Summary
Target genes implicated in cellular transformation and tumor progression have been divided into two categories: proto-oncogenes (that when activated become dominant events characterized by gain of function) and tumor-suppressor genes (recessive events characterized by the loss of function). Alterations in proto-oncogenes and tumor-suppressor genes seem equally prevalent among human cancers. Multiple mutations appear to be required to conform the malignant phenotype. It is therefore conceivable that cancer be viewed fundamentally as a genetic disease entailing inherited (also calledgerm-line) and/or acquired (also termedsomatic) mutations of genes in these two categories. Molecular studies of bladder neoplasms have identified a series of nonrandom genetic alterations affecting a particular set of oncogenes and tumor-suppressor genes. Because the modality of therapy for patients with bladder neoplasms primarily depends onmorphological evaluation and clinical staging, the diagnosis carries significant consequences. However, it is well known that morphologically similar tumors presenting in any assigned stage may behave in radically different fashions, which seriously hampers the physician's ability accurately to predict clinical behavior in a given case. Recent studies have shown that inactivation of certain tumor-suppressor genes, such as RB andTP53, occur in bladder tumors that have a more aggressive clinical outcome and poor prognosis. In the present paper we review the molecular abnormalities associated with these dominant and recessive genes in bladder cancer and discuss the potential clinical use of their detection. The implementation of objective predictive assays to identify these alterations in clinical material will enhance our ability to assess tumor biological activities and to design effective treatment regimens. The need now is to translate this newly developed scientific knowledge into diagnostic and therapeutic strategies, which in turn will enhance the quality of life and prolong the survival of patients with bladder cancer.
Similar content being viewed by others
References
Altausen AF, Prout GR, Daly JJ (1976) Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ. J Urol 116: 575
Atkin NB, Baker MC (1985) Cytogenetic study of ten carcinomas of the bladder: involvement of chromosomes 1 and 11. Cancer Genet Cytogenet 15: 253
Babu VR, Lutz MD, Miles BJ, Farah RN, Weiss L, Van DD (1987) Tumor behavior in transitional cell carcinoma of the bladder in relation to chromosomal markers and histopathology. Cancer Res 47: 6800
Bishop JM (1991) Molecular themes in oncogenesis. Cell 64: 235–248
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
Cairns P, Shaw ME, Knowles MA (1993) Preliminary mapping of the deleted region of chromosome 9 in bladder cancer. Cancer Res 53: 1230
Cairns P, Polascik TJ, Eby Y, et al (1995) Frequency of homozygous deletion at p16/CdKN2 in primary human tumours. Nature Genet 11: 210
Cordon-Cardo C (1995) Mutation of cell cycle regulators: biological and clinical implications for human neoplasias. Am J Pathol 145: 545
Cordon-Cardo C, Wartinger D, Petrylak D; et al (1992) Altered expression of the retinoblastoma gene product is a prognostic indicator in bladder cancer. J Natl Cancer Inst 84: 1251
Cordon-Cardo C, Dalbagni D, Sarkis A, Reuter VE (1994). Genetic alterations associated with bladder cancer. In: DeVita VT, Hellman S, Rosenberg SA (eds) Important advances in oncology. Lippincott, Philadelphia, pp. 71–83
Cordon-Cardo C, Dalbagni D, Saez GT, et al (1994) TP53 mutations in human bladder cancer: genotypic versus phenotypic patterns. Int J Cancer 56: 347
Czerniak B, Deitch D, Simmons H, Elkind P, Herz F, Koss LG (1990) Ha-ras gene codon 12 mutations and DNA ploidy in urinary bladder carcinomas. Br J Cancer 62: 762
Czerniak B, Cohen GL, Elkind P, et al (1992) Concurrent mutations of coding and regulatory sequences of the Ha-ras gene in urinary bladder carcinomas. Hum Pathol 23: 1199
Dalbagni G, Presti J, Reuter V, Fair WR, Cordon-Cardo C (1993) Genetic alterations in bladder cancer. Lancet 324: 469
Dalbagni G, Presti JC, Reuter VE, et al (1993) Molecular genetic alterations of chromosome 17 and p53 nuclear overexpression in human bladder cancer. Diagn Mol Pathol 2: 4
