Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles
Farshad Farshidfar(University of Calgary), Siyuan Zheng(The University of Texas MD Anderson Cancer Center), Marie‐Claude Gingras(Baylor College of Medicine), Yulia Newton(University of California, Santa Cruz), Juliann Shih(Broad Institute), A. Gordon Robertson(BC Cancer Agency), Toshinori Hinoue(Van Andel Institute), Katherine A. Hoadley(University of North Carolina at Chapel Hill), Ewan A. Gibb(BC Cancer Agency), Jason Roszik(The University of Texas MD Anderson Cancer Center), Kyle R. Covington(Baylor College of Medicine), Chia-Chin Wu(The University of Texas MD Anderson Cancer Center), Eve Shinbrot(Baylor College of Medicine), Nicolas Stransky(Blueprint Medicines (United States)), Apurva M. Hegde(The University of Texas MD Anderson Cancer Center), Ju Dong Yang(Mayo Clinic), Ed Reznik(Memorial Sloan Kettering Cancer Center), Sara Sadeghi(BC Cancer Agency), Chandra Sekhar Pedamallu(Broad Institute), Akinyemi I. Ojesina(University of Alabama at Birmingham), Julian M. Hess(Broad Institute), J. Todd Auman(University of North Carolina at Chapel Hill), Suhn K. Rhie(University of Southern California), Reanne Bowlby(BC Cancer Agency), Mitesh J. Borad(Mayo Clinic in Arizona), Rehan Akbani(The University of Texas MD Anderson Cancer Center), Loretta K. Allotey(University of California, Santa Cruz), Adrian Ally(Memorial Sloan Kettering Cancer Center), Domenico Alvaro(The University of Texas MD Anderson Cancer Center), Jesper B. Andersen(Broad Institute), Elizabeth L. Appelbaum(Harvard University), Arshi Arora(Mayo Clinic), J. Todd Auman(University of North Carolina at Chapel Hill), Miruna Balasundaram(Mayo Clinic), Saianand Balu(National Cancer Institute), Nabeel Bardeesy(Van Andel Institute), Oliver F. Bathe(University of Calgary), Stephen B. Baylin(University of North Carolina at Chapel Hill), Rameen Beroukhim(University of Calgary), Mario Berríos(University of Copenhagen), Tom Bodenheimer(Harvard University), Lori Boice(Mayo Clinic), Moiz S. Bootwalla(The University of Texas MD Anderson Cancer Center), Mitesh J. Borad(The University of Texas MD Anderson Cancer Center), Jay Bowen, Reanne Bowlby(BC Cancer Agency), Maria Consiglia Bragazzi, Denise Brooks(University of Copenhagen), Vincenzo Cardinale, Rebecca Carlsen(University of Calgary), Guido Carpino(University of North Carolina at Chapel Hill), André Lopes Carvalho, Roongruedee Chaiteerakij, Vishal C. Chandan(Harvard University), Andrew D. Cherniack(University of Calgary), Lynda Chin, Juok Cho, Gina Choe, Eric Chuah, Sudha Chudamani, Carrie Cibulskis, Matthew G. Cordes(Mayo Clinic in Arizona), Kyle R. Covington(Baylor College of Medicine), Daniel Crain(BC Cancer Agency), Erin Curley, Agostino Maria De Rose, Timothy Defreitas, John A. Demchok, Vikram Deshpande(Harvard University), Noreen Dhalla, Li Ding, Kimberley Evason, Farshad Farshidfar(Broad Institute), Ina Felau(The University of Texas MD Anderson Cancer Center), Martin L. Ferguson, Wai Chin Foo(The University of Texas MD Anderson Cancer Center), Antonio Franchitto, Scott Frazer, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton(Baylor College of Medicine), Stacey Gabriel, Johanna Gardner(University of North Carolina at Chapel Hill), Julie M. Gastier‐Foster, Eugenio Gaudio, Nils Gehlenborg, Giannicola Genovese(Harvard University), Mark Gerken, Gad Getz(University of Calgary), Nasra H. Giama, Richard A. Gibbs(University of Calgary), Marie-Claude Gingras(Baylor College of Medicine), Felice Giuliante, Gian Luca Grazi(The University of Texas MD Anderson Cancer Center), D. Neil Hayes, Apurva M. Hegde(The University of Texas MD Anderson Cancer Center), David I. Heiman, Julian M. Hess(Broad Institute), Toshinori Hinoue(Van Andel Institute), Katherine A. Hoadley(University of North Carolina at Chapel Hill), Andrea Holbrook, Robert A. Holt, Alan P. Hoyle, Mei Huang, Carolyn M. Hutter, Stuart R. Jefferys, Steven J.M. Jones, Corbin D. Jones, Katayoon Kasaian, Robin Kate Kelley(Baylor College of Medicine), Jaegil Kim, David E. Kleiner(National Cancer Institute), Jean‐Pierre Kocher, Lawrence N. Kwong(The University of