VHL and nonpapillary renal cell carcinoma: HIF-2α is believed to be the critical VHL target driving ccRCC carcinogenesis, since HIF-2α but not HIF-1α is overexpressed in potentially all VHL-null ccRCC patient tumors [44]; overexpression of HIF-2α but not HIF-1α is sufficient to restore ccRCC cell line tumorigenicity suppressed by VHL overexpression [48, 49]; and higher RCC tumor levels of HIF-2α portend a worse patient prognosis [50].