학술논문
Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles
Document Type
article
Author
Farshad Farshidfar; Siyuan Zheng; Marie-Claude Gingras; Yulia Newton; Juliann Shih; A. Gordon Robertson; Toshinori Hinoue; Katherine A. Hoadley; Ewan A. Gibb; Jason Roszik; Kyle R. Covington; Chia-Chin Wu; Eve Shinbrot; Nicolas Stransky; Apurva Hegde; Ju Dong Yang; Ed Reznik; Sara Sadeghi; Chandra Sekhar Pedamallu; Akinyemi I. Ojesina; Julian M. Hess; J. Todd Auman; Suhn K. Rhie; Reanne Bowlby; Mitesh J. Borad; Andrew X. Zhu; Josh M. Stuart; Chris Sander; Rehan Akbani; Andrew D. Cherniack; Vikram Deshpande; Taofic Mounajjed; Wai Chin Foo; Michael S. Torbenson; David E. Kleiner; Peter W. Laird; David A. Wheeler; Autumn J. McRee; Oliver F. Bathe; Jesper B. Andersen; Nabeel Bardeesy; Lewis R. Roberts; Lawrence N. Kwong
Source
Cell Reports, Vol 18, Iss 11, Pp 2780-2794 (2017)
Subject
Language
English
ISSN
2211-1247
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.