Additionally, SMAD4, encoding the SMAD4 transcription factor activating many genes in response to transforming growth factor beta (TGFB)/bone morphogenetic protein (BMP) signaling (69,70), is a well-known tumor suppressor gene that is highly mutated in many cancers, including pancreatic and colorectal cancers (71). This evidence concerns the gene SMAD4 and colorectal cancer.