Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.

TitleIntegrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.
Publication TypeJournal Article
Year of Publication2017
AuthorsFarshidfar, F, Zheng, S, Gingras, M-C, Newton, Y, Shih, J, A Robertson, G, Hinoue, T, Hoadley, KA, Gibb, EA, Roszik, J, Covington, KR, Wu, C-C, Shinbrot, E, Stransky, N, Hegde, A, Yang, JDong, Reznik, E, Sadeghi, S, Pedamallu, CSekhar, Ojesina, AI, Hess, JM, J Auman, T, Rhie, SK, Bowlby, R, Borad, MJ, Zhu, AX, Stuart, JM, Sander, C, Akbani, R, Cherniack, AD, Deshpande, V, Mounajjed, T, Foo, WChin, Torbenson, MS, Kleiner, DE, Laird, PW, Wheeler, DA, McRee, AJ, Bathe, OF, Andersen, JB, Bardeesy, N, Roberts, LR, Kwong, LN
Corporate AuthorsCancer Genome Atlas Network
JournalCell Rep
Volume18
Issue11
Pagination2780-2794
Date Published2017 03 14
ISSN2211-1247
KeywordsAdult, Aged, Aged, 80 and over, Bile Duct Neoplasms, Cholangiocarcinoma, Chromatin, DNA Methylation, Female, Gene Expression Regulation, Neoplastic, Genomics, Humans, Isocitrate Dehydrogenase, Liver, Liver Neoplasms, Male, Middle Aged, Mitochondria, Mutation, Nuclear Proteins, Pancreatic Neoplasms, Promoter Regions, Genetic, RNA, Long Noncoding, RNA, Messenger, Transcription Factors
Abstract

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.

DOI10.1016/j.celrep.2017.02.033
Alternate JournalCell Rep
PubMed ID28297679
PubMed Central IDPMC5493145
Grant ListP30 CA016672 / CA / NCI NIH HHS / United States
U24 CA143882 / CA / NCI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
U54 HG006097 / HG / NHGRI NIH HHS / United States
R01 GM109031 / GM / NIGMS NIH HHS / United States
U24 CA210950 / CA / NCI NIH HHS / United States
U24 CA143845 / CA / NCI NIH HHS / United States
U24 CA143799 / CA / NCI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
U24 CA144025 / CA / NCI NIH HHS / United States
U24 CA143840 / CA / NCI NIH HHS / United States
U24 CA143843 / CA / NCI NIH HHS / United States
U24 CA143858 / CA / NCI NIH HHS / United States
U24 CA143848 / CA / NCI NIH HHS / United States
U54 HG003079 / HG / NHGRI NIH HHS / United States
R01 CA180778 / CA / NCI NIH HHS / United States
U24 CA210949 / CA / NCI NIH HHS / United States
U24 CA143883 / CA / NCI NIH HHS / United States
U24 CA143867 / CA / NCI NIH HHS / United States
U24 CA199461 / CA / NCI NIH HHS / United States
U24 CA210990 / CA / NCI NIH HHS / United States

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