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

Fingerprint

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

Keywords

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

Cite this

Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles. / 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.; Ojesina, A. I.; Hess, J. M.; Auman, J. T.; Rhie, S. K.; Bowlby, R.; Borad, M. J.; Network, Cancer Genome Atlas; Zhu, A. X.; Stuart, J. M.; Sander, C.; Akbani, R.; Cherniack, A. D.; Deshpande, V.; Mounajjed, T.; Foo, W. C.; Torbenson, M. S.; Kleiner, D. E.; Laird, P. W.; Wheeler, D. A.; McRee, A. J.; Bathe, O. F.; Andersen, J. B.; Bardeesy, N.; Roberts, L. R.; Kwong, L. N.; Grazi, Gian Luca.

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

Research output: Contribution to journalArticle

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, Network, CGA, 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 & Grazi, GL 2017, 'Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles', Cell Reports, vol. 18, no. 11, pp. 2780-2794. https://doi.org/S2211-1247(17)30214-0 [pii]
Farshidfar F, Zheng S, Gingras MC, Newton Y, Shih J, Robertson AG et al. Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles. Cell Reports. 2017 Mar 14;18(11):2780-2794. https://doi.org/S2211-1247(17)30214-0 [pii]
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. ; Ojesina, A. I. ; Hess, J. M. ; Auman, J. T. ; Rhie, S. K. ; Bowlby, R. ; Borad, M. J. ; Network, Cancer Genome Atlas ; Zhu, A. X. ; Stuart, J. M. ; Sander, C. ; Akbani, R. ; Cherniack, A. D. ; Deshpande, V. ; Mounajjed, T. ; Foo, W. C. ; Torbenson, M. S. ; Kleiner, D. E. ; Laird, P. W. ; Wheeler, D. A. ; McRee, A. J. ; Bathe, O. F. ; Andersen, J. B. ; Bardeesy, N. ; Roberts, L. R. ; Kwong, L. N. ; Grazi, Gian Luca. / Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles. In: Cell Reports. 2017 ; Vol. 18, No. 11. pp. 2780-2794.
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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.",
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T1 - Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles

AU - Farshidfar, F.

AU - Zheng, S.

AU - Gingras, M. C.

AU - Newton, Y.

AU - Shih, J.

AU - Robertson, A. G.

AU - Hinoue, T.

AU - Hoadley, K. A.

AU - Gibb, E. A.

AU - Roszik, J.

AU - Covington, K. R.

AU - Wu, C. C.

AU - Shinbrot, E.

AU - Stransky, N.

AU - Hegde, A.

AU - Yang, J. D.

AU - Reznik, E.

AU - Sadeghi, S.

AU - Pedamallu, C. S.

AU - Ojesina, A. I.

AU - Hess, J. M.

AU - Auman, J. T.

AU - Rhie, S. K.

AU - Bowlby, R.

AU - Borad, M. J.

AU - Network, Cancer Genome Atlas

AU - Zhu, A. X.

AU - Stuart, J. M.

AU - Sander, C.

AU - Akbani, R.

AU - Cherniack, A. D.

AU - Deshpande, V.

AU - Mounajjed, T.

AU - Foo, W. C.

AU - Torbenson, M. S.

AU - Kleiner, D. E.

AU - Laird, P. W.

AU - Wheeler, D. A.

AU - McRee, A. J.

AU - Bathe, O. F.

AU - Andersen, J. B.

AU - Bardeesy, N.

AU - Roberts, L. R.

AU - Kwong, L. N.

AU - Grazi, Gian Luca

N1 - LR: 20170728; CI: Copyright (c) 2017; GR: U24 CA210978/CA/NCI NIH HHS/United States; GR: P30 CA016672/CA/NCI NIH HHS/United States; GR: U24 CA143882/CA/NCI NIH HHS/United States; GR: U54 HG003067/HG/NHGRI NIH HHS/United States; GR: U54 HG006097/HG/NHGRI NIH HHS/United States; GR: R01 GM109031/GM/NIGMS NIH HHS/United States; GR: U24 CA210950/CA/NCI NIH HHS/United States; GR: U24 CA143845/CA/NCI NIH HHS/United States; GR: U24 CA143799/CA/NCI NIH HHS/United States; GR: U54 HG003273/HG/NHGRI NIH HHS/United States; GR: U24 CA144025/CA/NCI NIH HHS/United States; GR: U24 CA143840/CA/NCI NIH HHS/United States; GR: U24 CA143843/CA/NCI NIH HHS/United States; GR: U24 CA143858/CA/NCI NIH HHS/United States; GR: U24 CA143848/CA/NCI NIH HHS/United States; GR: U54 HG003079/HG/NHGRI NIH HHS/United States; GR: R01 CA180778/CA/NCI NIH HHS/United States; GR: U24 CA210949/CA/NCI NIH HHS/United States; GR: U24 CA143883/CA/NCI NIH HHS/United States; GR: U24 CA143867/CA/NCI NIH HHS/United States; GR: U24 CA199461/CA/NCI NIH HHS/United States; GR: U24 CA210990/CA/NCI NIH HHS/United States; JID: 101573691; EIN: Cell Rep. 2017 Jun 27;19(13):2878-2880. PMID: 28658632; NIHMS866722; OTO: NOTNLM; 2016/05/23 [received]; 2017/01/04 [revised]; 2017/02/09 [accepted]; ppublish

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 - DNA methylation

KW - IDH

KW - RNA sequencing

KW - TCGA

KW - cholangiocarcinoma

KW - integrative genomics

KW - lncRNAs

KW - multi-omics

KW - whole exome

U2 - S2211-1247(17)30214-0 [pii]

DO - S2211-1247(17)30214-0 [pii]

M3 - Article

VL - 18

SP - 2780

EP - 2794

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 11

ER -