Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia

Timothy J. Ley, Christopher Miller, Li Ding, Benjamin J. Raphael, Andrew J. Mungall, Gordon Robertson, Katherine Hoadley, Timothy J. Triche, Peter W. Laird, Jack D. Baty, Lucinda L. Fulton, Robert Fulton, Sharon E. Heath, Joelle Kalicki-Veizer, Cyriac Kandoth, Jeffery M. Klco, Daniel C. Koboldt, Krishna Latha Kanchi, Shashikant Kulkarni, Tamara L. LamprechtDavid E. Larson, G. Lin, Charles Lu, Michael D. McLellan, Joshua F. McMichael, Jacqueline Payton, Heather Schmidt, David H. Spencer, Michael H. Tomasson, John W. Wallis, Lukas D. Wartman, Mark A. Watson, John Welch, Michael C. Wendl, Adrian Ally, Miruna Balasundaram, Inanc Birol, Yaron Butterfield, Readman Chiu, Andy Chu, Eric Chuah, Hye Jung Chun, Richard Corbett, Noreen Dhalla, Ranabir Guin, An He, Carrie Hirst, Martin Hirst, Robert A. Holt, Steven Jones, Aly Karsan, Darlene Lee, Haiyan I. Li, Marco A. Marra, Michael Mayo, Richard A. Moore, Karen Mungall, Jeremy Parker, Erin Pleasance, Patrick Plettner, Jacquie Schein, Dominik Stoll, Lucas Swanson, Angela Tam, Nina Thiessen, Richard Varhol, Natasja Wye, Yongjun Zhao, Stacey Gabriel, Gad Getz, Carrie Sougnez, Lihua Zou, Mark D.M. Leiserson, Fabio Vandin, Hsin Ta Wu, Frederick Applebaum, Stephen B. Baylin, Rehan Akbani, Bradley M. Broom, Ken Chen, Thomas C. Motter, Khanh Nguyen, John N. Weinstein, Nianziang Zhang, Martin L. Ferguson, Christopher Adams, Aaron Black, Jay Bowen, Julie Gastier-Foster, Thomas Grossman, Tara Lichtenberg, Lisa Wise, Tanja Davidsen, John A. Demchok, Kenna R. Mills Shaw, Margi Sheth, Heidi J. Sofia, Liming Yang, James R. Downing, Greg Eley, Shelley Alonso, Brenda Ayala, Julien Baboud, Mark Backus, Sean P. Barletta, Dominique L. Berton, Anna L. Chu, Stanley Girshik, Mark A. Jensen, Ari Kahn, Prachi Kothiyal, Matthew C. Nicholls, Todd D. Pihl, David A. Pot, Rohini Raman, Rashmi N. Sanbhadti, Eric E. Snyder, Deepak Srinivasan, Jessica Walton, Yunhu Wan, Zhining Wang, Jean Pierre J. Issa, Michelle Le Beau, Martin Carroll, Hagop Kantarjian, Steven Kornblau, Moiz S. Bootwalla, Phillip H. Lai, Hui Shen, David J. Van Den Berg, Daniel J. Weisenberger, Daniel C. Link, Matthew J. Walter, Bradley A. Ozenberger, Elaine R. Mardis, Peter Westervelt, Timothy A. Graubert, John F. DiPersio, Richard K. Wilson

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. METHODS: We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. RESULTS: AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation-related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. CONCLUSIONS: We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.)

Original languageEnglish (US)
Pages (from-to)2059-2074
Number of pages16
JournalNew England Journal of Medicine
Volume368
Issue number22
DOIs
StatePublished - May 30 2013

ASJC Scopus subject areas

  • Medicine(all)

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    Ley, T. J., Miller, C., Ding, L., Raphael, B. J., Mungall, A. J., Robertson, G., Hoadley, K., Triche, T. J., Laird, P. W., Baty, J. D., Fulton, L. L., Fulton, R., Heath, S. E., Kalicki-Veizer, J., Kandoth, C., Klco, J. M., Koboldt, D. C., Kanchi, K. L., Kulkarni, S., ... Wilson, R. K. (2013). Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. New England Journal of Medicine, 368(22), 2059-2074. https://doi.org/10.1056/NEJMoa1301689