PMID- 27276561
OWN - NLM
STAT- MEDLINE
DCOM- 20160621
LR  - 20221208
IS  - 1533-4406 (Electronic)
IS  - 0028-4793 (Print)
IS  - 0028-4793 (Linking)
VI  - 374
IP  - 23
DP  - 2016 Jun 9
TI  - Genomic Classification and Prognosis in Acute Myeloid Leukemia.
PG  - 2209-2221
LID - 10.1056/NEJMoa1516192 [doi]
AB  - 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.).
FAU - Papaemmanuil, Elli
AU  - Papaemmanuil E
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Gerstung, Moritz
AU  - Gerstung M
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Bullinger, Lars
AU  - Bullinger L
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Gaidzik, Verena I
AU  - Gaidzik VI
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Paschka, Peter
AU  - Paschka P
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Roberts, Nicola D
AU  - Roberts ND
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Potter, Nicola E
AU  - Potter NE
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Heuser, Michael
AU  - Heuser M
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Thol, Felicitas
AU  - Thol F
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Bolli, Niccolo
AU  - Bolli N
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Gundem, Gunes
AU  - Gundem G
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Van Loo, Peter
AU  - Van Loo P
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Martincorena, Inigo
AU  - Martincorena I
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Ganly, Peter
AU  - Ganly P
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Mudie, Laura
AU  - Mudie L
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - McLaren, Stuart
AU  - McLaren S
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - O'Meara, Sarah
AU  - O'Meara S
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Raine, Keiran
AU  - Raine K
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Jones, David R
AU  - Jones DR
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Teague, Jon W
AU  - Teague JW
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Butler, Adam P
AU  - Butler AP
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Greaves, Mel F
AU  - Greaves MF
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Ganser, Arnold
AU  - Ganser A
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Dohner, Konstanze
AU  - Dohner K
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Schlenk, Richard F
AU  - Schlenk RF
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Dohner, Hartmut
AU  - Dohner H
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
FAU - Campbell, Peter J
AU  - Campbell PJ
AD  - 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 Cancer, Institute of 
      Cancer Research, London (N.E.P., M.F.G.), and the Department of Haematology, 
      University of Cambridge, Cambridge (N.B.) - all in the United Kingdom; the 
      Departments of Epidemiology and Biostatistics and Cancer Biology, the Center for 
      Molecular Oncology and the Center for Hematologic Malignancies, Memorial Sloan 
      Kettering Cancer Center, New York (E.P.); the Department of Internal Medicine 
      III, Ulm University, Ulm (L.B., V.I.G., P.P., K.D., R.F.S., H.D.), and the 
      Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, 
      Hannover Medical School, Hannover (M.H., F.T., A.G.) - both in Germany; the 
      Division of Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, and 
      Department of Oncology and Onco-Hematology, University of Milan, Milan (N.B.); 
      the Department of Human Genetics, University of Leuven, Leuven, Belgium (P.V.L.); 
      and the Department of Pathology, University of Otago, Christchurch, New Zealand 
      (P.G., P.J.C.).
LA  - eng
SI  - ClinicalTrials.gov/NCT00146120
GR  - WT088340MA/Wellcome Trust/United Kingdom
GR  - 077012/Z/05/Z/Wellcome Trust/United Kingdom
GR  - 105104/Z/14/Z/Wellcome Trust/United Kingdom
GR  - 105104/Wellcome Trust/United Kingdom
GR  - 103858/Wellcome Trust/United Kingdom
GR  - 077012/Wellcome Trust/United Kingdom
PT  - Clinical Trial
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - N Engl J Med
JT  - The New England journal of medicine
JID - 0255562
RN  - 0 (DNMT3A protein, human)
RN  - 0 (FIZ1 protein, human)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (NPM1 protein, human)
RN  - 0 (Nuclear Proteins)
RN  - 117896-08-9 (Nucleophosmin)
RN  - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases)
RN  - EC 2.1.1.37 (DNA Methyltransferase 3A)
SB  - IM
CIN - N Engl J Med. 2016 Jun 9;374(23):2282-4. PMID: 27276567
CIN - N Engl J Med. 2016 Sep;375(9):900-1. PMID: 27579651
CIN - N Engl J Med. 2016 Sep;375(9):900. PMID: 27579652
CIN - Natl Med J India. 2016 Sep-Oct;29(5):283-285. PMID: 28098084
MH  - Adult
MH  - DNA (Cytosine-5-)-Methyltransferases/genetics
MH  - DNA Methyltransferase 3A
MH  - DNA Mutational Analysis
MH  - Epistasis, Genetic
MH  - Gene Fusion
MH  - Genotype
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/genetics
MH  - Leukemia, Myeloid, Acute/*genetics/mortality/therapy
MH  - Middle Aged
MH  - *Mutation
MH  - Nuclear Proteins/genetics
MH  - Nucleophosmin
MH  - Prognosis
MH  - Proportional Hazards Models
MH  - Prospective Studies
MH  - RNA Splicing
MH  - Survival Analysis
PMC - PMC4979995
MID - EMS69173
OID - NLM: EMS69173
EDAT- 2016/06/09 06:00
MHDA- 2016/06/22 06:00
PMCR- 2016/12/09
CRDT- 2016/06/09 06:00
PHST- 2016/06/09 06:00 [entrez]
PHST- 2016/06/09 06:00 [pubmed]
PHST- 2016/06/22 06:00 [medline]
PHST- 2016/12/09 00:00 [pmc-release]
AID - 10.1056/NEJMoa1516192 [doi]
PST - ppublish
SO  - N Engl J Med. 2016 Jun 9;374(23):2209-2221. doi: 10.1056/NEJMoa1516192.