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The present study aimed to characterize intrahepatic cholangiocarcinomas (iCCAs) with MDM2 amplification. A total of 213 cases of iCCA were examined using dual-color in situ hybridization for MDM2, immunohistochemistry for p53 and SMAD4, and gene sequencing for KRAS and IDH1/2. In situ hybridization on tissue microarrays identified MDM2 amplification in 13/213 (6%) cases. Using the recently proposed classification scheme of iCCAs (small-duct and large-duct types), all MDM2-amplified cases were of the large-duct type (13/110 cases, 12%). In whole section hybridization, MDM2 amplification appeared to be diffusely present in invasive areas. The loss of SMAD4 expression was more common in MDM2-amplified iCCAs than in those without MDM2 amplification. The relationship between MDM2 amplification and molecular alterations in p53 or KRAS was weak, with p53 overexpression and KRAS mutations only being found in 23% and 0% of cases, respectively. Overall survival was shorter in patients with MDM2-amplified iCCAs than in those with MDM2-nonamplified cancer (P=0.017); however, the lack of a prognostic impact of MDM2 amplification was confirmed in a subgroup analysis using only large-duct iCCAs. Additional studies on extrahepatic malignancies also identified MDM2 amplification in 8/68 (12%) hilar cholangiocarcinomas and 30/216 (14%) gallbladder cancers, but in 0/65 distal cholangiocarcinomas. In conclusion, MDM2 amplification in large-duct iCCAs is more common than presently considered, and it may represent a unique biliary carcinogenetic process in which KRAS and TP53 mutations are less frequent. MDM2 may become a promising drug target for not only large-duct iCCAs but also hilar and gallbladder cancers.