New oncogenes and tumor suppressor genes that play an important role in the pathogenesis of urothelial bladder carcinoma have been discovered. The objectives of this review were to summarize the most important oncogenes and tumor suppressor genes involved in urothelial carcinoma and to address their role in pathogenesis, their prognostic value, and their potential use as therapeutic targets. The collected data led the authors to propose a common pathway in which the fibroblastic growth factor receptor 3 (FGFR3) mutation seems to be the earliest genetic abnormality responsible for the transformation from normal tissue to atypia and dysplasia. Three different progression pathways were proposed: The first operative pathway is from dysplasia to superficial papillary pathologic Ta (pTa) tumors to pT1 tumors and, ultimately, to pT2 tumors with FGFR3 and tuberous sclerosis complex 1 (TSC1) the responsible genes. The second major operative pathway is from dysplasia, to carcinoma in situ, and to solid pT1 and pT2 tumors. The third pathway of progression is from dysplasia to papillary T1 and pT2 tumors. The genes involved in the last 2 pathways are the p53, serine threonine protein kinase 15 (STK15), triple-function domain (TRIO), fragile histidine triad (FHIT), p63 genes; and alterations of 20q and 5p, alterations of adhesions, angiogenesis, and matrix-remodeling gene products also are involved. Finally, murine leukemia viral oncogene homologue 1 (RAF1) and CD9 are involved in the progression from papillary pT1 tumors to pT2 tumors.
(c) 2006 American Cancer Society.