HIF-1α and HIF-2α stabilization, as well as HIF-α target genes, can be detected in VHL-deficient renal epithelial cells in the context of normal tubules or microscopic ccRCC precursor lesions in kidneys of patients with inherited VHL disease, indicating that constitutive HIF-α activity is present even before tumors form [6]. This evidence concerns the gene VHL and nonpapillary renal cell carcinoma.