Molecular genesis of non-muscle-invasive urothelial carcinoma (NMIUC)

Courtney Pollard; Steven C. Smith; Dan Theodorescu

doi:10.1017/S1462399410001407

Molecular genesis of non-muscle-invasive urothelial carcinoma (NMIUC)

Published online by Cambridge University Press: 25 March 2010

Courtney Pollard ,

Steven C. Smith and

Dan Theodorescu

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Courtney Pollard: Affiliation:
Department of Molecular Physiology, University of Virginia, Charlottesville, VA, USA.
Steven C. Smith: Affiliation:
Department of Molecular Physiology, University of Virginia, Charlottesville, VA, USA.
Dan Theodorescu*: Affiliation:
Department of Molecular Physiology, University of Virginia, Charlottesville, VA, USA. Mellon Urologic Cancer Institute, University of Virginia, Charlottesville, VA, USA.
*: *Corresponding author: Dan Theodorescu, Department of Molecular Physiology, University of Virginia, P.O. Box 800422, Charlottesville, VA 22908, USA. E-mail: dt9d@virginia.edu

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Abstract

Urothelial carcinoma (UC) is the most common type of bladder cancer in Western nations. Most patients present with the non-muscle-invasive (NMIUC) form of the disease, while up to a third harbour the invasive form (MIUC). Specifically, the aetiology of NMIUC appears to be multifactorial and very different from that of MIUC. Loss of specific tumour suppressor genes as well as gain-of-function mutations in proteins within defined cellular signalling pathways have been implicated in NMIUC aetiology. The regions of chromosome 9 that harbour CDKN2A, CDKN2B, TSC1, PTCH1 and DBC1 are frequently mutated in NMIUC, resulting in functional loss; in addition, HRAS and FGFR3, which are both proto-oncogenes encoding components of the Ras–MAPK signalling pathway, have been found to harbour activating mutations in a large number of NMIUCs. Interestingly, some of these molecular events are mutually exclusive, suggesting functional equivalence. Since several of these driving changes are amenable to therapeutic targeting, understanding the signalling events in NMIUC may offer novel approaches to manage the recurrence and progression of this disease.

Type: Review Article
Information: Expert Reviews in Molecular Medicine , Volume 12 , January 2010 , e10

DOI: https://doi.org/10.1017/S1462399410001407 [Opens in a new window]
Copyright: Copyright © Cambridge University Press 2010

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References

1Parkin, D.M. et al. (2005) Global cancer statistics, 2002. CA: A Cancer Journal for Clinicians 55, 74-108Google Scholar PubMed

2Montironi, R. and Lopez-Beltran, A. (2005) The 2004 WHO classification of bladder tumors: a summary and commentary. International Journal of Surgical Pathology 13, 143-153CrossRef Google Scholar PubMed

3Jemal, A. et al. (2009) Cancer statistics, 2009. CA: A Cancer Journal for Clinicians 59, 225-249Google Scholar PubMed

4Sonny, L.J. and Samuel, M.C. (1997) Epidemiology and etiology of bladder cancer. Seminars in Surgical Oncology 13, 291-298Google Scholar

5Kamat, A.M. and Lamm, D.L. (2000) Intravesical therapy for bladder cancer. Urology 55, 161-168CrossRef Google Scholar PubMed

6Pasin, E. et al. (2008) Superficial bladder cancer: an update on etiology, molecular development, classification, and natural history. Reviews in Urology 10, 31-43Google Scholar PubMed

7Sengelov, L., Kamby, C. and von der Maase, H. (1996) Pattern of metastases in relation to characteristics of primary tumor and treatment in patients with disseminated urothelial carcinoma. Journal of Urology 155, 111-114CrossRef Google Scholar PubMed

8Steinberg, G.D., Trump, D.L. and Cummings, K.B. (1992) Metastatic bladder cancer. Natural history, clinical course, and consideration for treatment. Urologic Clinics of North America 19, 735-746CrossRef Google Scholar PubMed

