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Molecular pathogenesis of bladder cancer

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Abstract

Bladder tumors show widely differing histopathology and clinical behavior. This is reflected in the molecular genetic alterations they contain. Much information has accumulated on somatic genomic alterations in bladder tumors of all grades and stages and when this information is related to the common histopathological appearances, a model for the pathogenesis of two major groups of bladder tumors has emerged. This review summarizes the genetic alterations that have been reported in bladder cancer and relates these to the current two-pathway model for tumor development. The molecular pathogenesis of high-grade noninvasive papillary tumors and of T1 tumors is not yet clear and possibilities are discussed.

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References

  1. Spruck CH 3rd, Ohneseit PF, Gonzalez-Zulueta M, et al. (1994) Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res 54:784–788

    PubMed  CAS  Google Scholar 

  2. Knowles MA (2006) Molecular subtypes of bladder cancer: Jekyll and Hyde or chalk and cheese? Carcinogenesis 27:361–373

    Article  PubMed  CAS  Google Scholar 

  3. Fadl-Elmula I, Gorunova L, Mandahl N, et al. (2000) Karyotypic characterization of urinary bladder transitional cell carcinomas. Genes Chromosomes Cancer 29:256–265

    Article  PubMed  CAS  Google Scholar 

  4. Gibas Z, Prout GR Jr, Connolly JG, et al. (1984) Nonrandom chromosomal changes in transitional cell carcinoma of the bladder. Cancer Res 44:1257–1264

    PubMed  CAS  Google Scholar 

  5. Cairns P, Shaw ME, Knowles MA (1993) Initiation of bladder cancer may involve deletion of a tumour-suppressor gene on chromosome 9. Oncogene 8:1083–1085

    PubMed  CAS  Google Scholar 

  6. Linnenbach AJ, Pressler LB, Seng BA, et al. (1993) Characterization of chromosome 9 deletions in transitional cell carcinoma by microsatellite assay. Hum Mol Genet 2:1407–1411

    Article  PubMed  CAS  Google Scholar 

  7. Tsai YC, Nichols PW, Hiti AL, et al. (1990) Allelic losses of chromosomes 9, 11, and 17 in human bladder cancer. Cancer Res 50:44–47

    PubMed  CAS  Google Scholar 

  8. Cairns P, Mao L, Merlo A, et al. (1994) Rates of p16 (MTS1) mutations in primary tumors with 9p loss. Science 265:415–417

    Article  PubMed  CAS  Google Scholar 

  9. Devlin J, Keen AJ, Knowles MA (1994) Homozygous deletion mapping at 9p21 in bladder carcinoma defines a critical region within 2cM of IFNA. Oncogene 9:2757–2760

    PubMed  CAS  Google Scholar 

  10. Orlow I, Lacombe L, Hannon GJ, et al. (1995) Deletion of the p16 and p15 genes in human bladder tumors. J Natl Cancer Inst 87:1524–1529

    Article  PubMed  CAS  Google Scholar 

  11. Williamson MP, Elder PA, Shaw ME, et al. (1995) p16 (CDKN2) is a major deletion target at 9p21 in bladder cancer. Hum Mol Genet 4:1569–1577

    Article  PubMed  CAS  Google Scholar 

  12. Berggren P, Kumar R, Sakano S, et al. (2003) Detecting homozygous deletions in the CDKN2A (p16(INK4a))/ARF(p14(ARF)) gene in urinary bladder cancer using real-time quantitative PCR. Clin Cancer Res 9:235–242

    PubMed  CAS  Google Scholar 

  13. Aboulkassim TO, LaRue H, Lemieux P, et al. (2003) Alteration of the PATCHED locus in superficial bladder cancer. Oncogene 22:2967–2971

    Article  PubMed  CAS  Google Scholar 

  14. McGarvey TW, Maruta Y, Tomaszewski JE, et al. (1998) PTCH gene mutations in invasive transitional cell carcinoma of the bladder. Oncogene 17:1167–1172

    Article  PubMed  CAS  Google Scholar 

  15. Hamed S, LaRue H, Hovington H, et al. (2004) Accelerated induction of bladder cancer in patched heterozygous mutant mice. Cancer Res 64:1938–1942

