VHL-inactivation may be associated with activation of the epidermal growth factor receptor/phosphatidylinositol-3-OH kinase/protein kinase B (AKT)/IkappaB-kinase alpha/NF-kappaB signalling cascade [28], and so RCC without VHL inactivation may be predisposed to dysregulate these key signalling pathways by preferential methylation of other regulators. This evidence concerns the gene VHL and renal cell carcinoma.