9Liebert, M. and Seigne, J. (1996) Characteristics of invasive bladder cancers: histological and molecular markers. Seminars in Urologic Oncology 14, 62-72Google Scholar PubMed

10Koss, L.G. (1992) Bladder cancer from a perspective of 40 years. Journal of Cellular Biochemistry (Suppl) 16I, 23-29CrossRef Google Scholar PubMed

11Wu, X-R. (2005) Urothelial tumorigenesis: a tale of divergent pathways. Nature Reviews Cancer 5, 713-725CrossRef Google Scholar PubMed

12Bakkar, A.A. et al. (2003) FGFR3 and TP53 gene mutations define two distinct pathways in urothelial cell carcinoma of the bladder. Cancer Research 63, 8108-8112Google Scholar PubMed

13Lamy, A. et al. (2006) Molecular profiling of bladder tumors based on the detection of FGFR3 and TP53 mutations. Journal of Urology 176, 2686-2689CrossRef Google Scholar PubMed

14Hernandez, S. et al. (2005) FGFR3 and Tp53 mutations in T1G3 transitional bladder carcinomas: independent distribution and lack of association with prognosis. Clinical Cancer Research 11, 5444-5450CrossRef Google Scholar PubMed

15Karsten, Z. et al. (2009) Consistent genomic alterations in carcinoma in situ of the urinary bladder confirm the presence of two major pathways in bladder cancer development. International Journal of Cancer 125, 2095-2103Google Scholar

16Tsai, Y.C. et al. (1990) Allelic losses of chromosomes 9, 11, and 17 in human bladder cancer. Cancer Research 50, 44-47Google Scholar

17Cairns, P., Shaw, M.E. and Knowles, M.A. (1993) Initiation of bladder cancer may involve deletion of a tumour-suppressor gene on chromosome 9. Oncogene 8, 1083-1085Google Scholar PubMed

18Miyao, N. et al. (1993) Role of chromosome 9 in human bladder cancer. Cancer Research 53, 4066-4070Google Scholar PubMed

19Llnnenbach, A.J. et al. (1993) Characterization of chromosome 9 deletions in transitional cell carcinoma by microsatellite assay. Human Molecular Genetics 2, 1407-1411CrossRef Google Scholar

20Orlow, I. et al. (1994) Chromosome 9 allelic losses and microsatellite alterations in human bladder tumors. Cancer Research 54, 2848-2851Google Scholar PubMed

21Habuchi, T. et al. (1995) Detailed deletion mapping of chromosome 9q in bladder cancer: evidence for two tumour suppressor loci. Oncogene 11, 1671-1674Google Scholar PubMed

22Keen, A.J. and Knowles, M.A. (1994) Definition of two regions of deletion on chromosome 9 in carcinoma of the bladder. Oncogene 9, 2083-2088Google Scholar PubMed

23Simoneau, A.R. et al. (1996) Evidence for two tumor suppressor loci associated with proximal chromosome 9p to q and distal chromosome 9q in bladder cancer and the initial screening for GAS1 and PTC mutations. Cancer Research 56, 5039-5043Google Scholar

24Serrano, M., Hannon, G.J. and Beach, D. (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366, 704-707CrossRef Google Scholar PubMed

25Hannon, G.J. and Beach, D. (1994) p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371, 257-261CrossRef Google Scholar PubMed

26Schulze, A. et al. (1994) Activation of the E2F transcription factor by cyclin D1 is blocked by p16INK4, the product of the putative tumor suppressor gene MTS1. Oncogene 9, 3475-3482Google Scholar PubMed

27Johnson, D.G. (1995) Regulation of E2F-1 gene expression by p130 (Rb2) and D-type cyclin kinase activity. Oncogene 11, 1685-1692Google Scholar PubMed

28Gonzalez-Zulueta, M. et al. (1995) high frequency of chromosome 9p allelic loss and CDKN2 tumor suppressor gene alterations in squamous cell carcinoma of the bladder. Journal of the National Cancer Institute 87, 1383-1393CrossRef Google Scholar PubMed

