title: Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia.
abstract: OBJECTIVE
  To study the incidence and prognostic impact of mutations in DNA methyltransferase 3A (DNMT3A) in patients with acute myeloid leukemia.
  
  
  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.
  
  
  CONCLUSIONS
  DNMT3A mutations are frequent in younger patients with AML and are associated with an unfavorable prognosis.
authors.affiliation: Hannover Medical School, Hannover, Germany.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Thol
authors.forename: Frederik
authors.initials: F
authors.lastname: Damm
authors.forename: Andrea
authors.initials: A
authors.lastname: Lüdeking
authors.forename: Claudia
authors.initials: C
authors.lastname: Winschel
authors.forename: Katharina
authors.initials: K
authors.lastname: Wagner
authors.forename: Michael
authors.initials: M
authors.lastname: Morgan
authors.forename: Haiyang
authors.initials: H
authors.lastname: Yun
authors.forename: Gudrun
authors.initials: G
authors.lastname: Göhring
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Dieter
authors.initials: D
authors.lastname: Hoelzer
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
authors.forename: Lothar
authors.initials: L
authors.lastname: Kanz
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kirchner
authors.forename: Gerhard
authors.initials: G
authors.lastname: Heil
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D015973:Gene Expression Regulation, Leukemic; D020022:Genetic Predisposition to Disease; D005858:Germany; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D008875:Middle Aged; D009154:Mutation; D000090243:Nucleophosmin; D018570:Risk Assessment; D012307:Risk Factors; D016019:Survival Analysis; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C000717967:DNMT3A protein, human; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A