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Genomic Classification and Prognosis in Acute Myeloid Leukemia.

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Date
2016-06
ICR Author
Greaves, Melvyn
Author
Papaemmanuil, E
Gerstung, M
Bullinger, L
Gaidzik, VI
Paschka, P
Roberts, ND
Potter, NE
Heuser, M
Thol, F
Bolli, N
Gundem, G
Van Loo, P
Martincorena, I
Ganly, P
Mudie, L
McLaren, S
O'Meara, S
Raine, K
Jones, DR
Teague, JW
Butler, AP
Greaves, MF
Ganser, A
Döhner, K
Schlenk, RF
Döhner, H
Campbell, PJ
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Type
Journal Article
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Abstract
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.).
URI
https://repository.icr.ac.uk/handle/internal/527
DOI
https://doi.org/10.1056/nejmoa1516192
Collections
  • Molecular Pathology
Subject
Humans
Intracellular Signaling Peptides and Proteins
Nuclear Proteins
Prognosis
Proportional Hazards Models
Survival Analysis
Prospective Studies
Gene Fusion
DNA Mutational Analysis
Epistasis, Genetic
RNA Splicing
Genotype
Mutation
Adult
Middle Aged
Leukemia, Myeloid, Acute
DNA (Cytosine-5-)-Methyltransferases
Research team
Biology of Childhood Leukaemia
Language
eng
License start date
2016-06
Citation
The New England journal of medicine, 2016, 374 (23), pp. 2209 - 2221

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