29Gonzalez-Zulueta, M. et al. (1995) Methylation of the 5' CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. Cancer Research 55, 4531-4535Google Scholar PubMed

30Orlow, I. et al. (1995) Deletion of the p16 and p15 genes in human bladder tumors. Journal of the National Cancer Institute 87, 1524-1529CrossRef Google Scholar PubMed

31Southgate, J. et al. (1995) Loss of cyclin-dependent kinase inhibitor genes and chromosome 9 karyotypic abnormalities in human bladder cancer cell lines. British Journal of Cancer 72, 1214-1218CrossRef Google Scholar PubMed

32Le Frere-Belda, M.A. et al. (2001) p15INK4b in bladder carcinomas: decreased expression in superficial tumours. British Journal of Cancer 85, 1515-1521CrossRef Google Scholar PubMed

33Hornigold, N. et al. (1999) Mutation of the 9q34 gene TSC1 in sporadic bladder cancer. Oncogene 18, 2567-2561CrossRef Google Scholar PubMed

34Hornigold, N. et al. (1997) A 1.7-megabase sequence-ready cosmid contig covering the TSC1 candidate region in 9q34. Genomics 41, 385-389CrossRef Google Scholar PubMed

35van Slegtenhorst, M. et al. (1997) Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277, 805-808CrossRef Google Scholar PubMed

36Knowles, M.A. et al. (2003) Mutation spectrum of the 9q34 tuberous sclerosis gene TSC1 in transitional cell carcinoma of the bladder. Cancer Research 63, 7652-7656Google Scholar PubMed

37Pymar, L.S. et al. (2008) Bladder tumour-derived somatic TSC1 missense mutations cause loss of function via distinct mechanisms. Human Molecular Genetics 17, 2006-2017CrossRef Google Scholar PubMed

38Adachi, H. et al. (2003) Human bladder tumors with 2-hit mutations of tumor suppressor gene TSC1 and decreased expression of p27. Journal of Urology 170, 601-604CrossRef Google Scholar PubMed

39Habuchi, T., Yoshida, O. and Knowles, M.A. (1997) A novel candidate tumour suppressor locus at 9q32-33 in bladder cancer: localization of the candidate region within a single 840 kb YAC. Human Molecular Genetics 6, 913-919CrossRef Google Scholar PubMed

40Habuchi, T. et al. (1998) Structure and methylation-based silencing of a gene (DBCCR1) within a candidate bladder cancer tumor suppressor region at 9q32–q33. Genomics 48, 277-288CrossRef Google Scholar PubMed

41Simoneau, M. et al. (1999) Four tumor suppressor loci on chromosome 9q in bladder cancer: evidence for two novel candidate regions at 9q22.3 and 9q31. Oncogene 18, 157-163CrossRef Google Scholar PubMed

42Joanne, E. et al. (2002) Identification of loci associated with putative recurrence genes in transitional cell carcinoma of the urinary bladder. Journal of Pathology 196, 380-385Google Scholar

43Friedrich, M.G. et al. (2001) Frequent p16/MTS1 inactivation in early stages of urothelial carcinoma of the bladder is not associated with tumor recurrence. European Urology 40, 518-524CrossRef Google Scholar

44Bartoletti, R. et al. (2007) Loss of P16 expression and chromosome 9p21 LOH in predicting outcome of patients affected by superficial bladder cancer. Journal of Surgical Research 143, 422-427CrossRef Google Scholar

45Bartlett, J.M. et al. (1998) Is chromosome 9 loss a marker of disease recurrence in transitional cell carcinoma of the urinary bladder? British Journal of Cancer 77, 2193-2198CrossRef Google Scholar

46Lopez-Beltran, A. et al. (2008) Loss of heterozygosity at 9q32-33 (DBC1 locus) in primary non-invasive papillary urothelial neoplasm of low malignant potential and low-grade urothelial carcinoma of the bladder and their associated normal urothelium. Journal of Pathology 215, 263-272CrossRef Google Scholar PubMed

