SMAD4 and cancer: The most common driver mutational events in PDAC occur in four cancer genes KRAS, TP53, SMAD4, and CDKN2A. KRAS is activated by mutation in almost 90% of cases, TP53 is inactivated in 50%–75% of cases, and CDK2NA is inactivated in about 30% of patients with PDAC [10,53].