Molecular pathogenesis of bladder cancer

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.

[1]  R. Vanni,et al.  Nonrandom chromosomal changes in transitional cell carcinoma of the bladder. , 1986, Cancer research.

[2]  P. Nichols,et al.  Allelic losses of chromosomes 9, 11, and 17 in human bladder cancer. , 1990, Cancer research.

[3]  M. Knowles,et al.  Amplification and over-expression of c-erbB-2 in transitional cell carcinoma of the urinary bladder. , 1991, British Journal of Cancer.

[4]  P. Green,et al.  Identification of p53 gene mutations in bladder cancers and urine samples. , 1991, Science.

[5]  J. Cairns,et al.  Amplification at chromosome 11q13 in transitional cell tumours of the bladder. , 1991, Oncogene.

[6]  M. Knowles,et al.  Loss of heterozygosity at the RB locus is frequent and correlates with muscle invasion in bladder carcinoma. , 1991, Oncogene.

[7]  A. Sahin,et al.  Altered expression of retinoblastoma protein and known prognostic variables in locally advanced bladder cancer. , 1992, Journal of the National Cancer Institute.

[8]  C. Cordon-Cardo,et al.  Altered expression of the retinoblastoma gene product: prognostic indicator in bladder cancer. , 1992, Journal of the National Cancer Institute.

[9]  T. Sugimura,et al.  Frequent association of p53 gene mutation in invasive bladder cancer. , 1992, Cancer research.

[10]  T. Akiyama,et al.  An immunohistologic evaluation of C‐erbB‐2 gene product in patients with urinary bladder carcinoma , 1992, Cancer.

[11]  R. Takahashi,et al.  Influence of cigarette smoking and schistosomiasis on p53 gene mutation in urothelial cancer. , 1993, Cancer research.

[12]  A. Yang,et al.  Distinct pattern of p53 mutations in bladder cancer: relationship to tobacco usage. , 1993, Cancer research.

[13]  W. Benedict,et al.  Loss of RB protein expression in primary bladder cancer correlates with loss of heterozygosity at the RB locus and tumor progression , 1993, International journal of cancer.

[14]  M. Williamson,et al.  Mutation of H-ras is infrequent in bladder cancer: confirmation by single-strand conformation polymorphism analysis, designed restriction fragment length polymorphisms, and direct sequencing. , 1993, Cancer research.

[15]  D. Sidransky,et al.  Evidence for two bladder cancer suppressor loci on human chromosome 9. , 1993, Cancer research.

[16]  P. Carroll,et al.  Heterogeneity of erbB-2 gene amplification in bladder cancer. , 1993, Cancer research.

[17]  J. Tomaszewski,et al.  Characterization of chromosome 9 deletions in transitional cell carcinoma by microsatellite assay. , 1993, Human molecular genetics.

[18]  M. Knowles,et al.  Initiation of bladder cancer may involve deletion of a tumour-suppressor gene on chromosome 9. , 1993, Oncogene.

[19]  M. Knowles,et al.  Definition of two regions of deletion on chromosome 9 in carcinoma of the bladder. , 1994, Oncogene.

[20]  Michael J. Fry,et al.  Phosphatidylinositol-3-OH kinase direct target of Ras , 1994, Nature.

[21]  R. Cote,et al.  Two molecular pathways to transitional cell carcinoma of the bladder. , 1994, Cancer research.

[22]  B. Mayall,et al.  Ha-ras codon 12 mutation in papillary tumors of the urinary-bladder - a retrospective study. , 1994, International journal of oncology.

[23]  C. Cordon-Cardo,et al.  Altered patterns of MDM2 and TP53 expression in human bladder cancer. , 1994, Journal of the National Cancer Institute.

[24]  D. Sidransky,et al.  Homozygous deletions of 9p21 in primary human bladder tumors detected by comparative multiplex polymerase chain reaction. , 1994, Cancer research.

