Colorectal cancers (CRCs) frequently harbor somatic mutations in the pathway members SMAD4. The prevalence of SMAD4, SMAD2, and SMAD3 mutations in sporadic CRCs was 8.6% (64 of 744), 3.4% (25 of 744), and 4.3% (32 of 744), respectively. Somatic SMAD4 mutations have been reported to be more common in advanced stages of CRCs and LOH at the SMAD4 locus has been associated with poor prognosis. SMAD4 mutations were associated with mucinous histology. SMAD4 P356L has been identified in tumors. Although it has not been biochemically characterized, it is a statistically significant hotspot and is predicted to be oncogenic.