The genomic landscape of pancreatic ductal adenocarcinoma (PDAC) has been defined by the four most commonly mutated pathways, including Kirsten rat sarcoma virus (KRAS) mutations, cellular tumor antigen p53 (TP53) mutations, cyclin-dependent kinase inhibitor 2A (CDKN2A) alterations, and SMAD family member 4 (SMAD4) inactivation, which were called the “big four” [2,3]. The gene discussed is SMAD4; the disease is pancreatic ductal adenocarcinoma.