47Eswarakumar, V.P., Lax, I. and Schlessinger, J. (2005) Cellular signaling by fibroblast growth factor receptors. Cytokine & Growth Factor Reviews 16, 139-149CrossRef Google Scholar PubMed

48Karuppiah, K. and David, G. (2000) FGF receptor mutations: dimerization syndromes, cell growth suppression, and animal models. IUBMB Life 49, 197-205Google Scholar

49L'Hôte, C.G.M. and Knowles, M.A. (2005) Cell responses to FGFR3 signalling: growth, differentiation and apoptosis. Experimental Cell Research 304, 417-431CrossRef Google Scholar PubMed

50Murgue, B. et al. (1994) Identification of a novel variant form of fibroblast growth factor receptor 3 (FGFR3 IIIb) in human colonic epithelium. Cancer Research 54, 5206-5211Google Scholar PubMed

51Rousseau, F. et al. (1994) Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371, 252-254CrossRef Google Scholar PubMed

52Shiang, R. et al. (1994) Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78, 335-342CrossRef Google Scholar PubMed

53Bellus, G.A. et al. (1995) A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nature Genetics 10, 357-359CrossRef Google Scholar PubMed

54Superti-Furga, A. et al. (1995) A glycine 375-to-cysteine substitution in the transmembrane domain of the fibroblast growth factor receptor-3 in a newborn with achondroplasia. European Journal of Pediatrics 154, 215-219CrossRef Google Scholar

55Ikegawa, S. et al. (1995) Mutations of the fibroblast growth factor receptor-3 gene in one familial and six sporadic cases of achondroplasia in Japanese patients. Human Genetics 96, 309-311CrossRef Google Scholar PubMed

56Tavormina, P.L. et al. (1995) Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nature Genetics 9, 321-328CrossRef Google Scholar PubMed

57Tavormina, P.L. et al. (1995) Another mutation that results in the substitution of an unpaired cysteine residue in the extracellular domain of FGFR3 in thanatophoric dysplasia type I. Human Molecular Genetics 4, 2175-2177CrossRef Google Scholar PubMed

58Fuu-Jen, T. et al. (1999) Mutations in the fibroblast growth factor receptor 3 (FGFR3) cause achondroplasia, hypochondroplasia, and thanatophoric dysplasia: Taiwanese data. American Journal of Medical Genetics 86, 300-301Google Scholar

59Bonaventure, J. et al. (1996) Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism. American Journal of Medical Genetics 63, 148-1543.0.CO;2-N>CrossRef Google Scholar PubMed

60Cappellen, D. et al. (1999) Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nature Genetics 23, 18-20CrossRef Google Scholar PubMed

61Karoui, M. et al. (2001) No evidence of somatic FGFR3 mutation in various types of carcinoma. Oncogene 20, 5059-5061CrossRef Google Scholar PubMed

62Sibley, K., Stern, P. and Knowles, M.A. (2001) Frequency of fibroblast growth factor receptor 3 mutations in sporadic tumours. Oncogene 20, 4416-4418CrossRef Google Scholar PubMed

63Webster, M.K. and Donoghue, D.J. (1997) FGFR activation in skeletal disorders: too much of a good thing. Trends in Genetics 13, 178-182CrossRef Google Scholar PubMed

64Naski, M.C. et al. (1996) Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nature Genetics 13, 233-237CrossRef Google Scholar PubMed

65Agazie, Y.M. et al. (2003) The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3. Oncogene 22, 6909-6918CrossRef Google Scholar PubMed

66Kanai, M. et al. (1997) Signal transduction pathway of human fibroblast growth factor receptor 3. Journal of Biological Chemistry 272, 6621-6628CrossRef Google Scholar PubMed

67Jebar, A.H. et al. (2005) FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma. Oncogene 24, 5218-5225CrossRef Google Scholar PubMed

