EVI1 expression is associated with aggressive behavior in intrahepatic cholangiocarcinoma
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Ecotropic virus integration site 1 protein homolog (EVI1), a well-known oncogenic transcriptional factor of hematopoietic cells, contributes to pancreatic cancer oncogenicity through increased expression of KRAS. Because EVI1 was upregulated in cholangiocarcinoma by referring The Cancer Genome Atlas, we investigated the importance of EVI1 in intrahepatic cholangiocarcinoma (ICC) which has been regarded as a heterogeneous group of cancers. Immunohistochemical analysis results demonstrated that EVI1 was overexpressed in about half of ICC (53/101, 52.5%). Moreover, all intraductal papillary neoplasms of the bile duct cases expressed EVI1 regardless of histological grading and subtypes such as gastric, intestinal, pancreatobiliary, or oncocytic (20/20, 100%). EVI1-positive ICC showed higher frequencies of aggressive pathological indicators such as periductal infiltrative growth (p = 0.022), hilar invasion (p = 0.041), advanced UICC stage (p = 0.026), major vascular invasion (p = 0.026), and perineural invasion (p = 0.007) than EVI1-negative ICC. Patients with EVI1-positive ICC showed worse overall survival and recurrence-free survival in all resected cases and in curative resected cases. Recently, we proposed type 1/2 (large/small duct types) classification of ICC based on mucin productivity and immunophenotypes (S100P, N-cadherin, and NCAM). Type 1 predominantly consisted of EVI1-positive ICC (33/42 cases, 79%), and the frequency was significantly higher than type 2 (18/55 cases, 32.7%) (p < 0.0001). EVI1-positive ICC was likely to express stomach-specific claudin CLDN18 (correlation coefficient r = 0.55373) and mucin MUC5AC (r = 0.42718). EVI1-positive ICC is an aggressive ICC showing both large-duct and/or gastric phenotypes. Consequently, a transcriptional factor EVI1 is associated with aggressive behavior in ICC and can be a therapeutic target molecule, while EVI1 might be a key molecule for the development of intraductal papillary neoplasms of the bile duct.
KeywordsEVI1 Intrahepatic cholangiocarcinoma Type 1 Type 2 Gastric phenotype
We thank all members of the Department of Pathology of The University of Tokyo especially for Kimiko Takeshita and Aiko Nishimoto. We also thank Dr. Yasunori Sato for the kind advice about statistical analysis.
MT and MF contributed to the design and organization and conducted the study and wrote the manuscript. JS, AH, and KM created the pathological database. SI, TU, TM, AS, AT, and HK advised the direction of study and the interpretation of the data. KS helped in the immunohistochemical process. TK, YI, JA, YS, and KH contributed to provide surgical samples and clinical data. All the authors reviewed and accepted the manuscript.
Compliance with ethical standards
The study was approved by the institutional review board.
Conflict of interest
The authors declare that they have no conflict of interest.
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