SMAD4 and familial pancreatic carcinoma: In particular, four genes (also known as the “Big 4”) are the most mutated in early pancreatic cancer, namely KRAS, TP53, CDKN2A, and SMAD4 (formerly known as DPC4), with their alterations detected for 94%, 64%, 21%, and 17% of all PDACs, respectively (30).