SMAD4 and colorectal carcinoma: Recently, in a study comprising more than 700 primary colorectal cancer (CRC) tumors and 36 CRC cell lines, missense mutations have been mapped in the co-Smad encoding gene SMAD4, and in SMAD2 and SMAD3[117]; these mutations cluster in two hot-spots located at the protein level in the MH2 domain of these Smads.