Dysplastic changes progress from low-grade PanIN to high-grade PanIN and eventually invasive PDAC by a sequence of further inactivation of tumor-suppressor genes such as TP53, transforming growth factor-beta (TGF-β) signaling genes (SMAD4, TGFBR1, TGFBR2) or cyclin-dependent kinase inhibitor 2A (CDKN2a) [27,28,29]. Here, SMAD4 is linked to neoplasm.