title: Kras(G12D) and p53 mutation cause primary intrahepatic cholangiocarcinoma.
abstract: Intrahepatic cholangiocarcinoma (IHCC) is a primary cancer of the liver with an increasing incidence and poor prognosis. Preclinical studies of the etiology and treatment of this disease are hampered by the relatively small number of available IHCC cell lines or genetically faithful animal models. Here we report the development of a genetically engineered mouse model of IHCC that incorporates two of the most common mutations in human IHCC, activating mutations of Kras (Kras(G12D)) and deletion of p53. Tissue-specific activation of Kras(G12D) alone resulted in the development of invasive IHCC with low penetrance and long latency. Latency was shortened by combining Kras(G12D) activation with heterozygous or homozygous deletion of p53 (mean survival of 56 weeks vs. 19 weeks, respectively), which also resulted in widespread local and distant metastasis. Serial analysis showed that the murine models closely recapitulated the multistage histopathologic progression of the human disease, including the development of stroma-rich tumors and the premalignant biliary lesions, intraductal papillary biliary neoplasms (IPBN), and Von Meyenburg complexes (VMC; also known as biliary hamartomas). These findings establish a new genetically and histopathologically faithful model of IHCC and lend experimental support to the hypothesis that IPBN and VMC are precursors to invasive cancers.
authors.affiliation: James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, New York 14642, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: O'Dell
authors.forename: Jing Li
authors.initials: JL
authors.lastname: Huang
authors.forename: Christa L
authors.initials: CL
authors.lastname: Whitney-Miller
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.forename: Paul
authors.initials: P
authors.lastname: Rothberg
authors.forename: Valerie
authors.initials: V
authors.lastname: Grose
authors.forename: Randall M
authors.initials: RM
authors.lastname: Rossi
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.forename: Hartmut
authors.initials: H
authors.lastname: Land
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.forename: Aram F
authors.initials: AF
authors.lastname: Hezel
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms; D001653:Bile Ducts, Intrahepatic; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005818:Genetic Engineering; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)