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

F. Farshidfar, S. Zheng, M. C. Gingras, Y. Newton, J. Shih, A. G. Robertson, T. Hinoue, K. A. Hoadley, E. A. Gibb, J. Roszik, K. R. Covington, C. C. Wu, E. Shinbrot, N. Stransky, A. Hegde, J. D. Yang, E. Reznik, S. Sadeghi, C. S. Pedamallu, A. I. OjesinaJ. M. Hess, J. T. Auman, S. K. Rhie, R. Bowlby, M. J. Borad, Cancer Genome Atlas Network, A. X. Zhu, J. M. Stuart, C. Sander, R. Akbani, A. D. Cherniack, V. Deshpande, T. Mounajjed, W. C. Foo, M. S. Torbenson, D. E. Kleiner, P. W. Laird, D. A. Wheeler, A. J. McRee, O. F. Bathe, J. B. Andersen, N. Bardeesy, L. R. Roberts, L. N. Kwong, Gian Luca Grazi

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)2780-2794
Number of pages15
JournalCell Reports
Volume18
Issue number11
DOIs
Publication statusPublished - Mar 14 2017

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Keywords

  • ARID1A
  • DNA methylation
  • IDH
  • RNA sequencing
  • TCGA
  • cholangiocarcinoma
  • integrative genomics
  • lncRNAs
  • multi-omics
  • whole exome

Cite this

Farshidfar, F., Zheng, S., Gingras, M. C., Newton, Y., Shih, J., Robertson, A. G., Hinoue, T., Hoadley, K. A., Gibb, E. A., Roszik, J., Covington, K. R., Wu, C. C., Shinbrot, E., Stransky, N., Hegde, A., Yang, J. D., Reznik, E., Sadeghi, S., Pedamallu, C. S., ... Grazi, G. L. (2017). Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles. Cell Reports, 18(11), 2780-2794. https://doi.org/S2211-1247(17)30214-0 [pii]