[25]  M. Knowles,et al.  Homozygous deletion mapping at 9p21 in bladder carcinoma defines a critical region within 2cM of IFNA. , 1994, Oncogene.

[26]  D. Sidransky,et al.  Rates of p16 (MTS1) mutations in primary tumors with 9p loss. , 1994, Science.

[27]  R. Takahashi,et al.  Oncogene amplification in urothelial cancers with p53 gene mutation or MDM2 amplification. , 1994, Journal of the National Cancer Institute.

[28]  G. Hannon,et al.  Deletion of the p16 and p15 genes in human bladder tumors. , 1995, Journal of the National Cancer Institute.

[29]  T. Uchida,et al.  p53 mutations and prognosis in bladder tumors. , 1995, The Journal of urology.

[30]  M. Knowles,et al.  Deletion mapping of chromosome II in carcinoma of the bladder , 1995 .

[31]  K. Rieger,et al.  Identification of H-ras mutations in urine sediments complements cytology in the detection of bladder tumors. , 1995, Journal of the National Cancer Institute.

[32]  B. Nilsson,et al.  Prognostic value of amplification of c-erb-B2 in bladder carcinoma. , 1995, Clinical cancer research : an official journal of the American Association for Cancer Research.

[33]  M. Williamson,et al.  p16 (CDKN2) is a major deletion target at 9p21 in bladder cancer. , 1995, Human molecular genetics.

[34]  M. Knowles,et al.  Deletion mapping implicates two tumor suppressor genes on chromosome 8p in the development of bladder cancer. , 1996, Oncogene.

[35]  E. Schuuring,et al.  Expression of cyclin D1 and EMS1 in bladder tumours; relationship with chromosome 11q13 amplification. , 1996, Oncogene.

[36]  M. Knowles,et al.  Mutation analysis of 8p genes POLB and PPP2CB in bladder cancer. , 1997, Cancer genetics and cytogenetics.

[37]  H. Moch,et al.  Marked genetic differences between stage pTa and stage pT1 papillary bladder cancer detected by comparative genomic hybridization. , 1997, Cancer research.

[38]  François Radvanyi,et al.  Frequent loss of heterozygosity on chromosome 10q in muscle-invasive transitional cell carcinomas of the bladder , 1997, Oncogene.

[39]  M. Knowles,et al.  A novel candidate tumour suppressor locus at 9q32-33 in bladder cancer: localization of the candidate region within a single 840 kb YAC. , 1997, Human molecular genetics.

[40]  J. Herman,et al.  Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers , 1998, Oncogene.

[41]  J. Tomaszewski,et al.  PTCH gene mutations in invasive transitional cell carcinoma of the bladder , 1998, Oncogene.

[42]  O. Yoshida,et al.  Clonal and chronological genetic analysis of multifocal cancers of the bladder and upper urinary tract. , 1998, Cancer research.

[43]  P. Carroll,et al.  Genetic alterations in primary bladder cancers and their metastases. , 1998, Cancer research.

[44]  H. Moch,et al.  Patterns of chromosomal imbalances in advanced urinary bladder cancer detected by comparative genomic hybridization. , 1998, The American journal of pathology.

[45]  R. Katz,et al.  Cluster of allele losses within a 2.5 cM region of chromosome 10 in high-grade invasive bladder cancer , 1998, Oncogene.

[46]  M. Knowles,et al.  Structure and methylation-based silencing of a gene (DBCCR1) within a candidate bladder cancer tumor suppressor region at 9q32-q33. , 1999, Genomics.

[47]  S. Groshen,et al.  Effect of p21WAF1/CIP1 expression on tumor progression in bladder cancer. , 1998, Journal of the National Cancer Institute.

[48]  H. Moch,et al.  Chromosomal imbalances in noninvasive papillary bladder neoplasms (pTa). , 1999, Cancer research.

[49]  H. Moch,et al.  Chromosomal imbalances are associated with a high risk of progression in early invasive (pT1) urinary bladder cancer. , 1999, Cancer research.