    Article  PubMed  CAS  Google Scholar 

  16. Habuchi T, Yoshida O, Knowles MA (1997) A novel candidate tumour suppressor locus at 9q32–33 in bladder cancer: localisation of the candidate region within a single 840kb YAC. Hum Mol Genet 6:913–919

    Article  PubMed  CAS  Google Scholar 

  17. Nishiyama H, Takahashi T, Kakehi Y, et al. (1999) Homozygous deletion at the 9q32–33 candidate tumor suppressor locus in primary human bladder cancer. Genes Chromosomes Cancer 26:171–175

    Article  PubMed  CAS  Google Scholar 

  18. Habuchi T, Luscombe M, Elder PA, Knowles MA (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

    Article  PubMed  CAS  Google Scholar 

  19. Habuchi T, Takahashi T, Kakinuma H, et al. (2001) Hypermethylation at 9q32–33 tumour suppressor region is age-related in normal urothelium and an early and frequent alteration in bladder cancer. Oncogene 20:531–537

    Article  PubMed  CAS  Google Scholar 

  20. Salem C, Liang G, Tsai YC, et al. (2000) Progressive increases in de novo methylation of CpG islands in bladder cancer. Cancer Res 60:2473–2476

    PubMed  CAS  Google Scholar 

  21. Louhelainen JP, Hurst CD, Pitt E, et al. (2005) DBC1 re-expression alters the expression of multiple components of the plasminogen pathway. Oncogene 25:2409–2419

    Article  CAS  Google Scholar 

  22. Pymar LS, Platt FM, Askham JM, et al. (2008) Bladder tumour derived somatic TSC1 missense mutations cause loss of function via distinct mechanisms. Hum Mol Genet 17:2006–2017

    Article  PubMed  CAS  Google Scholar 

  23. Knowles MA, Habuchi T, Kennedy W, Cuthbert-Heavens D (2003) Mutation spectrum of the 9q34 tuberous sclerosis gene TSC1 in transitional cell carcinoma of the bladder. Cancer Res 63:7652–7656

    PubMed  CAS  Google Scholar 

  24. Lindgren D, Liedberg F, Andersson A, et al. (2006) Molecular characterization of early-stage bladder carcinomas by expression profiles, FGFR3 mutation status, and loss of 9q. Oncogene 25:2685–2696

    Article  PubMed  CAS  Google Scholar 

  25. Simoneau M, LaRue H, Aboulkassim TO, et al. (2000) Chromosome 9 deletions and recurrence of superficial bladder cancer: identification of four regions of prognostic interest. Oncogene 19:6317–6323

    Article  PubMed  CAS  Google Scholar 

  26. Keen AJ, Knowles MA (1994) Definition of two regions of deletion on chromosome 9 in carcinoma of the bladder. Oncogene 9:2083–2088

    PubMed  CAS  Google Scholar 

  27. Ruppert JM, Tokino K, Sidransky D. (1993) Evidence for two bladder cancer suppressor loci on human chromosome 9. Cancer Res 53:5093–5095

    PubMed  CAS  Google Scholar 

  28. Chapman EJ, Harnden P, Chambers P, et al. (2005) 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 11:5740–5747

    Article  PubMed  CAS  Google Scholar 

  29. Takahashi T, Habuchi T, Kakehi Y, et al. (1998) Clonal and chronological genetic analysis of multifocal cancers of the bladder and upper urinary tract. Cancer Res 58:5835–5841

    PubMed  CAS  Google Scholar 

  30. Billerey C, Chopin D, Aubriot-Lorton MH, et al. (2001) Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. Am J Pathol 158:1955–1959

    PubMed  CAS  Google Scholar 

  31. Tomlinson D, Baldo O, Harnden P, Knowles M (2007) FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J Pathol 213:91–98

    Article  PubMed  CAS  Google Scholar 

  32. van Rhijn BW, Lurkin I, Radvanyi F, et al. (2001) The fibroblast growth factor receptor 3 (FGFR3) mutation is a strong indicator of superficial bladder cancer with low recurrence rate. Cancer Res 61:1265–1268

    PubMed  Google Scholar 

  33. Zieger K, Dyrskjot L, Wiuf C, et al. (2005) Role of activating fibroblast growth factor receptor 3 mutations in the development of bladder tumors. Clin Cancer Res 11:7709–7719

