Exclusion of SMAD4 mutation as an early genetic change in human pancreaticductal tumorigenesis

Pancreatic ductal carcinoma is one of the malignant diseases with the poore st prognosis. To develop effective methods for better treatment of pancreat ic cancer patients, we tried to analyze the course of multistep carcinogene sis of the pancreatic ductal cells. IPMT (intraductal papillary-mucinous tu mor) is thought to be one of the premalignant lesions of the pancreas, whic h would transform into carcinomas. Loss of 18q at the SMAD4 locus is known to be an early genetic change in pancreatic ductal carcinomas. It is not cl ear, however, whether or not the target gene for inactivation is SMAD4. Usi ng 18 IPMTs, we analyzed LOH at the SMAD4 locus and observed frequent LOH ( 7/14, 50%). No mutations were observed in any of the tumors. Moreover, the expression level of the SMAD4 protein did not show a reduction in IPMTs. Th ese results suggested that (i) inactivating mutation of the SMAD4 gene is a rather late genetic change in pancreatic carcinogenesis, and (ii) there ma y be an unknown tumor suppressor gene in 18q, other than SMAD4, that is inv olved in pancreatic ductal carcinogenesis. (C) 2001 Wiley-Liss, Inc.