[50]  M. Knowles,et al.  Somatic mutation of PTEN in bladder carcinoma , 1999, British Journal of Cancer.

[51]  B. Czerniak,et al.  Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer , 1999, Oncogene.

[52]  M. Knowles,et al.  Mutation of the 9q34 gene TSC1 in sporadic bladder cancer , 1999, Oncogene.

[53]  D. Chopin,et al.  Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas , 1999, Nature Genetics.

[54]  M. Knowles,et al.  Homozygous deletion at the 9q32–33 candidate tumor suppressor locus in primary human bladder cancer , 1999, Genes, chromosomes & cancer.

[55]  A Hofstetter,et al.  Frequent genetic alterations in simple urothelial hyperplasias of the bladder in patients with papillary urothelial carcinoma. , 1999, The American journal of pathology.

[56]  S. Muto,et al.  Genetic and epigenetic alterations in normal bladder epithelium in patients with metachronous bladder cancer. , 2000, Cancer research.

[57]  S. Juhng,et al.  Loss of heterozygosity at chromosome segments 8p22 and 8p11.2‐21.1 in transitional‐cell carcinoma of the urinary bladder , 2000 .

[58]  S. Groshen,et al.  Progressive increases in de novo methylation of CpG islands in bladder cancer. , 2000, Cancer research.

[59]  P. Steck,et al.  Inactivation of MMAC1 in bladder transitional‐cell carcinoma cell lines and specimens , 2000, Molecular carcinogenesis.

[60]  R. Simon,et al.  Patterns of chromosomal imbalances in muscle invasive bladder cancer. , 2000, International journal of oncology.

[61]  F. Mitelman,et al.  Karyotypic characterization of urinary bladder transitional cell carcinomas , 2000, Genes, chromosomes & cancer.

[62]  L. Moore,et al.  Chromosome 9 deletions and recurrence of superficial bladder cancer: identification of four regions of prognostic interest , 2000, Oncogene.

[63]  T. H. van der Kwast,et al.  Molecular evolution of multiple recurrent cancers of the bladder. , 2000, Human molecular genetics.

[64]  S. Noguchi,et al.  C-ERBB-2 gene amplification as a prognostic marker in human bladder cancer. , 2000, Urology.

[65]  A. Moinzadeh,et al.  Molecular analysis of PTEN and MXI1 in primary bladder carcinoma , 2000, International journal of cancer.

[66]  F. Radvanyi,et al.  Advances in Brief The Fibroblast Growth Factor Receptor 3 ( FGFR 3 ) Mutation Is a Strong Indicator of Superficial Bladder Cancer with Low Recurrence Rate 1 , 2001 .

[67]  M. Höglund,et al.  Identification of cytogenetic subgroups and karyotypic pathways in transitional cell carcinoma. , 2001, Cancer research.

[68]  C. Abbou,et al.  Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. , 2001, The American journal of pathology.

[69]  M. Knowles,et al.  Hypermethylation at 9q32-33 tumour suppressor region is age-related in normal urothelium and an early and frequent alteration in bladder cancer , 2001, Oncogene.

[70]  M. Knowles,et al.  Loss of heterozygosity at 4p16.3 and mutation of FGFR3 in transitional cell carcinoma , 2001, Oncogene.

[71]  M. Ittmann,et al.  Haploinsufficiency of the Pten tumor suppressor gene promotes prostate cancer progression , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[72]  A Semjonow,et al.  Cytogenetic analysis of multifocal bladder cancer supports a monoclonal origin and intraepithelial spread of tumor cells. , 2001, Cancer research.

[73]  A A Schäffer,et al.  Tree models for dependent copy number changes in bladder cancer. , 2001, International journal of oncology.

[74]  Jack A. Taylor,et al.  Splice variants but not mutations of DNA polymerase beta are common in bladder cancer. , 2002, Cancer research.

[75]  C. Harris,et al.  The IARC TP53 database: New online mutation analysis and recommendations to users , 2002, Human mutation.

