Thus, at present, it is well established that virtually all PDAC carry activating (point) mutations of KRAS (93% of tumors) [9,10] and inactivating alterations of the CDKN2A/p16 (95%) [3], TP53 (72–74%) [6,9], and SMAD4/DPC4 (50–78%) genes [3,6,9,11], which progressively accumulate from early pancreatic pre-neoplastic lesions to late-stage metastatic disease [12]. This evidence concerns the gene SMAD4 and metastatic neoplasm.