Loss of VHL function causes a release of HIF-1/2α from VHL-mediated ubiquitination and degradation, which allows for the accumulation of HIF-1/2α, thereby driving transcriptional activation of its downstream target genes related to metabolism, cell cycle and angiogenesis, in turn contributing to ccRCC development [11]. This evidence concerns the gene VHL and nonpapillary renal cell carcinoma.