MOLECULAR-GENETICS OF RENAL CARCINOGENESIS

Renal cell carcinoma (RCC) is the most common tumor of the adult kidne y, accounting for similar to 85% of renal neoplasms. RCC is heterogene ous in appearance, displaying diverse histologic and cytologic charact eristics, with the clear cell variant being the most common. Individua ls at high risk for this disease include persons with end-stage renal disease, those with hereditary predispositions such as von Hippel-Lind au syndrome (VHL) or tuberous sclerosis (TSC), and individuals with si gnificant environment exposures such as smoking or analgesic abuse. Re cently, several of the genetic targets for alterations involved in the development of human RCC have been identified. Solid RCC of the clear cell type is associated with alterations in the VHL tumor suppressor gene and hereditary papillary RCC is associated with alterations of th e c-met protooncogene. In the rat, the most commonly seen tumors are o f the non-clear cell type and it is the Tsc-2 tumor suppressor gene, r ather than the VHL tumor suppressor gene, that appears to be the prima ry target for both spontaneous and carcinogen-induced mutations in the se animals. These data suggest that different variants of RCC have dis tinct molecular etiologies and that there are species-specific determi nants that modulate the involvement of specific tumor suppressor genes in RCC. Interestingly, many of the genes involved in RCC also play si gnificant roles in kidney development. The Wilm's tumor suppressor gen e, WT-1, and Pax-2 regulate the mesenchymal epithelial transition that occurs during nephrogenesis and both these genes exhibit altered expr ession patterns and/or are mutated in renal tumors. Other genes such a s c-met and its ligand hepatocyte growth factor are also involved in n ormal development and tumorigenesis, suggesting that tumors arise as a result of altered functions that are reflective of events that occur during nephrogenesis.