TGFB1 and renal cell carcinoma: In particular, silencing of negative regulators of cell cycle (RASSF1 and KILLIN), activation of Wnt pathway by suppression of Wnt antagonists (SFRP1, SFRP2, SFRP5, and WIF-1), TGF-β activation by promoter methylation of negative regulators (GATA-3, GREM-1, and SMAD-6) and silencing pro-apoptotic genes (APAF-1) are the most important mechanisms that explain why gene hypermethylation plays an important role in development and progression of RCC [33,52].