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(Massachusetts General Hospital), 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(Massachusetts General Hospital), Arshi Arora(Mayo Clinic), J. Todd Auman(The University of Texas MD Anderson Cancer Center), Miruna Balasundaram(Mayo Clinic), Saianand Balu(National Cancer Institute), Nabeel Bardeesy(Van Andel Institute), Oliver F. Bathe(Baylor College of Medicine), Stephen B. Baylin(University of North Carolina at Chapel Hill), Rameen Beroukhim, Mario Berríos(University of Copenhagen), Tom Bodenheimer(Massachusetts General Hospital), Lori Boice(Mayo Clinic), Moiz S. Bootwalla, Mitesh J. Borad(The University of Texas MD Anderson Cancer Center), Jay Bowen, Reanne Bowlby, Maria Consiglia Bragazzi, Denise Brooks(University of Copenhagen), Vincenzo Cardinale, Rebecca Carlsen, Guido Carpino(University of North Carolina at Chapel Hill), André Lopes Carvalho, Roongruedee Chaiteerakij, Vishal C. Chandan(Massachusetts General Hospital), Andrew D. Cherniack, Lynda Chin, Juok Cho, Gina Choe, Eric Chuah, Sudha Chudamani, Carrie Cibulskis, Matthew G. Cordes(Mayo Clinic in Arizona), Kyle R. Covington, Daniel Crain(BC Cancer Agency), Erin Curley, Agostino Maria De Rose, Timothy Defreitas, John A. Demchok, Vikram Deshpande, Noreen Dhalla, Li Ding, Kimberley Evason, Farshad Farshidfar(Broad Institute), Ina Felau, Martin L. Ferguson, Wai Chin Foo, Antonio Franchitto, Scott Frazer, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton(Baylor College of Medicine), Stacey Gabriel, Johanna Gardner, Julie M. Gastier‐Foster, Eugenio Gaudio, Nils Gehlenborg, Giannicola Genovese(Massachusetts General Hospital), Mark Gerken, Gad Getz, Nasra H. Giama, Richard A. Gibbs(University of Calgary), Marie‐Claude Gingras, Felice Giuliante, Gian Luca Grazi(The University of Texas MD Anderson Cancer Center), D. Neil Hayes, Apurva M. Hegde, David I. Heiman, Julian M. Hess, Toshinori Hinoue, Katherine A. Hoadley, 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, 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, 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, Sam Meier, Shaowu Meng(Van Andel Institute), Matthew Meyerson, Piotr A. Mieczkowski, Christopher A. Miller, Gordon B. Mills, Richard A. Moore, Scott Morris, Lisle E. Mose, Catherine D. Moser, Taofic Mounajjed, Andrew J. Mungall, Karen Mungall, Bradley A. Murray, Rashi Naresh, Yulia Newton, Michael S. Noble, Daniel R. O’Brien(University of North Carolina at Chapel Hill), Akinyemi I. Ojesina, Joel S. Parker, Tushar Patel, Joseph Paulauskis, Chandra Sekhar Pedamallu, Robert Penny, Charles M. Perou, Amy H. Perou, Todd Pihl, Amie Radenbaugh, Nilsa C. Ramirez(Mayo Clinic), W. Kimryn Rathmell, Ed Reznik, Suhn K. Rhie, Jeffrey Roach, Lewis R. Roberts(University of California, Santa Cruz), A. Gordon Robertson, Sara Sadeghi, Gordon Saksena(University of Alabama at Birmingham), Chris Sander, Jacqueline E. Schein, Heather K. Schmidt, Steven E. Schumacher(Broad Institute), Candace Shelton, Troy Shelton, Ronglai Shen, Margi Sheth, Yan Shi, Juliann Shih, Eve Shinbrot, 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, Nicolas Stransky(Memorial Sloan Kettering Cancer Center), Joshua M. Stuart, Qiang Sun, Angela Tam, Donghui Tan, Roy Tarnuzzer, Nina Thiessen, Leigh B. Thorne, Michael Torbenson, 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, Richard K. Wilson(Blueprint Medicines (United States)), Lisa Wise(University of California, Santa Cruz), Tina Wong, Chia-Chin Wu, Ye Wu, Xi Liu, Ju Dong Yang, Liming Yang, Jean C. Zenklusen(Mayo Clinic), Hailei Zhang, Jiashan Zhang, Siyuan Zheng, Erik Zmuda, Andrew X. Zhu, Joshua M. Stuart, Chris Sander, Rehan Akbani, Andrew D. Cherniack(Baylor College of Medicine), Vikram Deshpande, Taofic Mounajjed, Wai Chin Foo, Michael Torbenson(The University of Texas MD Anderson Cancer Center), David E. Kleiner, Peter W. Laird, David A. Wheeler, Autumn J. McRee, Oliver F. Bathe, Jesper B. Andersen, Nabeel Bardeesy, Lewis R. Roberts(The University of Texas MD Anderson Cancer Center), Lawrence N. Kwong
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Abstract
Cholangiocarcinoma (CCA) is an aggressive malignancy\nof the bile ducts, with poor prognosis and\nlimited treatment options. Here, we describe the\nintegrated analysis of somatic mutations, RNA\nexpression, copy number, and DNA methylation\nby The Cancer Genome Atlas of a set of predominantly\nintrahepatic CCA cases and propose a molecular\nclassification scheme. We identified an IDH\nmutant-enriched subtype with distinct molecular\nfeatures including low expression of chromatin\nmodifiers, elevated expression of mitochondrial\ngenes, and increased mitochondrial DNA copy\nnumber. Leveraging the multi-platform data, we\nobserved that ARID1A exhibited DNA hypermethylation\nand decreased expression in the IDH mutant\nsubtype. More broadly, we found that IDH mutations\nare associated with an expanded histological\nspectrum of liver tumors with molecular features\nthat stratify with CCA. Our studies reveal insights\ninto the molecular pathogenesis and heterogeneity\nof cholangiocarcinoma and provide classification\ninformation of potential therapeutic significance.
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