SMAD4 and colorectal carcinoma: Numerous colorectal carcinoma GEMMs have been developed (41–43), from random mutagenesis-induced Apc inactivation in the ApcMin model characterized more than 30 years ago, to those precisely mirroring key human alterations (e.g., colon-specific conditional expression of biallelic Apc inactivation and Kras p.G12D mutation, with combinations of Trp53 mutation/loss and/or Smad4 inactivation; refs. 44, 45).