68van Rhijn, B.W.G. et al. (2001) The fibroblast growth factor receptor 3 (FGFR3) mutation is a strong indicator of superficial bladder cancer with low recurrence rate. Cancer Research 61, 1265-1268Google Scholar

69Billerey, C. et al. (2001) Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. American Journal of Pathology 158, 1955-1959CrossRef Google Scholar PubMed

70Spruck, C.H. III, et al. (1994) Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Research 54, 784-788Google Scholar PubMed

71Reznikoff, C.A. et al. (1996) A molecular genetic model of human bladder cancer pathogenesis. Seminars in Oncology 23, 571-584Google Scholar PubMed

72Lee, R. and Droller, M.J. (2000) The natural history of bladder cancer. Implications for therapy. Urologic Clinics of North America 27, 1-13CrossRef Google Scholar PubMed

73Sanchez-Carbayo, M. et al. (2002) Molecular profiling of bladder cancer using cDNA microarrays: defining histogenesis and biological phenotypes. Cancer Research 62, 6973-6980Google Scholar PubMed

74Sanchez-Carbayo, M. et al. (2003) Gene discovery in bladder cancer progression using cDNA microarrays. American Journal of Pathology 163, 505-516CrossRef Google Scholar PubMed

75Dyrskjøt, L. et al. (2003) Identifying distinct classes of bladder carcinoma using microarrays. Nature Genetics 33, 90-96CrossRef Google Scholar PubMed

76Takahiro, K. et al. (2001) The incidence of thanatophoric dysplasia mutations in FGFR3 gene is higher in low-grade or superficial bladder carcinomas. Cancer 92, 2555-2561Google Scholar

77van Rhijn, B.W. et al. (2002) Frequent FGFR3 mutations in urothelial papilloma. Journal of Pathology 198, 245-251CrossRef Google Scholar PubMed

78Cordon-Cardo, C. et al. (1994) p53 mutations in human bladder cancer: genotypic versus phenotypic patterns. International Journal of Cancer 56, 347-353CrossRef Google Scholar PubMed

79Spiess, P.E. and Czerniak, B. (2006) Dual-track pathway of bladder carcinogenesis: practical implications. Archives of Pathology and Laboratory Medicine 130, 844-852CrossRef Google Scholar PubMed

80van Rhijn, B.W.G. et al. (2004) FGFR3 and P53 characterize alternative genetic pathways in the pathogenesis of urothelial cell carcinoma. Cancer Research 64, 1911-1914CrossRef Google Scholar PubMed

81Mhawech-Fauceglia, P. et al. (2006) FGFR3 and p53 protein expressions in patients with pTa and pT1 urothelial bladder cancer. European Journal of Surgical Oncology 32, 231-237CrossRef Google Scholar

82Lott, S. et al. (2009) FGFR3 and TP53 mutation analysis in inverted urothelial papilloma: incidence and etiological considerations. Modern Pathology 22, 627-632CrossRef Google Scholar PubMed

83van Rhijn, B.W.G. 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. Journal of Clinical Oncology 21, 1912-1921CrossRef Google Scholar PubMed

84Hernandez, S. et al. (2006) Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. Journal of Clinical Oncology 24, 3664-3671CrossRef Google Scholar PubMed

85Burger, M. et al. (2008) Prediction of progression of non-muscle-invasive bladder cancer by WHO 1973 and 2004 grading and by FGFR3 mutation status: a prospective study. European Urology 54, 835-844CrossRef Google Scholar PubMed

86Francesca, B. et al. (2008) Strong immunohistochemical expression of fibroblast growth factor receptor 3, superficial staining pattern of cytokeratin 20, and low proliferative activity define those papillary urothelial neoplasms of low malignant potential that do not recur. Cancer 112, 636-644Google Scholar

87Gazdar, A.F. et al. (2004) Mutations and addiction to EGFR: the Achilles ‘heal’ of lung cancers? Trends in Molecular Medicine 10, 481-486CrossRef Google Scholar PubMed

