title: Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia.
abstract: The prevalence, the prognostic effect, and interaction with other molecular markers of DNMT3A mutations was studied in 415 patients with acute myeloid leukemia (AML) younger than 60 years. We show mutations in DNMT3A in 96 of 415 patients with newly diagnosed AML (23.1%). Univariate Cox regression analysis showed that patients with DNMT3A(mutant) AML show significantly worse overall survival (OS; P = .022; hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.04-1.81), and relapse-free survival (RFS; P = .005; HR, 1.52; 95% CI, 1.13-2.05) than DNMT3A(wild-type) AMLs. In a multivariable analysis, DNMT3A mutations express independent unfavorable prognostic value for OS (P = .003; HR, 1.82; 95% CI, 1.2-2.7) and RFS (P < .001; HR, 2.2; 95% CI, 1.4-3.3). In a composite genotypic subset of cytogenetic intermediate-risk AML without FLT3-ITD and NPM1 mutations, this association is particularly evident (OS: P = .013; HR, 2.09; 95% CI, 1.16-3.77; RFS: P = .001; HR, 2.65; 95% CI, 1.48-4.89). The effect of DNMT3A mutations in human AML remains elusive, because DNMT3A(mutant) AMLs did not express a methylation or gene expression signature that discriminates them from patients with DNMT3A(wild-type) AML. We conclude that DNMT3A mutation status is an important factor to consider for risk stratification of patients with AML.
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Ana Flávia Tibúrcio
authors.initials: AF
authors.lastname: Ribeiro
authors.forename: Marta
authors.initials: M
authors.lastname: Pratcorona
authors.forename: Claudia
authors.initials: C
authors.lastname: Erpelinck-Verschueren
authors.forename: Veronika
authors.initials: V
authors.lastname: Rockova
authors.forename: Mathijs
authors.initials: M
authors.lastname: Sanders
authors.forename: Saman
authors.initials: S
authors.lastname: Abbas
authors.forename: Maria E
authors.initials: ME
authors.lastname: Figueroa
authors.forename: Annelieke
authors.initials: A
authors.lastname: Zeilemaker
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor; D016000:Cluster Analysis; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D050505:Mutant Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D000090243:Nucleophosmin; D011379:Prognosis; D012008:Recurrence; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C000717967:DNMT3A protein, human; D050505:Mutant Proteins; C000716967:NPM1 protein, human; D009363:Neoplasm Proteins; D000090243:Nucleophosmin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A