SMAD4 and colorectal cancer: It has been genetically demonstrated using human normal intestinal organoids that the simultaneous introduction of mutations in APC, KRAS, PIK3CA, SMAD4, and TP53, four or five major driver genes for colorectal cancer, induces epithelial cell transformation resulting in the development of transplantable tumors in vivo (Drost et al., 2015; Matano et al., 2015).