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

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 Kyong 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; Cancer Genome Atlas Network

doi:10.1016/j.celrep.2017.02.033

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

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 OjesinaJulian M Hess, J Todd Auman, Suhn Kyong 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, Cancer Genome Atlas Network

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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.

Original language	English
Journal	Cell Reports
Volume	18
Issue number	11
Pages (from-to)	2780-2794
Number of pages	15
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2017.02.033
Publication status	Published - 14 Mar 2017

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Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular ProfilesFinal published version, 2.05 MBLicence: CC BY

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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., ... Cancer Genome Atlas Network (2017). Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles. Cell Reports, 18(11), 2780-2794. https://doi.org/10.1016/j.celrep.2017.02.033

Farshidfar, F, Zheng, S, Gingras, M-C, Newton, Y, Shih, J, Robertson, AG, Hinoue, T, Hoadley, KA, Gibb, EA, Roszik, J, Covington, KR, Wu, C-C, 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, 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 & Cancer Genome Atlas Network 2017, 'Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles', Cell Reports, vol. 18, no. 11, pp. 2780-2794. https://doi.org/10.1016/j.celrep.2017.02.033

@article{6985e85dfe1d44ada66519134869cdc3,

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.",

author = "Farshad Farshidfar and Siyuan Zheng and Marie-Claude Gingras 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 Chia-Chin Wu 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 Kyong} 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 {Cancer Genome Atlas Network}",

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doi = "10.1016/j.celrep.2017.02.033",

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

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 Kyong

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 - Cancer Genome Atlas Network

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.

U2 - 10.1016/j.celrep.2017.02.033

DO - 10.1016/j.celrep.2017.02.033

M3 - Journal article

C2 - 28297679

SN - 2211-1247

VL - 18

SP - 2780

EP - 2794

JO - Cell Reports

JF - Cell Reports

IS - 11

ER -

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

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