SMAD4 and hepatocellular carcinoma: For example, TβRII mutations are frequently found in colorectal cancer (CRC),90SMAD2 mutations have been reported in CRC, hepatocellular carcinoma (HCC), and lung cancer,91,92 and the deletion or mutation of SMAD4 is often identified in pancreatic cancer, CRC, and HCC.93,94 There are several advanced tumors that still retain an intact canonical TGFβ pathway, such as glioma, melanoma, and breast cancer.