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Genomic Classification and Prognosis in Acute Myeloid Leukemia.
Papaemmanuil, Elli; Gerstung, Moritz; Bullinger, Lars; Gaidzik, Verena I; Paschka, Peter; Roberts, Nicola D; Potter, Nicola E; Heuser, Michael; Thol, Felicitas; Bolli, Niccolo; Gundem, Gunes; Van Loo, Peter; Martincorena, Inigo; Ganly, Peter; Mudie, Laura; McLaren, Stuart; O'Meara, Sarah; Raine, Keiran; Jones, David R; Teague, Jon W; Butler, Adam P; Greaves, Mel F; Ganser, Arnold; Döhner, Konstanze; Schlenk, Richard F; Döhner, Hartmut; Campbell, Peter J.
Afiliação
  • Papaemmanuil E; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Gerstung M; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Bullinger L; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Gaidzik VI; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Paschka P; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Roberts ND; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Potter NE; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Heuser M; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Thol F; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Bolli N; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Gundem G; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Van Loo P; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Martincorena I; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Ganly P; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Mudie L; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • McLaren S; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • O'Meara S; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Raine K; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Jones DR; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Teague JW; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Butler AP; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Greaves MF; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Ganser A; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Döhner K; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Schlenk RF; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Döhner H; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
  • Campbell PJ; Cancer Genome Project, Wellcome Trust Sanger Institute (E.P., M.G., N.D.R., N.B., G.G., P.V.L., I.M., L.M., S.M., S.O., K.R., D.R.J., J.W.T., A.P.B., P.J.C.), and the European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI) (M.G.), Hinxton, the Centre for Evolution and Can
N Engl J Med ; 374(23): 2209-2221, 2016 Jun 09.
Article em En | MEDLINE | ID: mdl-27276561
BACKGROUND: Recent studies have provided a detailed census of genes that are mutated in acute myeloid leukemia (AML). Our next challenge is to understand how this genetic diversity defines the pathophysiology of AML and informs clinical practice. METHODS: We enrolled a total of 1540 patients in three prospective trials of intensive therapy. Combining driver mutations in 111 cancer genes with cytogenetic and clinical data, we defined AML genomic subgroups and their relevance to clinical outcomes. RESULTS: We identified 5234 driver mutations across 76 genes or genomic regions, with 2 or more drivers identified in 86% of the patients. Patterns of co-mutation compartmentalized the cohort into 11 classes, each with distinct diagnostic features and clinical outcomes. In addition to currently defined AML subgroups, three heterogeneous genomic categories emerged: AML with mutations in genes encoding chromatin, RNA-splicing regulators, or both (in 18% of patients); AML with TP53 mutations, chromosomal aneuploidies, or both (in 13%); and, provisionally, AML with IDH2(R172) mutations (in 1%). Patients with chromatin-spliceosome and TP53-aneuploidy AML had poor outcomes, with the various class-defining mutations contributing independently and additively to the outcome. In addition to class-defining lesions, other co-occurring driver mutations also had a substantial effect on overall survival. The prognostic effects of individual mutations were often significantly altered by the presence or absence of other driver mutations. Such gene-gene interactions were especially pronounced for NPM1-mutated AML, in which patterns of co-mutation identified groups with a favorable or adverse prognosis. These predictions require validation in prospective clinical trials. CONCLUSIONS: The driver landscape in AML reveals distinct molecular subgroups that reflect discrete paths in the evolution of AML, informing disease classification and prognostic stratification. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT00146120.).
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Mutação Tipo de estudo: Clinical_trials / Observational_studies / Prognostic_studies Limite: Adult / Humans / Middle aged Idioma: En Ano de publicação: 2016 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Mutação Tipo de estudo: Clinical_trials / Observational_studies / Prognostic_studies Limite: Adult / Humans / Middle aged Idioma: En Ano de publicação: 2016 Tipo de documento: Article