SMAD4 and neoplasm: In this context, it was evident from these studies that telomere shortening and activating mutations in KRAS are among the more frequent and early events in pancreatic carcinogenesis; these gene abnormalities are followed at later stages of tumor development by inactivating mutations of the p16 (CDKN2A) tumor suppressor and in the TP53 and SMAD4 tumor suppressor genes.