T1G3 bladder cancer. World J Urol. 2009;27:277–283
  143. Thalmann G. Organ preservation for T1G3 bladder cancer: Is it feasible?. Eur Urol. 2008;53:27–29
  144. Queipo-Zaragoza JA, Ruiz-Cerda JL, Vera-Donoso CD, et al. Prognostic value of p53, Ki-67, microstaging and microvessel density in pT1G3 bladder tumors: Creation of risk groups for progression. Scand J Urol Nephrol. 2007;41:283–289
  145. Serretta V, Morgia G, Altieri V, et al.; members of Gruppo Studi Tumori Urologici (GSTU) Foundation (2010). A 1-year maintenance after early adjuvant intravesical chemotherapy has a limited efficacy in preventing recurrence of intermediate risk non-muscle-invasive bladder cancer. BJU Int (in press).
  146. Dalbagni G, Vora K, Kaag M, et al. Clinical Outcome in a Contemporary Series of Restaged Patients with Clinical T1 Bladder Cancer. Eur Urol. 2009;56:903–910
  147. Richter J, Wagner U, Schraml P, et al. Chromosomal imbalances are associated with a high risk of progression in early invasive (pT1) urinary bladder cancer. Cancer Res. 1999;59:5687–5691
  148. van Tilborg AA, de Vries A, de Bont M, et al. Molecular evolution of multiple recurrent cancers of the bladder. Hum Mol Genet. 2000;9:2973–2980
  149. van Rhijn BW, van der Kwast TH, Vis AN, et al. FGFR3 and P53 characterize alternative genetic pathways in the pathogenesis of urothelial cell carcinoma. Cancer Res. 2004;64:1911–1914
  150. Richter J, Jiang F, Gorog JP, et al. Marked genetic differences between stage pTa and stage pT1 papillary bladder cancer detected by comparative genomic hybridization. Cancer Res. 1997;57:2860–2864
  151. Linnenbach AJ, Pressler LB, Seng BA, et al. Characterization of chromosome 9 deletions in transitional cell carcinoma by microsatellite assay. Hum Mol Genet. 1993;2:1407–1411
  152. Tsai YC, Nichols PW, Hiti AL, et al. Allelic losses of chromosomes 9, 11, and 17 in human bladder cancer. Cancer Res. 1990;50:44–47
  153. Fadl-Elmula I, Gorunova L, Mandahl N, et al. Karyotypic characterization of urinary bladder transitional cell carcinomas. Genes Chromosomes Cancer. 2000;29:256–265
  154. Gibas Z, Prout GR, Connolly JG, et al. Nonrandom chromosomal changes in transitional cell carcinoma of the bladder. Cancer Res. 1984;44:1257–1264
  155. Cairns P, Mao L, Merlo A, et al. Rates of p16 (MTS1) mutations in primary tumors with 9p loss. Science. 1994;265:415–417
  156. Devlin J, Keen AJ, Knowles MA. Homozygous deletion mapping at 9p21 in bladder carcinoma defines a critical region within 2cM of IFN-A. Oncogene. 1994;9:2757–2760
  157. Orlow I, Lacombe L, Hannon GJ, et al. Deletion of the p16 and p15 genes in human bladder tumors. J Natl Cancer Inst. 1995;87:1524–1529
  158. Williamson MP, Elder PA, Shaw ME, et al. p16 (CDKN2) is a major deletion target at 9p21 in bladder cancer. Hum Mol Genet. 1995;4:1569–1577
  159. Chapman EJ, Harnden P, Chambers P, et al. 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;11:5740–5747
  160. Bartoletti R, Cai T, Nesi G, et al. Loss of P16 expression and chromosome 9p21 LOH in predicting outcome of patients affected by superficial bladder cancer. J Surg Res. 2007;143:422–427
  161. Berggren de Verdier PJ, Kumar R, Adolfsson J, et al. Prognostic significance of homozygous deletions and multiple duplications at the CDKN2A (p16INK4a)/ARF (p14ARF) locus in urinary bladder cancer. Scand J Urol Nephrol. 2006;40:363–369
