Microsatellite instability and alternative genetic pathway in intrahepatic cholangiocarcinoma

Hirohito Momoi, Tomoko Itoh, Yoshihiro Nozaki, Yuriko Arima, Hiroshi Okabe, Seiji Satoh, Yoshinobu Toda, Eiichi Sakai, Kanichi Nakagawara, Peer Flemming, Masayuki Yamamoto, Yasuyuki Shimahara, Yoshio Yamaoka, Manabu Fukumoto

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)


Background/Aims: Intrahepatic cholangiocarcinoma (ICC) arises from intrahepatic bile duct epithelium and is the second most prevalent among primary liver cancers. The aim of this study was to clarify the mechanism of cholangiocarcinogenesis. Methods: We studied the incidence of microsatellite instability (MSI) involving eight highly polymorphic microsatellite markers and alternations of the 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 cases (4.6%) at codon 12. Analysis of p53 alterations was performed in 28 cases 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 cases analyzed. In 22 frozen samples, seven (31.8%) cases showed mdm-2 amplification and four (18.2%) cases revealed MSI-positive phenotype. Among the cases analyzed, all the tumors with mdm-2 amplification/overexpression harbored the wild-type p53 gene and all the microsatellite instability-positive cases were from mass-forming (MF) + 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 that MSI is associated with a subset of MF ± PI type tumors.

Original languageEnglish
Pages (from-to)235-244
Number of pages10
JournalJournal of Hepatology
Issue number2
Publication statusPublished - 2001
Externally publishedYes


  • Carcinogenesis
  • Intrahepatic cholangiocarcinoma
  • K-ras
  • Mdm-2
  • Microsatellite instability
  • P53

ASJC Scopus subject areas

  • Hepatology


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