88Weinstein, I.B., Joe, A. and Felsher, D. (2008) Oncogene addiction. Cancer Research 68, 3077-3080CrossRef Google Scholar PubMed

89Trudel, S. et al. (2005) CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood 105, 2941-2948CrossRef Google Scholar PubMed

90Mohammadi, M. et al. (1997) Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science 276, 955-960CrossRef Google Scholar PubMed

91Grand, E.K. et al. (2004) Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074. Leukemia 18, 962-966CrossRef Google Scholar PubMed

92Trudel, S. et al. (2004) Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma. Blood 103, 3521-3528CrossRef Google Scholar

93Mohammadi, M. et al. (1998) Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO Journal 17, 5896-5904CrossRef Google Scholar

94Laird, A.D. et al. (2000) SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Research 60, 4152-4160Google Scholar PubMed

95Rauchenberger, R. et al. (2003) Human combinatorial Fab library yielding specific and functional antibodies against the human fibroblast growth factor receptor 3. Journal of Biological Chemistry 278, 38194-38205CrossRef Google Scholar PubMed

96Martínez -Torrecuadrada, J. et al. (2005) Targeting the extracellular domain of fibroblast growth factor receptor 3 with human single-chain Fv antibodies inhibits bladder carcinoma cell line proliferation. Clinical Cancer Research 11, 6280-6290CrossRef Google Scholar PubMed

97Gorbenko, O. et al. (2009) Generation of monoclonal antibody targeting fibroblast growth factor receptor 3. Hybridoma 28, 295-300CrossRef Google Scholar PubMed

98Qing, J. et al. (2009) Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. Journal of Clinical Investigation 119, 1216-1229CrossRef Google Scholar

99Martínez-Torrecuadrada, J.L. et al. (2008) Antitumor activity of fibroblast growth factor receptor 3–specific immunotoxins in a xenograft mouse model of bladder carcinoma is mediated by apoptosis. Molecular Cancer Therapeutics 7, 862-873CrossRef Google Scholar

100Herrera, R. and Sebolt-Leopold, J.S. (2002) Unraveling the complexities of the Raf/MAP kinase pathway for pharmacological intervention. Trends in Molecular Medicine 8, S27-S31CrossRef Google Scholar PubMed

101Jiang, B. et al. (2009) Chapter 2 PI3K/PTEN signaling in angiogenesis and tumorigenesis. Advances in Cancer Research 102, 19-65Google Scholar

102Rusanescu, G. et al. (2001) Regulation of Ras signaling specificity by protein kinase C. Molecular and Cellular Biology 21, 2650-2658CrossRef Google Scholar PubMed

103Feinberg, A.P. et al. (1983) Mutation affecting the 12th amino acid of the c-Ha-ras oncogene product occurs infrequently in human cancer. Science 220, 1175-1177CrossRef Google Scholar PubMed

104Fujita, J. et al. (1984) Ha-ras oncogenes are activated by somatic alterations in human urinary tract tumours. Nature 309, 464-466CrossRef Google Scholar PubMed

105Fujita, J. et al. (1985) Frequency of molecular alterations affecting ras protooncogenes in human urinary tract tumors. Proceedings of the National Academy of Sciences of the United States of America 82, 3849-3853CrossRef Google Scholar PubMed

106Visvanathan, K.V., Pocock, R.D. and Summerhayes, I.C. (1988) Preferential and novel activation of H-ras in human bladder carcinomas. Oncogene Research 3, 77-86Google Scholar PubMed

107Joyce, A.D. et al. (1989) Detection of altered H-ras proteins in human tumors using western blot analysis. Laboratory Investigation 61, 212-218Google Scholar PubMed

108Saito, S. et al. (1997) Screening of H-ras gene point mutations in 50 cases of bladder carcinoma. International Journal of Urology 4, 178-185CrossRef Google Scholar PubMed

109Boulalas, I. et al. (2009) Activation of RAS family genes in urothelial carcinoma. Journal of Urology 181, 2312-2319CrossRef Google Scholar PubMed

