SMAD4 encodes a tumor suppressor and transcription factor that is a downstream effector in the TGF-ss signal transduction pathway. Germline mutations in SMAD4 have been associated with juvenile polyposis syndrome (JPS). Loss of SMAD4 expression or somatic mutations in SMAD4 are found in pancreatic cancer and are associated with tumor grade. Somatic alterations in SMAD4 are observed at lower frequencies in multiple tumor types, including colon and lung adenocarcinoma. SMAD4 R361C lies at a hotspot residue within MH2 domain of the Smad4 protein (UniProt.org). R361C confers a loss of function to the Smad4 protein as demonstrated by reduced Smad4 transactivating activity in cell assays. The SMAD4 R361C mutation is likely oncogenic. Studies of loss of function somatic mutations and studies of loss of heterozygosity (LOH) at the SMAD4 locus have shown an association with poor prognosis. There are ongoing clinical trials for colorectal tumors harboring SMAD4 alterations.