SMAD4 and colorectal carcinoma: Similar conclusions were reached by Kawaguchi et al. who analyzed the possible relationship between somatic gene mutation profile and outcome in 507 metastatic CRC patients who underwent CLM resection: BRAF, RAS, TP53, and SMAD4 mutations were significantly associated with overall survival, coexisting mutations in RAS, TP53, and SMAD4 were associated with negative outcome (reduced OS and RFS) than coexisting mutations in any two of these genes and mutations in one or more of these genes [60].