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  35. Lopez-Knowles E, Hernandez S, Malats N, et al. (2006) PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors. Cancer Res 66:7401–7404

    Article  PubMed  CAS  Google Scholar 

  36. Rodriguez-Viciana P, Warne PH, Dhand R, et al. (1994) Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370:527–532

    Article  PubMed  CAS  Google Scholar 

  37. Ramjaun AR, Downward J (2007) Ras and phosphoinositide 3-kinase: partners in development and tumorigenesis. Cell Cycle 6:2902–2905

    PubMed  CAS  Google Scholar 

  38. Blaveri E, Brewer JL, Roydasgupta R, et al. (2005) Bladder cancer stage and outcome by array-based comparative genomic hybridization. Clin Cancer Res 11:7012–7022

    Article  PubMed  CAS  Google Scholar 

  39. Richter J, Jiang F, Gorog JP, et al. (1997) Marked genetic differences between stage pTa and stage pT1 papillary bladder cancer detected by comparative genomic hybridization. Cancer Res 57:2860–2864

    PubMed  CAS  Google Scholar 

  40. Zhao J, Richter J, Wagner U, et al. (1999) Chromosomal imbalances in noninvasive papillary bladder neoplasms (pTa). Cancer Res 59:4658–4661

    PubMed  CAS  Google Scholar 

  41. Fujimoto K, Yamada Y, Okajima E, et al. (1992) Frequent association of p53 gene mutation in invasive bladder cancer. Cancer Res 52:1393–1398

    PubMed  CAS  Google Scholar 

  42. Uchida T, Wada C, Ishida H, et al. (1995) p53 mutations and prognosis in bladder tumors. J Urol 153:1097–1104

    Article  PubMed  CAS  Google Scholar 

  43. Olivier M, Eeles R, Hollstein M, et al. (2002) The IARC TP53 database: new online mutation analysis and recommendations to users. Hum Mutat 19:607–614

    Article  PubMed  CAS  Google Scholar 

  44. Simon R, Struckmann K, Schraml P, et al. (2002) Amplification pattern of 12q13–q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer. Oncogene 21:2476–2483

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  46. George B, Datar RH, Wu L, 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  PubMed  CAS  Google Scholar 

  47. Cairns P, Proctor AJ, Knowles MA (1991) Loss of heterozygosity at the RB locus is frequent and correlates with muscle invasion in bladder carcinoma. Oncogene 6:2305–2309

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  49. Logothetis CJ, Xu H-J, Ro JY, et al. (1992) Altered expression of retinoblastoma protein and known prognostic variables in locally advanced bladder cancer. J Natl Cancer Inst 84:1256–1261

    Article  PubMed  CAS  Google Scholar 

  50. Xu HJ, Cairns P, Hu SX, et al. (1993) Loss of RB protein expression in primary bladder cancer correlates with loss of heterozygosity at the RB locus and tumor progression. Int J Cancer 53:781–784

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  52. Chatterjee SJ, Datar R, Youssefzadeh D, 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  54. Feber A, Clark J, Goodwin G, et al. (2004) Amplification and overexpression of E2F3 in human bladder cancer. Oncogene 23:1627–1630

    Article  PubMed  CAS  Google Scholar 

  55. Hurst CD, Tomlinson DC, Williams SV, et al. (2007) Inactivation of the Rb pathway and overexpression of both isoforms of E2F3 are obligate events in bladder tumours with 6p22 amplification. Oncogene 27:2716–2727

    Article  PubMed  CAS  Google Scholar 

  56. Oeggerli M, Schraml P, Ruiz C, et al. (2006) E2F3 is the main target gene of the 6p22 amplicon with high specificity for human bladder cancer. Oncogene 25:6538–6543

    Article  PubMed  CAS  Google Scholar 

  57. Oeggerli M, Tomovska S, Schraml P, 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

    Article  PubMed  CAS  Google Scholar 

  58. Olsson AY, Feber A, Edwards S, et al. (2007) Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells. Oncogene 26:1028–1037

    Article  PubMed  CAS  Google Scholar 

  59. Steinthorsdottir V, Thorleiffson G, Reynisdottir I, et al. (2007) A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 39:770–775

