SMAD4 and cancer: Nonhypermutated tumors carry common “driver” mutations in APC, TP53, KRAS, PIK3CA, FBXW7, SMAD4, TCF7L2, NRAS, CTNNB1, SMAD2, FAM123B, SOX9, ATM, and ARID1A, while hypermutated tumors commonly have alterations in ACVR2A, APC, TGFBR2, BRAF, MSH3, MSH6, SLC9A9, and TCF7L2. In both nonhypermutated and hypermutated tumors, alterations in “cancer genes” target the WNT, RTK/RAS, PI3K, TGF-β, and TP53 pathways [6], demonstrating that the genetic complexity of CRC is likely limited to various mutations within signaling and metabolic pathways [3].