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

CONSORTIA

Research output: Contribution to journalArticle

91 Citations (Scopus)

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 (US)
Pages (from-to)2780-2794
Number of pages15
JournalCell Reports
Volume18
Issue number11
DOIs
StatePublished - Mar 14 2017
Externally publishedYes

Fingerprint

Cholangiocarcinoma
Genes
Mitochondrial DNA
Liver
Ducts
Chromatin
Tumors
RNA
Neoplasms
Mutation
Mitochondrial Genes
Atlases
DNA
DNA Methylation
Bile Ducts
Genome
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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

In: Cell Reports, Vol. 18, No. 11, 14.03.2017, p. 2780-2794.

Research output: Contribution to journalArticle

@article{51f778ba12fe4efab6208418d45d3b94,
title = "Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles",
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.",
keywords = "ARID1A, cholangiocarcinoma, DNA methylation, IDH, integrative genomics, lncRNAs, multi-omics, RNA sequencing, TCGA, whole exome",
author = "CONSORTIA and Farshad Farshidfar and Siyuan Zheng and Gingras, {Marie Claude} and Yulia Newton and Juliann Shih and Robertson, {A. Gordon} and Toshinori Hinoue and Hoadley, {Katherine A.} and Gibb, {Ewan A.} and Jason Roszik and Covington, {Kyle R.} and Wu, {Chia Chin} and Eve Shinbrot and Nicolas Stransky and Apurva Hegde and Yang, {Ju Dong} and Ed Reznik and Sara Sadeghi and Pedamallu, {Chandra Sekhar} and Ojesina, {Akinyemi I.} and Hess, {Julian M.} and Auman, {J. Todd} and Rhie, {Suhn K.} and Reanne Bowlby and Borad, {Mitesh J.} and Zhu, {Andrew X.} and Stuart, {Josh M.} and Chris Sander and Rehan Akbani and Cherniack, {Andrew D.} and Vikram Deshpande and Taofic Mounajjed and Foo, {Wai Chin} and Torbenson, {Michael S.} and Kleiner, {David E.} and Laird, {Peter W.} and Wheeler, {David A.} and McRee, {Autumn J.} and Bathe, {Oliver F.} and Andersen, {Jesper B.} and Nabeel Bardeesy and Roberts, {Lewis R.} and Kwong, {Lawrence N.} and Allotey, {Loretta K.} and Adrian Ally and Domenico Alvaro and Appelbaum, {Elizabeth L.} and Arshi Arora and Auman, {J. Todd} and Gordon Mills",
year = "2017",
month = "3",
day = "14",
doi = "10.1016/j.celrep.2017.02.033",
language = "English (US)",
volume = "18",
pages = "2780--2794",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",

}

TY - JOUR

T1 - Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles

AU - CONSORTIA

AU - Farshidfar, Farshad

AU - Zheng, Siyuan

AU - Gingras, Marie Claude

AU - Newton, Yulia

AU - Shih, Juliann

AU - Robertson, A. Gordon

AU - Hinoue, Toshinori

AU - Hoadley, Katherine A.

AU - Gibb, Ewan A.

AU - Roszik, Jason

AU - Covington, Kyle R.

AU - Wu, Chia Chin

AU - Shinbrot, Eve

AU - Stransky, Nicolas

AU - Hegde, Apurva

AU - Yang, Ju Dong

AU - Reznik, Ed

AU - Sadeghi, Sara

AU - Pedamallu, Chandra Sekhar

AU - Ojesina, Akinyemi I.

AU - Hess, Julian M.

AU - Auman, J. Todd

AU - Rhie, Suhn K.

AU - Bowlby, Reanne

AU - Borad, Mitesh J.

AU - Zhu, Andrew X.

AU - Stuart, Josh M.

AU - Sander, Chris

AU - Akbani, Rehan

AU - Cherniack, Andrew D.

AU - Deshpande, Vikram

AU - Mounajjed, Taofic

AU - Foo, Wai Chin

AU - Torbenson, Michael S.

AU - Kleiner, David E.

AU - Laird, Peter W.

AU - Wheeler, David A.

AU - McRee, Autumn J.

AU - Bathe, Oliver F.

AU - Andersen, Jesper B.

AU - Bardeesy, Nabeel

AU - Roberts, Lewis R.

AU - Kwong, Lawrence N.

AU - Allotey, Loretta K.

AU - Ally, Adrian

AU - Alvaro, Domenico

AU - Appelbaum, Elizabeth L.

AU - Arora, Arshi

AU - Auman, J. Todd

AU - Mills, Gordon

PY - 2017/3/14

Y1 - 2017/3/14

N2 - 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.

AB - 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.

KW - ARID1A

KW - cholangiocarcinoma

KW - DNA methylation

KW - IDH

KW - integrative genomics

KW - lncRNAs

KW - multi-omics

KW - RNA sequencing

KW - TCGA

KW - whole exome

UR - http://www.scopus.com/inward/record.url?scp=85015247880&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85015247880&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2017.02.033

DO - 10.1016/j.celrep.2017.02.033

M3 - Article

C2 - 28297679

AN - SCOPUS:85015247880

VL - 18

SP - 2780

EP - 2794

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 11

ER -