Esrig D, Elmajian D, Groshen S, et al (1994) Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 331: 1259
Fearon ER, Feinberg AP, Hamilton SH, Vogelstein B (1985) Loss of genes on the short arm of chromosome 11 in bladder cancer. Nature 318: 377
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
Fujimoto K, Yamada Y, Okajima E, et al (1992) Frequent association of p53 gene mutation in invasive bladder cancer. Cancer Res 52: 1393
Fujifa K, Srivastava SK, Kraus MH (1985) Frequency of molecular alterations affecting ras protooncogenes in human urinary tract tumors. Proc Natl Acad Sci USA 82: 3849
Gibas Z, Prout GR, Connolly JG, Pontes JE, Sandberg AA (1984) Nonrandom chromosomal changes in transitional cell carcinoma of the bladder. Cancer Res 44: 1257
Gruis NA, Weaver-Feldhaus J, Liu Q (1995) Genetic evidence in melanoma and bladder cancers that p16 and p53 function in separate pathways of tumor suppression. Am J Pathol 146: 1199
Habuchi T, Ogawa O, Kakehi Y, et al (1993) Accumulated allelic losses in the development of invasive urothelial cancer. Int J Cancer 53: 579
Hannon GJ, Beach D (1994) p15INK4B is a potential effector of TGF-β-induced cell cycle arrest. Nature 371: 257
Hopman AHN, Moesker O, Smeets W, Pauwels RPE, Vooijs GP, Ramaekers FCS (1991) Numerical chromosome l, 7, 9, and 11 aberrations in bladder cancer detected by in situ hybridization. Cancer Res 51: 644
Ishikawa J, Xu H-J, Hu S-X, et al (1991) Inactivation of the retinoblastoma gene in human bladder and renal cell carcinomas. Cancer Res 51: 5736
Kamb A, Liu Q, Harshman K, Tavtigian S, Cordon-Cardo C, Skolnick MH (1994) Rates of p16 (MTS1) mutations in primary tumors with 9p loss. Science 265: 416
Kamb A, Gruis NA, Weaver-Feldhaus J, et al (1994) A cell cycle regulator potentially involved in genesis of many tumor types. Science 264: 436
Koss LG (1975) Atlas of tumor pathology: tumors of the urinary bladder (fasicle 11), 2nd edn. Armed Forces Institute of Pathology, Washington, D.C.
Koss L (1992) Diagnostic cytology and its histopathologic bases. 4th edn. Lippincott, Philadelphia
Levine AJ (1993) The tumor suppressor genes. Annu Rev Biochem 62: 623–651
Lianes P, Orlow I, Zhang ZZ, et al (1994) Altered patterns of MDM2 and TP53 expression in human bladder cancer. J Natl Cancer Inst 86: 1325
Lipponen PK (1993) Over-expression of p53 nuclear oncoprotein in transitional-cell bladder cancer and its prognostic value. Int J Cancer 53: 365
Logothetis CJ, Xu H-J, Ro JY, et al (1992) Altered retinoblastoma protein expression and known prognostic variables in locally advanced bladder cancer. J Natl Cancer Inst 84: 1257
Marshall CJ (1991) Tumor suppressor genes. Cell 64: 313–326
Messing EM (1990) Clinical implications of the expression of epidermal growth factor receptors in human transitional cell carcinomas. Cancer Res 50: 2530
Miyao N, Tsai YC, Lerner SP, et al (1993) Role of chromosome 9 in human bladder cancer. Cancer Res 53: 4066
Momand J, Zambetti G, Olson D, et al (1992) The mdm-2 oncogene product forms a complex with the p-53 protein and inhibits TP53-mediated transactivation. Cell 69: 1237
Neal DE, Marsh C, Bennet MK, Hall RR, Harris AL (1985) Epidermal growth-factor receptors in human bladder cancer: comparison of invasive and superficial tumors. lancet I: 366
Neal DE, Sharples L, Smith K, Fennelly J, Hall RR, Harris AL (1990) The epidermal growth factor receptor and the prognosis of bladder cancer. Cancer 65: 1619
Nguyen PL, Swanson PE, Jaszcz W, et al (1994) Expression of epidermal growth factor receptor in invasive transitional cell carcinoma of the urinary bladder: multivariate survival analysis. Am J Clin Pathol 101: 166
Oliner JD, Kinzler KW, Metlzer PS, et al (1992) Amplification of a gene encoding a p53 associated protein in human sarcomas. Nature 358: 80
Olumi AF, Tsai YC, Nichols Pw, et al (1990) Allelic loss of chromosomes 17p distinguishes high grade from low grade transitional cell carcinoma of the bladder. Cancer Res 50: 7081
Ooi A, Herz F, Setsuko I, et al (1994) Ha-ras codon 12 mutation in papillary tumors of the urinary bladder. A retrospective study. Int J Oncol 4: 85
Orlow I, Lianes P, Lacombe L, Dalbagni G, Reuter VE, Cordon-Cardo C (1994) Chromosome 9 deletions and microsatellite alterations in human bladder tumors. Cancer Res 54: 2848