  162. Aboulkassim TO, LaRue H, Lemieux P, et al. Alteration of the PATCHED locus in superficial bladder cancer. Oncogene. 2003;22:2967–2971
  163. McGarvey TW, Maruta Y, Tomaszewski JE, et al. PTCH gene mutations in invasive transitional cell carcinoma of the bladder. Oncogene. 1998;17:1167–1172
  164. Habuchi T, Luscombe M, Elder PA, et al. Structure and methylation-based silencing of a gene (DBCCR1) within a candidate bladder cancer tumor suppressor region at 9q32 q33. Genomics. 1998;48:277–288
  165. Nishiyama H, Hornigold N, Davies A, et al. A sequence-ready 840-kb PAC contig spanning the candidate tumor suppressor locus DBC1 on human chromosome 9q32 q33. Genomics. 1999;59:335–338
  166. Stadler WM, Steinberg G, Yang X, et al. Alterations of the 9p21 and 9q33 chromosomal bands in clinical bladder cancer specimens by fluorescence in situ hybridization. Clin Cancer Res. 2001;7:1676–1682
  167. Habuchi T, Yoshida O, Knowles MA. A novel candidate tumor suppressor locus at 9q32 33 in bladder cancer: Localization of the candidate region within a single 840kb YAC. Hum Mol Genet. 1997;6:913–919
  168. Nishiyama H, Takahashi T, Kakehi Y, et al. Homozygous deletion at the 9q32 33 candidate tumor suppressor locus in primary human bladder cancer. Genes Chromosomes Cancer. 1999;26:171–175
  169. Fujiwara H, Emi M, Nagai H, et al. Definition of a 1-Mb homozygous deletion at 9q32 q33 in a human bladder-cancer cell line. J Hum Genet. 2001;46:372–377
  170. Habuchi T, Takahashi T, Kakinuma H, et al. Hypermethylation at 9q32 33 tumor suppressor region is age-related in normal urothelium and an early and frequent alteration in bladder cancer. Oncogene. 2001;20:531–537
  171. Salem C, Liang G, Tsai YC, et al. Progressive increases in de novo Methylation of CpG islands in bladder cancer. Cancer Res. 2000;60:2473–2476
  172. Nishiyama H, Gill JH, Pitt E, et al. Negative regulation of G(1)/S transition by the candidate bladder tumor suppressor gene DBCCR1. Oncogene. 2001;20:2956–2964
  173. Hirao S, Hirao T, Marsit CJ, et al. Loss of heterozygosity on chromosome 9q and p53 alterations in human bladder cancer. Cancer. 2005;104:1918–1923
  174. Simoneau M, LaRue H, Aboulkassim TO, et al. Chromosome 9 deletions and recurrence of superficial bladder cancer: Identification of 4 regions of prognostic interest. Oncogene. 2000;19:6317–6323
  175. Edwards J, Duncan P, Going JJ, et al. Identification of loci associated with putative recurrence genes in transitional cell carcinoma of the urinary bladder. J Pathol. 2002;196:380–385
  176. van Tilborg AA, de Vries A, de Bont M, et al. Molecular evolution of multiple recurrent cancers of the bladder. Hum Mol Genet. 2000;9:2973–2980
  177. Louhelainen J, Wijkstrom H, Hemminki K. Initiation development modeling of allelic losses on chromosome 9 in multifocal bladder cancer. Eur J Cancer. 2000;36:1441–1451
  178. van Tilborg AA, de Vries A, de Bont M, et al. The random development of LOH on chromosome 9q in superficial bladder cancers. J Pathol. 2002;198:352–358
  179. Keen AJ, Knowles MA. Definition of 2 regions of deletion on chromosome 9 in carcinoma of the bladder. Oncogene. 1994;9:2083–2088
  180. Ruppert JM, Tokino K, Sidransky D. Evidence for 2 bladder cancer suppressor loci on human chromosome 9. Cancer Res. 1993;53:5093–5095