    Article  PubMed  CAS  Google Scholar 

  60. Aveyard JS, Skilleter A, Habuchi T, Knowles MA (1999) Somatic mutation of PTEN in bladder carcinoma. Br J Cancer 80:904–908

    Article  PubMed  CAS  Google Scholar 

  61. Cappellen D, Gil Diez de Medina S, Chopin D, et al. (1997) Frequent loss of heterozygosity on chromosome 10q in muscle-invasive transitional cell carcinomas of the bladder. Oncogene 14:3059–3066

    Article  PubMed  CAS  Google Scholar 

  62. Kagan J, Liu J, Stein JD, et al. (1998) Cluster of allele losses within a 2.5 cM region of chromosome 10 in high-grade invasive bladder cancer. Oncogene 16:909–913

    Article  PubMed  CAS  Google Scholar 

  63. Wang DS, Rieger-Christ K, Latini JM, et al. (2000) Molecular analysis of PTEN and MXI1 in primary bladder carcinoma. Int J Cancer 88:620–625

    Article  PubMed  CAS  Google Scholar 

  64. Liu J, Babaian DC, Liebert M, et al. (2000) Inactivation of MMAC1 in bladder transitional-cell carcinoma cell lines and specimens. Mol Carcinog 29:143–150

    Article  PubMed  CAS  Google Scholar 

  65. Kwabi-Addo B, Giri D, Schmidt K, et al. (2001) Haploin-sufficiency of the Pten tumor suppressor gene promotes prostate cancer progression. Proc Natl Acad Sci U S A 98:11563–11568

    Article  PubMed  CAS  Google Scholar 

  66. Kwon CH, Zhao D, Chen J, et al. (2008) Pten haploinsufficiency accelerates formation of high-grade astrocytomas. Cancer Res 68:3286–3294

    Article  PubMed  CAS  Google Scholar 

  67. Gildea JJ, Herlevsen M, Harding MA, et al. (2004) PTEN can inhibit in vitro organotypic and in vivo orthotopic invasion of human bladder cancer cells even in the absence of its lipid phosphatase activity. Oncogene 23:6788–6797

    Article  PubMed  CAS  Google Scholar 

  68. Tsuruta H, Kishimoto H, Sasaki T, et al. (2006) Hyperplasia and carcinomas in Pten-deficient mice and reduced PTEN protein in human bladder cancer patients. Cancer Res 66:8389–8396

    Article  PubMed  CAS  Google Scholar 

  69. Coombs LM, Pigott DA, Sweeney E, et al. (1991) Amplification and over-expression of c-erbB-2 in transitional cell carcinoma of the urinary bladder. Br J Cancer 63:601–608

    PubMed  CAS  Google Scholar 

  70. Lonn U, Lonn S, Friberg S, et al. (1995) Prognostic value of amplification of c-erb-B2 in bladder carcinoma. Clin Cancer Res 1:1189–1194

    PubMed  CAS  Google Scholar 

  71. Miyamoto H, Kubota Y, Noguchi S, et al. (2000) C-ERBB-2 gene amplification as a prognostic marker in human bladder cancer. Urology 55:679–683

    Article  PubMed  CAS  Google Scholar 

  72. Sauter G, Moch H, Moore D, et al. (1993) Heterogeneity of erbB-2 gene amplification in bladder cancer. Cancer Res 53:2199–2203

    PubMed  CAS  Google Scholar 

  73. Simon R, Atefy R, Wagner U, et al. (2003) HER-2 and TOP2A coamplification in urinary bladder cancer. Int J Cancer 107:764–772

    Article  PubMed  CAS  Google Scholar 

  74. Hovey RM, Chu L, Balazs M, et al. (1998) Genetic alterations in primary bladder cancers and their metastases. Cancer Res 58:3555–3560

    PubMed  CAS  Google Scholar 

  75. Simon R, Burger H, Semjonow A, et al. (2000) Patterns of chromosomal imbalances in muscle invasive bladder cancer. Int J Oncol 17:1025–1029

    PubMed  CAS  Google Scholar 

  76. Veltman JA, Fridlyand J, Pejavar S, et al. (2003) Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors. Cancer Res 63:2872–2880

    PubMed  CAS  Google Scholar 

  77. Simon R, Eltze E, Schafer KL, et al. (2001) Cytogenetic analysis of multifocal bladder cancer supports a monoclonal origin and intraepithelial spread of tumor cells. Cancer Res 61:355–362

