The negative regulators of the RAS-RAF-MAPK pathway, which inhibit RAS activity (RASSF1A, RASSF2A, RASSF5, RASAL1) or inhibit the RAF kinase (SPRED1, SPRED2) are frequently repressed by promoter methylation in HCC [38, 65]. Here, RASSF5 is linked to hepatocellular carcinoma.