SMAD4 and neoplasm: In addition to high-frequency alteration of KRAS, TP53, and SMAD4, ∼30% of PDACs harbor inactivating mutations in CDKN2A, which encodes for two tumor suppressors: (1) INK4A that encodes p16INK4A, a stoichiometric inhibitor of CDK4/6; and (2) ARF that encodes p14ARF, a regulator of the MDM2>TP53 pathway (Otto and Sicinski, 2017).