110Tabin, C.J. et al. (1982) Mechanism of activation of a human oncogene. Nature 300, 143-149CrossRef Google Scholar PubMed

111Reddy, E.P. et al. (1982) A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature 300, 149-152CrossRef Google Scholar PubMed

112Taparowsky, E. et al. (1982) Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. Nature 300, 762-765CrossRef Google Scholar PubMed

113Theodorescu, D. et al. (1990) Overexpression of normal and mutated forms of HRAS induces orthotopic bladder invasion in a human transitional cell carcinoma. Proceedings of the National Academy of Sciences of the United States of America 87, 9047-9051CrossRef Google Scholar

114Czerniak, B. et al. (1992) Concurrent mutations of coding and regulatory sequences of the Ha-ras gene in urinary bladder carcinomas. Human Pathology 23, 1199-1204CrossRef Google Scholar PubMed

115John, J.G. et al. (2000) Genetic and phenotypic changes associated with the acquisition of tumorigenicity in human bladder cancer. Genes, Chromosomes and Cancer 27, 252-263Google Scholar

116Knowles, M.A. and 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 Research 53, 133-139Google Scholar PubMed

117Fitzgerald, J.M. et al. (1995) Identification of H-ras mutations in urine sediments complements cytology in the detection of bladder tumors. Journal of the National Cancer Institute 87, 129-133CrossRef Google Scholar PubMed

118Zhang, Z.T. et al. (2001) Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation. Oncogene 20, 1973-1980CrossRef Google Scholar PubMed

119Gao, J. et al. (2004) p53 deficiency provokes urothelial proliferation and synergizes with activated Ha-ras in promoting urothelial tumorigenesis. Oncogene 23, 687-696CrossRef Google Scholar PubMed

120Mo, L. et al. (2007) Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis. Journal of Clinical Investigation 117, 314-325CrossRef Google Scholar

121Saison-Behmoaras, T. et al. (1991) Short modified antisense oligonucleotides directed against Ha-ras point mutation induce selective cleavage of the mRNA and inhibit T24 cells proliferation. EMBO Journal 10, 1111-1118CrossRef Google Scholar PubMed

122Eastham, J.A. and Ahlering, T.E. (1996) Use of an anti-ras ribozyme to alter the malignant phenotype of a human bladder cancer cell line. Journal of Urology 156, 1186-1188CrossRef Google Scholar PubMed

123Irie, A. et al. (1999) Therapeutic efficacy of an adenovirus-mediated anti-H-ras ribozyme in experimental bladder cancer. Antisense and Nucleic Acid Drug Development 9, 341-349CrossRef Google Scholar PubMed

124Choudhary, S. and Wang, H-C.R. (2007) Proapoptotic ability of oncogenic H-Ras to facilitate apoptosis induced by histone deacetylase inhibitors in human cancer cells. Molecular Cancer Therapeutics 6, 1099-1111CrossRef Google Scholar PubMed

125Choudhary, S. and Wang, H.C. (2007) Pro-apoptotic activity of oncogenic H-Ras for histone deacetylase inhibitor to induce apoptosis of human cancer HT29 cells. Journal of Cancer Research and Clinical Oncology 133, 725-739CrossRef Google Scholar PubMed

126Choudhary, S. and Wang, H.C. (2009) Role of reactive oxygen species in proapoptotic ability of oncogenic H-Ras to increase human bladder cancer cell susceptibility to histone deacetylase inhibitor for caspase induction. Journal of Cancer Research and Clinical Oncology 135, 1601-1613CrossRef Google Scholar PubMed

127Luo, J. et al. (2009) A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137, 835-848CrossRef Google Scholar PubMed

128Scholl, C. et al. (2009) Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 137, 821-834CrossRef Google Scholar PubMed

129Zhu, K., Hamilton, A.D. and Sebti, S.M. (2004) Farnesyltransferase inhibitors as anticancer agents: current status. Current Opinion in Investigational Drugs 4, 1428-1435Google Scholar

