SMAD4 and pancreatic adenocarcinoma: The adenoma-carcinoma sequence leading to the development of pancreatic adenocarcinoma is currently under investigation but include as major events telomere shortening, KRAS activating mutation, loss and/or mutation of SMAD4 and p53. [14] Since recent whole-exome analysis, GNAS mutations also appear to have a key role in IPMN pathogenesis.[15] With KRAS, it is therefore, one of the 2 most prevalent mutations in these tumors.