TY - JOUR
T1 - Microsatellite instability and alternative genetic pathway in intrahepatic cholangiocarcinoma
AU - Momoi, Hirohito
AU - Itoh, Tomoko
AU - Nozaki, Yoshihiro
AU - Arima, Yuriko
AU - Okabe, Hiroshi
AU - Satoh, Seiji
AU - Toda, Yoshinobu
AU - Sakai, Eiichi
AU - Nakagawara, Kanichi
AU - Flemming, Peer
AU - Yamamoto, Masayuki
AU - Shimahara, Yasuyuki
AU - Yamaoka, Yoshio
AU - Fukumoto, Manabu
N1 - Funding Information:
This work was supported in part by grants from a Grant-in-Aid from the Ministry of Education, Sports and Culture, and Health Labour and Welfare of Japan, and under contracts with the Nuclear Safety Research Association of Japan and Japan Space Forum.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
KW - Carcinogenesis
KW - Intrahepatic cholangiocarcinoma
KW - K-ras
KW - Mdm-2
KW - Microsatellite instability
KW - P53
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U2 - 10.1016/S0168-8278(01)00106-4
DO - 10.1016/S0168-8278(01)00106-4
M3 - Article
C2 - 11580146
AN - SCOPUS:17944370494
VL - 35
SP - 235
EP - 244
JO - Journal of Hepatology
JF - Journal of Hepatology
SN - 0168-8278
IS - 2
ER -