TET2 Mutations Improve the New European LeukemiaNet Risk Classification of Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study

Autor: Meir Wetzler, John Curfman, Michael A. Caligiuri, Heiko Becker, Sebastian Schwind, Klaus H. Metzeler, Joseph O. Moore, Dean Margeson, Richard A. Larson, Kati Maharry, Susan P. Whitman, Thomas H. Carter, Maria R. Baer, William Blum, Andrew J. Carroll, Yue-Zhong Wu, Jonathan E. Kolitz, Bayard L. Powell, Kelsi B. Holland, Clara D. Bloomfield, Michael D. Radmacher, Krzysztof Mrózek, Guido Marcucci
Rok vydání: 2011
Předmět:
Male
Oncology
Cancer Research
Time Factors
DNA Mutational Analysis
Kaplan-Meier Estimate
Gene mutation
Bioinformatics
Polymerase Chain Reaction
European LeukemiaNet
Risk Factors
Antineoplastic Combined Chemotherapy Protocols
CEBPA
Medicine
Aged
80 and over
Gene Expression Regulation
Leukemic
Myeloid leukemia
Middle Aged
DNA-Binding Proteins
Leukemia
Myeloid
Acute
Leukemia
Phenotype
Treatment Outcome
Cytogenetic Analysis
Female
Nucleophosmin
Adult
medicine.medical_specialty
NPM1
Adolescent
Risk Assessment
Disease-Free Survival
Dioxygenases
Young Adult
Proto-Oncogene Proteins
Internal medicine
Original Reports
Humans
Genetic Predisposition to Disease
Aged
Proportional Hazards Models
business.industry
Proportional hazards model
Gene Expression Profiling
Cancer
medicine.disease
United States
MicroRNAs
Mutation
business
Zdroj: Journal of Clinical Oncology. 29:1373-1381
ISSN: 1527-7755
0732-183X
Popis: Purpose To determine the frequency of TET2 mutations, their associations with clinical and molecular characteristics and outcome, and the associated gene- and microRNA-expression signatures in patients with primary cytogenetically normal acute myeloid leukemia (CN-AML). Patients and Methods Four-hundred twenty-seven patients with CN-AML were analyzed for TET2 mutations by polymerase chain reaction and direct sequencing and for established prognostic gene mutations. Gene- and microRNA-expression profiles were derived using microarrays. Results TET2 mutations, found in 23% of patients, were associated with older age (P < .001) and higher pretreatment WBC (P = .04) compared with wild-type TET2 (TET2-wt). In the European LeukemiaNet (ELN) favorable-risk group (patients with CN-AML who have mutated CEBPA and/or mutated NPM1 without FLT3 internal tandem duplication [FLT3-ITD]), TET2-mutated patients had shorter event-free survival (EFS; P < .001) because of a lower complete remission (CR) rate (P = .007), and shorter disease-free survival (DFS; P = .003), and also had shorter overall survival (P = .001) compared with TET2-wt patients. TET2 mutations were not associated with outcomes in the ELN intermediate-I–risk group (CN-AML with wild-type CEBPA and wild-type NPM1 and/or FLT3-ITD). In multivariable models, TET2 mutations were associated with shorter EFS (P = .004), lower CR rate (P = .03), and shorter DFS (P = .05) only among favorable-risk CN-AML patients. We identified a TET2 mutation-associated gene-expression signature in favorable-risk but not in intermediate-I–risk patients and found distinct mutation-associated microRNA signatures in both ELN groups. Conclusion TET2 mutations improve the ELN molecular-risk classification in primary CN-AML because of their adverse prognostic impact in an otherwise favorable-risk patient subset. Our data suggest that these patients may be candidates for alternative therapies.
Databáze: OpenAIRE
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