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

Farshidfar F, Zheng S, Gingras MC, Newton Y, Shih J, Robertson AG, Hinoue T, Hoadley KA, Gibb EA, Roszik J, Covington KR, Wu CC, Shinbrot E, Stransky N, Hegde A, Yang JD, Reznik E, Sadeghi S, Pedamallu CS, Ojesina AI, Hess JM, Auman JT, Rhie SK, Bowlby R, Borad MJ, Cancer Genome Atlas Network, Zhu AX, Stuart JM, Sander C, Akbani R, Cherniack AD, Deshpande V, Mounajjed T, Foo WC, Torbenson MS, Kleiner DE, Laird PW, Wheeler DA, McRee AJ, Bathe OF, Andersen JB, Bardeesy N, Roberts LR, Kwong LN
Cell Rep. 2017 18 (11): 2780-2794

PMID: 28297679 · PMCID: PMC5493145 · DOI:10.1016/j.celrep.2017.02.033

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.

Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

MeSH Terms (25)

Adult Aged Aged, 80 and over Bile Duct Neoplasms Cholangiocarcinoma Chromatin DNA Methylation Female Gene Expression Regulation, Neoplastic Genomics 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

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