SMAD4 and familial pancreatic carcinoma: To confirm unequivocally that the neoplastic cells in the duodenal mucosa were of pancreatic origin, rather than reactive intestinal cells secondary to PDAC infiltration into the submucosa, we used two independent immunohistochemical markers, SMAD4 and p53; SMAD4 is lost in approximately half of all pancreatic cancer cases [19]; while TP53 mutations, which lead to accumulation of mutant p53 protein, are detectable in 50% of patients, independently of alterations in SMAD419.