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    Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia

    Access Status
    Fulltext not available
    Authors
    Ley, T.
    Miller, C.
    Ding, L.
    Raphael, B.
    Mungall, A.
    Robertson, G.
    Hoadley, K.
    Triche, T.
    Laird, P.
    Baty, J.
    Fulton, L.
    Fulton, R.
    Heath, S.
    Kalicki-Veizer, J.
    Kandoth, C.
    Klco, J.
    Koboldt, D.
    Kanchi, K.
    Kulkarni, S.
    Lamprecht, T.
    Larson, D.
    Lin, G.
    Lu, C.
    McLellan, M.
    McMichael, J.
    Payton, J.
    Schmidt, H.
    Spencer, D.
    Tomasson, M.
    Wallis, J.
    Wartman, L.
    Watson, M.
    Welch, J.
    Wendl, M.
    Ally, A.
    Balasundaram, M.
    Birol, I.
    Butterfield, Y.
    Chiu, R.
    Chu, A.
    Chuah, E.
    Chun, H.
    Corbett, R.
    Dhalla, N.
    Guin, R.
    He, A.
    Hirst, C.
    Hirst, M.
    Holt, R.
    Jones, S.
    Karsan, A.
    Lee, D.
    Li, H.
    Marra, M.
    Mayo, M.
    Moore, R.
    Mungall, K.
    Parker, J.
    Pleasance, E.
    Plettner, P.
    Schein, J.
    Stoll, D.
    Swanson, L.
    Tam, A.
    Thiessen, N.
    Varhol, Richard
    Wye, N.
    Zhao, Y.
    Gabriel, S.
    Getz, G.
    Sougnez, C.
    Zou, L.
    Leiserson, M.
    Vandin, F.
    Wu, H.
    Applebaum, F.
    Baylin, S.
    Akbani, R.
    Broom, B.
    Chen, K.
    Motter, T.
    Nguyen, K.
    Weinstein, J.
    Zhang, N.
    Ferguson, M.
    Adams, C.
    Black, A.
    Bowen, J.
    Gastier-Foster, J.
    Grossman, T.
    Lichtenberg, T.
    Wise, L.
    Davidsen, T.
    Demchok, J.
    Mills Shaw, K.
    Sheth, M.
    Sofia, H.
    Yang, L.
    Downing, J.
    Eley, G.
    Date
    2013
    Type
    Journal Article
    
    Metadata
    Show full item record
    Citation
    Ley, T. and Miller, C. and Ding, L. and Raphael, B. and Mungall, A. and Robertson, G. and Hoadley, K. et al. 2013. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. New England Journal of Medicine. 368 (22): pp. 2059-2074.
    Source Title
    New England Journal of Medicine
    DOI
    10.1056/NEJMoa1301689
    ISSN
    0028-4793
    School
    Department of Health Policy and Management
    URI
    http://hdl.handle.net/20.500.11937/38906
    Collection
    • Curtin Research Publications
    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.) Copyright © 2013 Massachusetts Medical Society.

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