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Hepatology. 2019 Jan 7. doi: 10.1002/hep.30493. [Epub ahead of print]

Integrative analysis defines distinct prognostic subgroups of intrahepatic cholangiocarcinoma.

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Institute of Pathology, University Clinic of Heidelberg, Heidelberg, Germany.
Liver Cancer Center Heidelberg (LCCH).
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Institute of Pathology, Ernst-Moritz-Arndt University, Greifswald, Germany.
Boston Children's Hospital, Boston, USA.
Department of General Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Germany.
German Consortium for Translational Cancer Research (DKTK).


Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer. It is defined by cholangiocytic differentiation and has poor prognosis. Recently, epigenetic processes have been shown to play an important role in cholangiocarcinogenesis. We here performed an integrative analysis on 52 iCCAs using both genetic and epigenetic data with specific focus on DNA methylation components. We found recurrent IDH1 and IDH2 (28%) gene mutations, recurrent arm-length copy number alterations (CNAs), and focal alterations such as deletion of 3p21 or amplification of 12q15 which affect BAP1, PBRM1, and MDM2. DNA methylome analysis revealed excessive hypermethylation of iCCA, mainly affecting bivalent genomic regions marked with both active and repressive histone modifications. Integrative clustering of genetic and epigenetic data identified four iCCA subgroups with prognostic relevance further designated as IDH, high (H), medium (M) and low (L) alterations group. The IDH group comprised all samples with IDH1 or IDH2 mutations and showed, together with the H group, a highly disrupted genome, characterized by frequent deletions of chromosome arms 3p and 6q. Both groups showed excessive hypermethylation with distinct patterns. The M group showed intermediate characteristics regarding both genetic and epigenetic marks, whereas the L group exhibited few methylation changes and mutations and a lack of CNAs. Methylation-based latent component analysis of cell-type composition identified differences between these four groups. Prognosis of the H and M groups was significantly worse than that of the L group. CONCLUSION: Using an integrative genomic and epigenomic analysis approach, we identified four major iCCA subgroups with widespread genomic and epigenomic differences and prognostic implications. Furthermore, our data suggest differences in the cell-of-origin of the iCCA subtypes. This article is protected by copyright. All rights reserved.


DNA Methylation; Integrative clustering; Intrahepatic cholangiocarcinoma; Molecular subgroups; iCluster


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