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 Mar 14
ISSN2211-1247
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
Grant ListR01 CA180778 / CA / NCI NIH HHS / United States
R01 GM109031 / GM / NIGMS NIH HHS / United States
U24 CA210990 / CA / NCI NIH HHS / United States
U54 HG006097 / HG / NHGRI NIH HHS / United States