VHL and nonpapillary renal cell carcinoma: Subsequent pre-clinical work identified that, in the majority of sporadic ccRCC cases, alterations of the von Hippel-Lindau (VHL) gene by deletion, mutation, or methylation led to inactivation, causing upregulation of HIF-α and increased production of VEGF and platelet-derived growth factor (PDGF), promoting tumor angiogenesis, growth, and metastasis [69,70,71].