130Sebti, S.M. and Hamilton, A.D. (2000) Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: lessons from mechanism and bench-to-bedside translational studies. Oncogene 19, 6584-6593CrossRef Google Scholar PubMed

131Sebti, S.M. and Adjei, A.A. (2004) Farnesyltransferase inhibitors. Seminars in Oncology 31, 28-39CrossRef Google Scholar PubMed

132Brunner, T.B. et al. (2003) Farnesyltransferase inhibitors: an overview of the results of preclinical and clinical investigations. Cancer Research 63, 5656-5668Google Scholar PubMed

133Cohen-Jonathan, E. et al. (2000) Farnesyltransferase inhibitors potentiate the antitumor effect of radiation on a human tumor xenograft expressing activated HRAS. Radiation Research 154, 125-132CrossRef Google Scholar PubMed

134Davies, H. et al. (2002) Mutations of the BRAF gene in human cancer. Nature 417, 949-954CrossRef Google Scholar PubMed

135Singer, G. et al. (2003) Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. Journal of the National Cancer Institute 95, 484-486CrossRef Google Scholar PubMed

136Kimura, E.T. et al. (2003) High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Research 63, 1454-1457Google Scholar PubMed

137Mansour, S.J. et al. (1994) Transformation of mammalian cells by constitutively active MAP kinase kinase. Science 265, 966-970CrossRef Google Scholar PubMed

138Hoshino, R. et al. (1999) Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18, 813-822CrossRef Google Scholar PubMed

139Katz, M.E. and McCormick, F. (1997) Signal transduction from multiple Ras effectors. Current Opinion in Genetics & Development 7, 75-79CrossRef Google Scholar PubMed

140Williams, N.G. and Roberts, T.M. (1994) Signal transduction pathways involving the Raf proto-oncogene. Cancer and Metastasis Reviews 13, 105-116CrossRef Google Scholar PubMed

141Lee, J.T. and McCubrey, J.A. (2003) BAY-43-9006 Bayer/Onyx. Current Opinion in Investigational Drugs 4, 757-763Google Scholar PubMed

142Hotte, S.J. and Hirte, H.W. (2002) BAY 43-9006: early clinical data in patients with advanced solid malignancies. Current Pharmaceutical Design 8, 2249-2253CrossRef Google Scholar PubMed

143DeGrendele, H. (2003) Activity of the Raf kinase inhibitor BAY 43-9006 in patients with advanced solid tumors. Clinical Colorectal Cancer 3, 16-18CrossRef Google Scholar

144Sebolt-Leopold, J.S. et al. (1999) Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nature Medicine 5, 810-816CrossRef Google Scholar PubMed

145Allen, L.F., Sebolt-Leopold, J. and Meyer, M.B. (2003) CI-1040 (PD184352), a targeted signal transduction inhibitor of MEK (MAPKK). Seminars in Oncology 30, 105-116CrossRef Google Scholar PubMed

146Rinehart, J. et al. (2004) Multicenter Phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. Journal of Clinical Oncology 22, 4456-4462CrossRef Google Scholar PubMed

147Yeh, T.C. et al. (2007) Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clinical Cancer Research 13, 1576-1583CrossRef Google Scholar PubMed

148Davies, B.R. et al. (2007) AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Molecular Cancer Therapeutics 6, 2209-2219CrossRef Google Scholar PubMed

149Lojo Rial, C., Wilby, D. and Sooriakumaran, P. (2009) Role and rationale of gene therapy and other novel therapies in the management of NMIBC. Expert Review of Anticancer Therapy 9, 1777-1782CrossRef Google Scholar PubMed

150Botteman, M.F. et al. (2003) The health economics of bladder cancer: a comprehensive review of the published literature. Pharmacoeconomics 21, 1315-1330CrossRef Google Scholar PubMed

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Molecular genesis of non-muscle-invasive urothelial carcinoma (NMIUC)

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Article contents

Molecular genesis of non-muscle-invasive urothelial carcinoma (NMIUC)

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