[76]  R. Montironi,et al.  Frequent FGFR3 mutations in urothelial papilloma , 2002, The Journal of pathology.

[77]  H. Moch,et al.  Amplification pattern of 12q13-q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer , 2002, Oncogene.

[78]  K. Shigeno,et al.  Human bladder tumors with 2-hit mutations of tumor suppressor gene TSC1 and decreased expression of p27. , 2003, The Journal of urology.

[79]  H. Wallerand,et al.  FGFR3 and TP53 gene mutations define two distinct pathways in urothelial cell carcinoma of the bladder. , 2003, Cancer research.

[80]  M. Knowles,et al.  Mutation spectrum of the 9q34 tuberous sclerosis gene TSC1 in transitional cell carcinoma of the bladder. , 2003, Cancer research.

[81]  T. H. van der Kwast,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. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[82]  Robert Maurer,et al.  High‐throughput tissue microarray analysis of 11q13 gene amplification (CCND1, FGF3, FGF4, EMS1) in urinary bladder cancer , 2003, The Journal of pathology.

[83]  Wen-Lin Kuo,et al.  Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors. , 2003, Cancer research.

[84]  R. Knuechel,et al.  Frequent genetic alterations in flat urothelial hyperplasias and concomitant papillary bladder cancer as detected by CGH, LOH, and FISH analyses , 2003, The Journal of pathology.

[85]  J. Adolfsson,et al.  Detecting homozygous deletions in the CDKN2A(p16(INK4a))/ARF(p14(ARF)) gene in urinary bladder cancer using real-time quantitative PCR. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[86]  G. Sauter,et al.  HER‐2 and TOP2A coamplification in urinary bladder cancer , 2003, International journal of cancer.

[87]  F. Rousseau,et al.  Alteration of the PATCHED locus in superficial bladder cancer , 2003, Oncogene.

[88]  G. Sauter,et al.  E2F3 amplification and overexpression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer , 2004, Oncogene.

[89]  C. Moskaluk,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 phosphatase activity , 2004, Oncogene.

[90]  S. Shariat,et al.  p53, p21, pRB, and p16 expression predict clinical outcome in cystectomy with bladder cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[91]  R. Wooster,et al.  Amplification and overexpression of E2F3 in human bladder cancer , 2004, Oncogene.

[92]  S. Baylin,et al.  Deletions of chromosome 8p and loss of sFRP1 expression are progression markers of papillary bladder cancer , 2004, Laboratory Investigation.

[93]  S. Groshen,et al.  Combined effects of p53, p21, and pRb expression in the progression of bladder transitional cell carcinoma. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[94]  M. Droller FGFR3 and P53 Characterize Alternative Genetic Pathways in the Pathogenesis of Urothelial Cell Carcinoma , 2004 .

[95]  E. Latulippe,et al.  Accelerated Induction of Bladder Cancer in Patched Heterozygous Mutant Mice , 2004, Cancer Research.

[96]  Roland Eils,et al.  Pathways of urothelial cancer progression suggested by Bayesian network analysis of allelotyping data , 2004, International journal of cancer.

[97]  M. Knowles,et al.  Loss of heterozygosity analysis and DNA copy number measurement on 8p in bladder cancer reveals two mechanisms of allelic loss. , 2005, Cancer research.

[98]  M. Knowles,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 , 2005, Clinical Cancer Research.

[99]  C. Taylor,et al.  Mutation analysis of the 8p candidate tumour suppressor genes DBC2 (RHOBTB2) and LZTS1 in bladder cancer. , 2005, Cancer letters.

[100]  Carsten Wiuf,et al.  Role of Activating Fibroblast Growth Factor Receptor 3 Mutations in the Development of Bladder Tumors , 2005, Clinical Cancer Research.

[101]  Mattias Höglund,et al.  Statistical behavior of complex cancer karyotypes , 2005, Genes, chromosomes & cancer.

