Most of Smad4 gene mutations in human cancer are missense, nonsense, and frameshift mutations at the mad homology 2 region (MH2) which interfere with the homo-oligomer formation of Smad4 protein and hetero-oligomer formation between Smad4 and Smad2 proteins, resulting in disruption of TGF-β signaling (Shi, 2001; Woodford-Richens et al., 2001; Roth et al., 2003). Here, SMAD4 is linked to cancer.