  181. Modlich O, Prisack HB, Pitschke G, et al. Identifying superficial, muscle invasive, and metastasizing transitional cell carcinoma of the bladder: Use of cDNA array analysis of gene expression profiles. Clin Cancer Res. 2004;10:3410–3421
  182. Sanchez-Carbayo M, Socci ND, Lozano J, et al. Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. J Clin Oncol. 2006;24:778–789
  183. Koed K, Wiuf C, Christensen LL, et al. High-density single nucleotide polymorphism array defines novel stage and location dependent allelic imbalances in human bladder tumors. Cancer Res. 2005;65:34–45
  184. Hoque MO, Lee CC, Cairns P, et al. Genome-wide genetic characterization of bladder cancer: A comparison of high-density single-nucleotide polymorphism arrays and PCR-based microsatellite analysis. Cancer Res. 2003;63:2216–2222
  185. Goebell PJ. Outcomes and response to therapy in bladder cancer – are biomarkers of any help?. Minerva Urol Nefrol. 2009;61:91–107
  186. Takahashi T, Habuchi T, Kakehi Y, et al. Clonal and chronological genetic analysis of multifocal cancers of the bladder and upper urinary tract. Cancer Res. 1998;58:5835–5841
  187. Hoglund M, Sall T, Heim S, et al. Identification of cytogenetic subgroups and karyotypic pathways in transitional cell carcinoma. Cancer Res. 2001;61:8241–8246
  188. Bulashevska S, Szakacs O, Brors B, et al. Pathways of urothelial cancer progression suggested by Bayesian network analysis of allelotyping data. Int J Cancer. 2004;110:850–856
  189. Hoglund M, Frigyesi A, Sall T, et al. Statistical behavior of complex cancer karyotypes. Genes Chromosomes Cancer. 2005;42:327–341
  190. Sung MT, Maclennan GT, Lopez-Beltran A, et al. Natural history of urothelial inverted papilloma. Cancer. 2006;107:2622–2627
  191. Sung MT, Eble JN, Wang M, et al. Inverted papilloma of the urinary bladder: A molecular genetic appraisal. Mod Pathol. 2006;19:1289–1294
  192. Eiber M, van Oers JM, Zwarthoff EC, et al. Low frequency of molecular changes and tumor recurrence in inverted papillomas of the urinary tract. Am J Surg Pathol. 2007;31:938–946
  193. Hartmann A, Moser K, Kriegmair M, et al. Frequent genetic alterations in simple urothelial hyperplasias of the bladder in patients with papillary urothelial carcinoma. Am J Pathol. 1999;154:721–727
  194. Obermann EC, Junker K, Stoehr R, et al. Frequent genetic alterations in flat urothelial hyperplasias and concomitant papillary bladder cancer as detected by CGH, LOH, and FISH analyses. J Pathol. 2003;199:50–57
  195. van Oers JM, Adam C, Denzinger S. Chromosome 9 deletions are more frequent than FGFR3 mutations in flat urothelial hyperplasias of the bladder. Int J Cancer. 2006;119:1212–1215
  196. Muto S, Horie S, Takahashi S, et al. Genetic and epigenetic alterations in normal bladder epithelium in patients with metachronous bladder cancer. Cancer Res. 2000;60:4021–4025
  197. Kattan MW. Prediction models for transitional cell carcinoma. J Urol. 2009;182:423–424
  198. Vickers A. Prediction models in urology: Are they any good, and how would we know anyway?. Eur Urol. 2010;57:571–573
  199. Hemingway H, Riley RD, Altman DG. Ten steps towards improving prognosis research. BMJ. 2009;339:b4184

PII: S1078-1439(10)00113-4

doi: 10.1016/j.urolonc.2010.04.003

Urologic Oncology: Seminars and Original Investigations
Volume 28, Issue 4 , Pages 409-428 , July 2010