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Incidence and Prognostic Influence of DNMT3A Mutations in Acute Myeloid Leukemia
- Source :
- Journal of Clinical Oncology. 29:2889-2896
- Publication Year :
- 2011
- Publisher :
- American Society of Clinical Oncology (ASCO), 2011.
-
Abstract
- Purpose To study the incidence and prognostic impact of mutations in DNA methyltransferase 3A (DNMT3A) in patients with acute myeloid leukemia. Patients and Methods A total of 489 patients with AML were examined for mutations in DNMT3A by direct sequencing. The prognostic impact of DNMT3A mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors (cytogenetic risk group; mutations in NPM1, FLT3, CEBPA, IDH1, IDH2, MLL1, NRAS, WT1, and WT1 SNPrs16754; expression levels of BAALC, ERG, EVI1, MLL5, MN1, and WT1). Results DNMT3A mutations were found in 87 (17.8%) of 489 patients with AML who were younger than 60 years of age. Patients with DNMT3A mutations were older, had higher WBC and platelet counts, more often had a normal karyotype and mutations in NPM1, FLT3, and IDH1 genes, and had higher MLL5 expression levels as compared with patients with wild-type DNMT3A. Mutations in DNMT3A independently predicted a shorter overall survival (OS; hazard ratio [HR], 1.59; 95% CI, 1.15 to 2.21; P = .005) by multivariate analysis, but were not associated with relapse-free survival (RFS) or complete remission (CR) rate when the entire patient cohort was considered. In cytogenetically normal (CN) AML, 27.2% harbored DNMT3A mutations that independently predicted shorter OS (HR = 2.46; 95% CI, 1.58 to 3.83; P < .001) and lower CR rate (OR, 0.42; 95% CI, 0.21 to 0.84; P = .015), but not RFS (P = .32). Within patients with CN-AML, DNMT3A mutations had an unfavorable effect on OS, RFS, and CR rate in NPM1/FLT3-ITD high-risk but not in low-risk patients. Conclusion DNMT3A mutations are frequent in younger patients with AML and are associated with an unfavorable prognosis.
- Subjects :
- Adult
Oncology
Cancer Research
NPM1
medicine.medical_specialty
Time Factors
Myeloid
Adolescent
DNA Mutational Analysis
medicine.disease_cause
Risk Assessment
Disease-Free Survival
DNA Methyltransferase 3A
Young Adult
Risk Factors
Germany
Internal medicine
CEBPA
Biomarkers, Tumor
medicine
Humans
Genetic Predisposition to Disease
DNA (Cytosine-5-)-Methyltransferases
Survival rate
BAALC
Mutation
Gene Expression Regulation, Leukemic
business.industry
Age Factors
Myeloid leukemia
DNA Methylation
Middle Aged
medicine.disease
Survival Analysis
Survival Rate
Leukemia, Myeloid, Acute
Leukemia
Treatment Outcome
medicine.anatomical_structure
embryonic structures
Cancer research
business
Nucleophosmin
Subjects
Details
- ISSN :
- 15277755 and 0732183X
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Oncology
- Accession number :
- edsair.doi.dedup.....db776561693f172a645e5b14371db20b