    PubMed  CAS  Google Scholar 

  78. Richter J, Beffa L, Wagner U, et al. (1998) Patterns of chromosomal imbalances in advanced urinary bladder cancer detected by comparative genomic hybridization. Am J Pathol 153:1615–1621

    PubMed  CAS  Google Scholar 

  79. Schaffer AA, Simon R, Desper R, et al. (2001) Tree models for dependent copy number changes in bladder cancer. Int J Oncol 18:349–354

    PubMed  CAS  Google Scholar 

  80. Adams J, Williams SV, Aveyard JS, Knowles MA (2005) Loss of heterozygosity analysis and DNA copy number measurement on 8p in bladder cancer reveals two mechanisms of allelic loss. Cancer Res 65:66–75

    PubMed  CAS  Google Scholar 

  81. Choi C, Kim MH, Juhng SW, Oh BR (2000) Loss of heterozygosity at chromosome segments 8p22 and 8p11.2–21.1 in transitional-cell carcinoma of the urinary bladder. Int J Cancer 86:501–505

    Article  PubMed  CAS  Google Scholar 

  82. Stoehr R, Wissmann C, Suzuki H, et al. (2004) Deletions of chromosome 8p and loss of sFRP1 expression are progression markers of papillary bladder cancer. Lab Invest 465–478

  83. Takle LA, Knowles MA (1996) Deletion mapping implicates two tumor suppressor genes on chromosome 8p in the development of bladder cancer. Oncogene 12:1083–1087

    PubMed  CAS  Google Scholar 

  84. Williams SV, Adams J, Coulter J, et al. (2005) Assessment by M-FISH of karyotypic complexity and cytogenetic evolution in bladder cancer in vitro. Genes Chromosomes Cancer 43:315–328

    Article  PubMed  CAS  Google Scholar 

  85. Thompson TE, Rogan PK, Risinger JI, Taylor JA (2002) Splice variants but not mutations of DNA polymerase beta are common in bladder cancer. Cancer Res 62:3251–3256

    PubMed  CAS  Google Scholar 

  86. Adams J, Cuthbert-Heavens D, Bass S, Knowles MA (2005) Infrequent mutation of TRAIL receptor 2 (TRAIL-R2/DR5) in transitional cell carcinoma of the bladder with 8p21 loss of heterozygosity. Cancer Lett 220:137–144

    Article  PubMed  CAS  Google Scholar 

  87. Eydmann ME, Knowles MA (1997) Mutation analysis of 8p genes POLB and PPP2CB in bladder cancer. Cancer Genet Cytogenet 93:167–171

    Article  PubMed  CAS  Google Scholar 

  88. Knowles MA, Aveyard JS, Taylor CF, et al. (2005) Mutation analysis of the 8p candidate tumour suppressor genes DBC2 (RHOBTB2) and LZTS1 in bladder cancer. Cancer Lett 225:121–130

    Article  PubMed  CAS  Google Scholar 

  89. Hernandez S, Lopez-Knowles E, Lloreta J, et al. (2006) Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. J Clin Oncol 24:3664–3671

    Article  PubMed  CAS  Google Scholar 

  90. Richter J, Wagner U, Schraml P, et al. (1999) Chromosomal imbalances are associated with a high risk of progression in early invasive (pT1) urinary bladder cancer. Cancer Res 59:5687–5691

    PubMed  CAS  Google Scholar 

  91. van Tilborg AA, de Vries A, de Bont M, et al. (2000) Molecular evolution of multiple recurrent cancers of the bladder. Hum Mol Genet 9:2973–2980

    Article  PubMed  Google Scholar 

  92. Hernandez S, Lopez-Knowles E, Lloreta J, 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

    Article  PubMed  CAS  Google Scholar 

  93. Bakker AA, Wallerand H, Radvanyi F, et al. (2003) FGFR3 and TP53 gene mutations define two distinct pathways in urothelial cell carcinoma of the bladder. Cancer Res 63:8108–8112

    Google Scholar 

  94. van Rhijn BW, van der Kwast TH, Vis AN, et al. (2004) FGFR3 and P53 characterize alternative genetic pathways in the pathogenesis of urothelial cell carcinoma. Cancer Res 64:1911–1914

