SMAD4 mediates the transcriptional response to TGF-beta and loss of SMAD4 has been implicated in several cancers. Simple variants in SMAD4 are found in about 3% of all tumors, including up to 50% of gastrointestinal tumors (intestine and pancreas). Mutations in SMAD4 are involved in several hereditary syndromes with cancer predisposition, including juvenile polyposis syndrome and hemorrhagic hereditary telangiectasia (HHT) syndrome. SMAD4 loss is associated with a worse prognosis in colorectal and pancreatic carcinomas.