SMAD4 and pachyonychia congenita: The cellular origin of PDAC is still disputable, as both acinar and ductal cells are heterogeneous in their capacity to be transformed.14,15 Nevertheless, mutation in the proto-oncogene KRAS is the most common event and the primary regulator of the initiation of PC,16,17 abetted by sequential inhibition or inactivation of tumor suppressor genes during the progression of precancerous lesions [pancreatic intraepithelial neoplasia (PanIN)], including cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor suppressor p53 (TP53), and SMAD family member 4 (SMAD4).