Microsatellite instability and alternative genetic pathway in intrahepaticcholangiocarcinoma

Background/Aims: Intrahepatic cholangiocarcinoma (ICC) arises from intrahep atic bile duct epithelium and is the second most prevalent among primary li ver cancers. The aim of this study was to clarify the mechanism of cholangi ocarcinogenesis. Methods: We studied the incidence of microsatellite instability (NISI) invo lving eight highly polymorphic microsatellite markers and alternations of t he K-ras, p53 and mdm-2 genes in human ICC tissues. Overexpression of mdm-2 oncoprotein was also immunohistochemically studied. Results: Of all 65 cases examined, K-ras gene mutation was found in three c ases (4.6%) at codon 12.Analysis of p53 alterations was performed in 28 cas es including 22 frozen samples and mutations were found in three cases (10. 7%). Overexpression of mdm-2 protein was observed in 25 (41.7%) out of 60 c ases analyzed. In 22 frozen samples, seven (31.8%) cases showed mdm-2 ampli fication and four (18.2%) cases revealed NISI-positive phenotype. Among the cases analyzed, all the tumors with mdm-2 amplification/overexpression har bored the wild-type p53 gene and all the microsatellite instability-positiv e cases were from mass-forming (NIF) + periductal-infiltrating (PI) subtype . Conclusions: These results suggest that mdm-2 plays a role, which might be partially through inhibiting p53 activity, in cholangiocarcinogenesis and t hat MSI is associated with a subset of MF +/- PI type tumors. (C) 2001 Euro pean Association for the Study of the Liver. Published by Elsevier Science BN. All rights reserved.