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  96. van Rhijn BW, Vis AN, van der Kwast TH, et al. (2003) 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 21:1912–1921

    Article  PubMed  CAS  Google Scholar 

  97. Muto S, Horie S, Takahashi S, et al. (2000) Genetic and epigenetic alterations in normal bladder epithelium in patients with metachronous bladder cancer. Cancer Res 60:4021–4025

    PubMed  CAS  Google Scholar 

  98. Hartmann A, Moser K, Kriegmair M, 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

    PubMed  CAS  Google Scholar 

  99. Obermann EC, Junker K, Stoehr R, et al. (2003) Frequent genetic alterations in flat urothelial hyperplasias and concomitant papillary bladder cancer as detected by CGH, LOH, and FISH analyses. J Pathol 199:50–57

    Article  PubMed  CAS  Google Scholar 

  100. van Oers JM, Adam C, Denzinger S, et al. (2006) Chromosome 9 deletions are more frequent than FGFR3 mutations in flat urothelial hyperplasias of the bladder. Int J Cancer 119:1212–1215

    Article  PubMed  CAS  Google Scholar 

  101. van Rhijn BW, Montironi R, Zwarthoff EC, et al. (2002) Frequent FGFR3 mutations in urothelial papilloma. J Pathol 198:245–251

    Article  PubMed  CAS  Google Scholar 

  102. Sung MT, Maclennan GT, Lopez-Beltran A, et al. (2006) Natural history of urothelial inverted papilloma. Cancer 107:2622–2627

    Article  PubMed  Google Scholar 

  103. Sung MT, Eble JN, Wang MT, et al. (2006) Inverted papilloma of the urinary bladder: a molecular genetic appraisal. Mod Pathol 19:1289–1294

    Article  PubMed  CAS  Google Scholar 

  104. Eiber M, van Oers JM, Zwarthoff EC, et al. (2007) Low frequency of molecular changes and tumor recurrence in inverted papillomas of the urinary tract. Am J Surg Pathol 31:938–946

    Article  PubMed  Google Scholar 

  105. Hoglund M, Sall T, Heim S, et al. (2001) Identification of cytogenetic subgroups and karyotypic pathways in transitional cell carcinoma. Cancer Res 61:8241–8246

    PubMed  CAS  Google Scholar 

  106. Bulashevska S, Szakacs O, Brors B, et al. (2004) Pathways of urothelial cancer progression suggested by Bayesian network analysis of allelotyping data. Int J Cancer 110:850–856

    Article  PubMed  CAS  Google Scholar 

  107. Hoglund M, Frigyesi A, Sall T, et al. (2005) Statistical behavior of complex cancer karyotypes. Genes Chromosomes Cancer 42:327–341

    Article  PubMed  CAS  Google Scholar 

  108. Knowles MA, Williamson M (1993) Mutation of H-ras is infrequent in bladder cancer: confirmation by single-strand conformation polymorphism analysis, designed restriction fragment length polymorphisms, and direct sequencing. Cancer Res 53:133–139

    PubMed  CAS  Google Scholar 

  109. Ooi A, Herz F, Ii S, et al. (1994) Ha-ras codon 12 mutation in papillary tumors of the urinary bladder: a retrospective study. Int J Oncol 4:85–90

    CAS  Google Scholar 

  110. Fitzgerald JM, Ramchurren N, Rieger K, et al. (1995) Identification of H-ras mutations in urine sediments complements cytology in the detection of bladder tumors. J Natl Cancer Inst 87:129–133

    Article  PubMed  CAS  Google Scholar 

  111. Cappellen D, De Oliveira C, Ricol D, et al. (1999) Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet 23:18–20

    PubMed  CAS  Google Scholar 

  112. Sibley K, Cuthbert-Heavens D, Knowles MA (2001) Loss of heterozygosity at 4p16.3 and mutation of FGFR3 in transitional cell carcinoma. Oncogene 20:686–691

    Article  PubMed  CAS  Google Scholar 

  113. Proctor AJ, Coombs LM, Cairns JP, Knowles MA (1991) Amplification at chromosome 11q13 in transitional cell tumours of the bladder. Oncogene 6:789–795