Texas MD Anderson Cancer Center), Phillip H. Lai, Peter W. Laird(Broad Institute), Michael S. Lawrence(Van Andel Institute), Kristen Leraas(University of North Carolina at Chapel Hill), Tara M. Lichtenberg, Pei Lin(Mayo Clinic), Wenbin Liu, Jia Liu, Laxmi Lolla, Yiling Lu, Yussanne Ma, David Mallery, Elaine R. Mardis, Marco A. Marra, Marcus Matsushita, Michael Mayo(National Cancer Institute), Michael D. McLellan, Autumn J. McRee(University of North Carolina at Chapel Hill), Sam Meier(Van Andel Institute), Shaowu Meng(Van Andel Institute), Matthew Meyerson(The University of Texas MD Anderson Cancer Center), Piotr A. Mieczkowski, Christopher A. Miller, Gordon B. Mills, Richard A. Moore, Scott Morris, Lisle E. Mose, Catherine D. Moser(Broad Institute), Taofic Mounajjed(University of North Carolina at Chapel Hill), Andrew J. Mungall(Baylor College of Medicine), Karen Mungall, Bradley A. Murray, Rashi Naresh, Yulia Newton(Mayo Clinic), Michael S. Noble, Daniel R. O’Brien(University of North Carolina at Chapel Hill), Akinyemi I. Ojesina(HudsonAlpha Institute for Biotechnology), Joel S. Parker, Tushar Patel, Joseph Paulauskis, Chandra Sekhar Pedamallu(Dana-Farber Cancer Institute), Robert Penny, Charles M. Perou, Amy H. Perou, Todd Pihl, Amie Radenbaugh, Nilsa C. Ramirez(Mayo Clinic), W. Kimryn Rathmell, Ed Reznik(Memorial Sloan Kettering Cancer Center), Suhn K. Rhie(University of Southern California), Jeffrey Roach, Lewis R. Roberts(University of California, Santa Cruz), A. Gordon Robertson(BC Cancer Agency), Sara Sadeghi(BC Cancer Agency), Gordon Saksena(University of Alabama at Birmingham), Chris Sander(Memorial Sloan Kettering Cancer Center), Jacqueline E. Schein, Heather K. Schmidt, Steven E. Schumacher(Broad Institute), Candace Shelton(Mayo Clinic), Troy Shelton, Ronglai Shen, Margi Sheth(University of North Carolina at Chapel Hill), Yan Shi, Juliann Shih(Dana-Farber Cancer Institute), Eve Shinbrot(Baylor College of Medicine), Rachna T. Shroff(Memorial Sloan Kettering Cancer Center), Janae V. Simons(University of Southern California), Payal Sipahimalani, Tara Skelly(Mayo Clinic), Heidi J. Sofia(BC Cancer Agency), Matthew G. Soloway(BC Cancer Agency), Hubert Stöppler(BC Cancer Agency), Nicolas Stransky(Memorial Sloan Kettering Cancer Center), Joshua M. Stuart(University of California, Santa Cruz), Qiang Sun, Angela Tam, Donghui Tan, Roy Tarnuzzer, Nina Thiessen, Leigh B. Thorne, Michael Torbenson(Mayo Clinic), David Van Den Berg(Broad Institute), Umadevi Veluvolu(Baylor College of Medicine), Roel G.W. Verhaak, Doug Voet, Yunhu Wan, Zhining Wang, John N. Weinstein, Daniel J. Weisenberger, David A. Wheeler(Baylor College of Medicine), Richard K. Wilson(Blueprint Medicines (United States)), Lisa Wise(University of California, Santa Cruz), Tina Wong, Chia-Chin Wu(The University of Texas MD Anderson Cancer Center), Ye Wu, Xi Liu, Ju Dong Yang(Mayo Clinic), Liming Yang, Jean C. Zenklusen(Mayo Clinic), Hailei Zhang, Jiashan Zhang, Siyuan Zheng(The University of Texas MD Anderson Cancer Center), Erik Zmuda, Andrew X. Zhu(BC Cancer Agency), Joshua M. Stuart(BC Cancer Agency), Chris Sander(Memorial Sloan Kettering Cancer Center), Rehan Akbani(The University of Texas MD Anderson Cancer Center), Andrew D. Cherniack(Baylor College of Medicine), Vikram Deshpande(Harvard University), Taofic Mounajjed(Mayo Clinic), Wai Chin Foo(The University of Texas MD Anderson Cancer Center), Michael Torbenson(Mayo Clinic), David E. Kleiner(The University of Texas MD Anderson Cancer Center), Peter W. Laird(Van Andel Institute), David A. Wheeler(Mayo Clinic), Autumn J. McRee(University of North Carolina at Chapel Hill), Oliver F. Bathe(University of Calgary), Jesper B. Andersen(University of Copenhagen), Nabeel Bardeesy(Massachusetts General Hospital), Lewis R. Roberts(The University of Texas MD Anderson Cancer Center), Lawrence N. Kwong(The University of Texas MD Anderson Cancer Center)
Cited by 611Open Access
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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The Cancer Genome Atlas Research Network|New England Journal of Medicine|2013|5.1k