Integrative Analysis Defines Distinct Prognostic Subgroups of Intrahepatic Cholangiocarcinoma

Benjamin Goeppert*, Reka Toth, Stephan Singer, Thomas Albrecht, Daniel B. Lipka, Pavlo Lutsik, David Brocks, Marion Baehr, Oliver Muecke, Yassen Assenov, Lei Gu, Volker Endris, Albrecht Stenzinger, Arianeb Mehrabi, Peter Schirmacher, Christoph Plass, Dieter Weichenhan, Stephanie Roessler

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

46 Citations (Scopus)

Abstract

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 performed an integrative analysis on 52 iCCAs using both genetic and epigenetic data with a specific focus on DNA methylation components. We found recurrent isocitrate dehydrogenase 1 (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 BRCA1 Associated Protein 1, polybromo 1, and mouse double minute 2 homolog. DNA methylome analysis revealed excessive hypermethylation of iCCA, affecting primarily the 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) alteration groups. The IDH group consisted of 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 among 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.

Original languageEnglish
Pages (from-to)2091-2106
Number of pages16
JournalHepatology
Volume69
Issue number5
DOIs
Publication statusPublished - May 2019
Externally publishedYes

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