Mutational inactivation of downstream mediators of the activin signaling axis that overlap with TGF-β, such as the SMAD2/3/4 [69,70,71,72,73,74], has been well-documented in many cancer types, providing further genetic support that activin/TGF-β signaling axes are tumor-suppressive and are selectively inactivated genetically during tumor clonal evolution. This evidence concerns the gene SMAD2 and neoplasm.