    PubMed  CAS  Google Scholar 

  114. Bringuier PP, Tamimi Y, Schuuring E, et al. (1996) Expression of cyclin D1 and EMS1 in bladder tumours; relationship with chromosome 11q13 amplification. Oncogene 12:1747–1753

    PubMed  CAS  Google Scholar 

  115. Habuchi T, Kinoshita H, Yamada H, et al. (1994) Oncogene amplification in urothelial cancers with p53 gene mutation or MDM2 amplification. J Natl Cancer Inst 86:1331–1335

    Article  PubMed  CAS  Google Scholar 

  116. Lianes P, Orlow I, Zhang Z-F, et al. (1994) Altered patterns of MDM2 and TP53 expression in human bladder cancer. J Natl Cancer Inst 86:1325–1330

    Article  PubMed  CAS  Google Scholar 

  117. Cairns P, Tokino K, Eby Y, Sidransky D (1994) Homozygous deletions of 9p21 in primary human bladder tumors detected by comparative multiplex polymerase chain reaction. Cancer Res 54:1422–1424

    PubMed  CAS  Google Scholar 

  118. Hornigold N, Devlin J, Davies AM, et al. (1999) Mutation of the 9q34 gene TSC1 in sporadic bladder cancer. Oncogene 18:2657–2661

    Article  PubMed  CAS  Google Scholar 

  119. Adachi H, Igawa M, Shiina H, et al. (2003) Human bladder tumors with two-hit mutations of tumor suppressor gene TSC1 and decreased expression of p27. J Urol 170:601–604

    Article  PubMed  CAS  Google Scholar 

  120. Shaw ME, Knowles MA (1995) Deletion mapping of chromosome 11 in carcinoma of the bladder. Genes Chromosomes Cancer 13:1–8

    Article  PubMed  CAS  Google Scholar 

  121. Sato K, Moriyama M, Mori S, et al. (1992) An immunohistologic evaluation of c-erbB-2 gene product in patients with urinary bladder carcinoma. Cancer 70:2493–2498

    Article  PubMed  CAS  Google Scholar 

  122. Sauter G, Moch H, Moore D, et al. (1993) Heterogeneity of erbB-2 gene amplification in bladder cancer. Cancer Res 53:2199–2203

    PubMed  CAS  Google Scholar 

  123. Zaharieva BM, Simon R, Diener PA, et al. (2003) High-throughput tissue microarray analysis of 11q13 gene amplification (CCND1, FGF3, FGF4, EMS1) in urinary bladder cancer. J Pathol 201:603–608

    Article  PubMed  CAS  Google Scholar 

  124. Cairns P, Evron E, Okami K, et al. (1998) Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers. Oncogene 16:3215–3218

    Article  PubMed  CAS  Google Scholar 

  125. Cappellen D, Gil Diez de Medina S, Chopin D, et al. (1997) Frequent loss of heterozygosity on chromosome 10q in muscleinvasive transitional cell carcinomas of the bladder. Oncogene 14:3059–3066

    Article  PubMed  CAS  Google Scholar 

  126. Habuchi T, Takahashi R, Yamada H, et al. (1993) Influence of cigarette smoking and schistosomiasis on p53 gene mutation in urothelial cancer. Cancer Res 53:3795–3799

    PubMed  CAS  Google Scholar 

  127. Sidransky D, von Eschenbach A, Tsai YC, et al. (1991) Identification of p53 gene mutations in bladder cancers and urine samples. Science 252:706–709

    Article  PubMed  CAS  Google Scholar 

  128. Spruck CH III, Rideout WM III, Olumi AF, et al. (1993) Distinct pattern of p53 mutations in bladder cancer: relationship to tobacco usage. Cancer Res 3:1162–1166

    Google Scholar 

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  1. Cancer Research UK Clinical Centre, Leeds Institute of Molecular Medicine, St James’s University Hospital, Beckett Street, Leeds, LS9 7TF, UK

    Margaret A. Knowles

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  1. Margaret A. Knowles
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Correspondence to Margaret A. Knowles.

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Knowles, M.A. Molecular pathogenesis of bladder cancer. Int J Clin Oncol 13, 287–297 (2008). https://doi.org/10.1007/s10147-008-0812-0

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  • DOI: https://doi.org/10.1007/s10147-008-0812-0

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