[102]  Adel H Jebar,et al.  FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma , 2005, Oncogene.

[103]  Jane Fridlyand,et al.  Bladder Cancer Stage and Outcome by Array-Based Comparative Genomic Hybridization , 2005, Clinical Cancer Research.

[104]  M. Knowles,et al.  Infrequent mutation of TRAIL receptor 2 (TRAIL-R2/DR5) in transitional cell carcinoma of the bladder with 8p21 loss of heterozygosity. , 2005, Cancer letters.

[105]  N. Malats,et al.  FGFR3 and Tp53 Mutations in T1G3 Transitional Bladder Carcinomas: Independent Distribution and Lack of Association with Prognosis , 2005, Clinical Cancer Research.

[106]  M. Knowles,et al.  Assessment by M‐FISH of karyotypic complexity and cytogenetic evolution in bladder cancer in vitro , 2005, Genes, chromosomes & cancer.

[107]  M. Knowles Molecular subtypes of bladder cancer: Jekyll and Hyde or chalk and cheese? , 2006, Carcinogenesis.

[108]  P. Tan,et al.  Inverted papilloma of the urinary bladder: a molecular genetic appraisal , 2006, Modern Pathology.

[109]  N. Malats,et al.  Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[110]  N. Malats,et al.  The p53 Pathway and Outcome among Patients with T1G3 Bladder Tumors , 2006, Clinical Cancer Research.

[111]  Å. Borg,et al.  Molecular characterization of early-stage bladder carcinomas by expression profiles, FGFR3 mutation status, and loss of 9q , 2006, Oncogene.

[112]  T. H. van der Kwast,et al.  Chromosome 9 deletions are more frequent than FGFR3 mutations in flat urothelial hyperplasias of the bladder , 2006, International journal of cancer.

[113]  T. Mak,et al.  Hyperplasia and carcinomas in Pten-deficient mice and reduced PTEN protein in human bladder cancer patients. , 2006, Cancer research.

[114]  G. Sauter,et al.  E2F3 is the main target gene of the 6p22 amplicon with high specificity for human bladder cancer , 2006, Oncogene.

[115]  N. Malats,et al.  PIK3CA MUTATIONS ARE AN EARLY GENETIC ALTERATION ASSOCIATED WITH FGFR3 MUTATIONS IN SUPERFICIAL PAPILLARY BLADDER TUMORS , 2006 .

[116]  H. Pickett,et al.  DBC1 re-expression alters the expression of multiple components of the plasminogen pathway , 2006, Oncogene.

[117]  A. Lopez‐Beltran,et al.  Natural history of urothelial inverted papilloma , 2006, Cancer.

[118]  J. Gulcher,et al.  A variant in CDKAL1 influences insulin response and risk of type 2 diabetes , 2007, Nature Genetics.

[119]  M. Knowles,et al.  FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer , 2007, The Journal of pathology.

[120]  J. Downward,et al.  Ras and Phosphoinositide 3-Kinase: Partners in Development and Tumorigenesis , 2007, Cell cycle.

[121]  J. Cheville,et al.  Low Frequency of Molecular Changes and Tumor Recurrence in Inverted Papillomas of the Urinary Tract , 2007, The American journal of surgical pathology.

[122]  C. Cooper,et al.  Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells , 2007, Oncogene.

[123]  Peter A. Jones,et al.  p53 gene and protein status: the role of p53 alterations in predicting outcome in patients with bladder cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[124]  M. Knowles,et al.  Bladder tumour-derived somatic TSC1 missense mutations cause loss of function via distinct mechanisms , 2008, Human molecular genetics.

[125]  R. Mason,et al.  Pten haploinsufficiency accelerates formation of high-grade astrocytomas. , 2008, Cancer research.

[126]  M. Knowles,et al.  Inactivation of the Rb pathway and overexpression of both isoforms of E2F3 are obligate events in bladder tumours with 6p22 amplification , 2008, Oncogene.