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
Parsons JT, Parsons SJ (1993) Protein-tyrosine kinases, oncogenes, and cancer. In: DeVita VT, Hellman S, Rosenberg SA (eds) Important advances in oncology. Lippincott, Philadelphia, pp 3–17
Presti JC, Reuter VE, Galan T, Fair WR, Cordon-Cardo C (1991) Molecular genetic alterations in superficial and locally advanced human bladder cancer. Cancer Res 51: 5405
Prout GR (1977) Bladder carcinoma and a TNM system of classification. J Urol 117: 583
Rao JY, Hemstreet GP, Hurst RE, et al (1993) Alterations in phenotypic biochemical markers in bladder epithelium during tumorigenesis. Proc Natl Acad Sci USA 90: 8287
Reddy EP, Reynolds RK, Santos E, Barbacid M (1982) A point mutation is responsible for the acquisition of transforming properties by the T24 bladder carcinoma oncogene. Nature 300: 149
Reuter VE, Melamed MR (1989) The lower urinary tract. In: Sternberg SS (ed) Diagnostic surgical pathology. Raven, New York, p 1355
Ruppert JM, Tokino K, Sidransky D (1994) Evidence for two bladder cancer suppressor loci on human chromosome 9. Cancer Res 53: 5093
Sarkis AS, Zhang Z-F, Cordon-Cardo C, et al (1993) p53 nuclear overexpression and disease progression in Ta bladder carcinoma. Int J Oncol 3: 355
Sarkis AS, Dalbagni G, Cordon-Cardo C, et al (1993) Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression. J Natl Cancer Inst 85: 53
Sarkis AS, Dalbagni G, Cordon-Cardo C, et al (1994) Association of p53 nuclear overexpression and tumor progression in carcinoma in situ of the bladder. J Urol 152: 388
Sarkis AS, Bajorin DF, Reuter VE, et al (1995) The prognostic value of p53 nuclear overexpression in patientes with invasive bladder cancer treated with neoadjuvant M-VAC. J Clin Oncol 13: 1384
Sato K, Moriyama M, Moris S, et al (1992) An immunohistologic evaluation of c-erbB-2 gene product in patients with urinary bladder carcinoma. Cancer 70: 2493
Sauter G, Moch H, Moore D, et al (1993) Heterogeneity of erbB-2 gene amplification in bladder cancer. Cancer Res 53: 2199
Sauter G, Deng G, Moch H, et al (1994) Physical deletion of the p53 gene in bladder cancer. Am J Pathol 144: 756
Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366: 704
Sidransky D, Von Eschenbach A, Tsai YC, et al (1991) Identification of p53 gene mutations in bladder cancers and urine samples. Science 252: 706.
Smeets W, Pauwels R, Laarakkers L, Debruyne F, Geraedts J (1987) Chromosomal analysis of bladder cancer. III. Nonrandom alterations. Cancer Genet Cytogenet 29: 29
Spruck CH, Ohneseit PE, Gonzalez-Zulueta M, et al (1994) Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res 54: 784
Spruck CH, Gonzalez-Zulueta M, Shibata A, et al (1994) p16 gene in uncultured tumours. Nature 370: 183
Tsai YC, Nichols Pw, Hiti AL, Williams Z, Skinner DG, Jones PA (1990) Allelic losses of chromosomes 9, 11, and 17 in human bladder cancer. Cancer Res 50: 44
Underwood M, Barlett J, Reeves J, Gardiner DS, Scott R, Cooke T (1995) C-erbB-2 gene amplification: a molecular marker in recurrent bladder tumors? Cancer Res 55: 2422
Vanni R, Scarpa RM, Nieddu M, Usai E (1988) Cytogenetic investigation on 30 bladder carcinomas. Cancer Genet Cytogenet 30: 55
Visvanathan KV, Pocock RD, Summerhayes IC (1988) Preferential and novel activation of Ha-ras in human bladder carcinoma. Oncogene Res 3: 77
Waldman FM, Carroll PR, Kerschmann R, Cohen MB, Field FG, Mayall BH (1991) Centromeric copy number of chromosome 7 is strongly correlated with tumor grade and labeling index in human bladder cancer. Cancer Res 51: 3807
Williamson M, Elder PA, Shaw ME, Devlin J, Knowles M (1995) p16(CDKN2) is a major deletion target at 9p21 in bladder cancer. Hum Mol Genet 4: 1569
Wood D, Wartinger DD, Reuter V, Cordon-Cardo C, Fair WR, Chaganti RS (1991) DNA, RNA and immunohistochemical characterization of the HER-2/neu oncogene in transitional cell carcinoma of the bladder. J Urol 146: 1398
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Cordon-Cardo, C., Sheinfeld, J. Molecular and immunopathology studies of oncogenes and tumor-suppressor genes in bladder cancer. World J Urol 15, 112–119 (1997). https://doi.org/10.1007/BF02201982
Issue Date:
DOI: https://doi.org/10.1007/BF02201982