Microsatellite instability and alternative genetic pathway in intrahepatic cholangiocarcinoma.
OBJECTIVE
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 M
Momoi
H
H
Department of Gastroenterological Surgery, Kyoto University Graduate School of Medicine, Japan.
Itoh
T
T
Nozaki
Y
Y
Arima
Y
Y
Okabe
H
H
Satoh
S
S
Toda
Y
Y
Sakai
E
E
Nakagawara
K
K
Flemming
P
P
Yamamoto
M
M
Shimahara
Y
Y
Yamaoka
Y
Y
Fukumoto
M
M
D000328:Adult; D000368:Aged; D001483:Base Sequence; D001650:Bile Duct Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D018281:Cholangiocarcinoma / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins; D011110:Polymorphism, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2
D004273:DNA, Neoplasm; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2