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dc.contributor.authorPapaemmanuil, Een_US
dc.contributor.authorGerstung, Men_US
dc.contributor.authorBullinger, Len_US
dc.contributor.authorGaidzik, VIen_US
dc.contributor.authorPaschka, Pen_US
dc.contributor.authorRoberts, NDen_US
dc.contributor.authorPotter, NEen_US
dc.contributor.authorHeuser, Men_US
dc.contributor.authorThol, Fen_US
dc.contributor.authorBolli, Nen_US
dc.contributor.authorGundem, Gen_US
dc.contributor.authorVan Loo, Pen_US
dc.contributor.authorMartincorena, Ien_US
dc.contributor.authorGanly, Pen_US
dc.contributor.authorMudie, Len_US
dc.contributor.authorMcLaren, Sen_US
dc.contributor.authorO'Meara, Sen_US
dc.contributor.authorRaine, Ken_US
dc.contributor.authorJones, DRen_US
dc.contributor.authorTeague, JWen_US
dc.contributor.authorButler, APen_US
dc.contributor.authorGreaves, MFen_US
dc.contributor.authorGanser, Aen_US
dc.contributor.authorDöhner, Ken_US
dc.contributor.authorSchlenk, RFen_US
dc.contributor.authorDöhner, Hen_US
dc.contributor.authorCampbell, PJen_US
dc.date.accessioned2017-03-24T15:32:53Z
dc.date.issued2016-06en_US
dc.identifier.citationThe New England journal of medicine, 2016, 374 (23), pp. 2209 - 2221en_US
dc.identifier.issn0028-4793en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/527
dc.identifier.eissn1533-4406en_US
dc.identifier.doi10.1056/nejmoa1516192en_US
dc.description.abstract<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.).en_US
dc.formatPrinten_US
dc.format.extent2209 - 2221en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserveden_US
dc.subjectHumansen_US
dc.subjectIntracellular Signaling Peptides and Proteinsen_US
dc.subjectNuclear Proteinsen_US
dc.subjectPrognosisen_US
dc.subjectProportional Hazards Modelsen_US
dc.subjectSurvival Analysisen_US
dc.subjectProspective Studiesen_US
dc.subjectGene Fusionen_US
dc.subjectDNA Mutational Analysisen_US
dc.subjectEpistasis, Geneticen_US
dc.subjectRNA Splicingen_US
dc.subjectGenotypeen_US
dc.subjectMutationen_US
dc.subjectAdulten_US
dc.subjectMiddle Ageden_US
dc.subjectLeukemia, Myeloid, Acuteen_US
dc.subjectDNA (Cytosine-5-)-Methyltransferasesen_US
dc.titleGenomic Classification and Prognosis in Acute Myeloid Leukemia.en_US
dc.typeJournal Article
rioxxterms.versionofrecord10.1056/nejmoa1516192en_US
rioxxterms.licenseref.startdate2016-06en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfThe New England journal of medicineen_US
pubs.issue23en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Biology of Childhood Leukaemia
pubs.publication-statusPublisheden_US
pubs.volume374en_US
pubs.embargo.termsNot knownen_US
icr.researchteamBiology of Childhood Leukaemiaen_US
dc.contributor.icrauthorGreaves, Melvynen_US


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