Genomic Classification and Prognosis in Acute Myeloid Leukemia.
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.).
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.).
Elli
E
Papaemmanuil
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.).
Moritz
M
Gerstung
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.).
Lars
L
Bullinger
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.).
Verena I
VI
Gaidzik
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.).
Peter
P
Paschka
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.).
Nicola D
ND
Roberts
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.).
Nicola E
NE
Potter
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.).
Michael
M
Heuser
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.).
Felicitas
F
Thol
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.).
Niccolo
N
Bolli
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.).
Gunes
G
Gundem
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.).
Peter
P
Van Loo
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.).
Inigo
I
Martincorena
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.).
Peter
P
Ganly
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.).
Laura
L
Mudie
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.).
Stuart
S
McLaren
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.).
Sarah
S
O'Meara
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.).
Keiran
K
Raine
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.).
David R
DR
Jones
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.).
Jon W
JW
Teague
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.).
Adam P
AP
Butler
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.).
Mel F
MF
Greaves
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.).
Arnold
A
Ganser
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.).
Konstanze
K
Döhner
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.).
Richard F
RF
Schlenk
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.).
Hartmut
H
Döhner
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.).
Peter J
PJ
Campbell
D000328:Adult; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D004252:DNA Mutational Analysis; D004843:Epistasis, Genetic; D050939:Gene Fusion; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012326:RNA Splicing; D016019:Survival Analysis
C000717967:DNMT3A protein, human; C485638:FIZ1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A