VHL and nonpapillary renal cell carcinoma: Inactivation of VHL by mutations has been demonstrated to cause to the accumulation and/or activation of HIFs, Akt and other substrates, thereby triggering oncogenic pathways and driving the development of the hereditary von Hippel–Lindau (VHL) disease and certain types of human cancer such as sporadic clear-cell renal cell carcinoma (ccRCC) [5, 10, 11].