PMID- 21670448
OWN - NLM
STAT- MEDLINE
DCOM- 20110916
LR  - 20220318
IS  - 1527-7755 (Electronic)
IS  - 0732-183X (Linking)
VI  - 29
IP  - 21
DP  - 2011 Jul 20
TI  - Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia.
PG  - 2889-96
LID - 10.1200/JCO.2011.35.4894 [doi]
AB  - 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.
FAU - Thol, Felicitas
AU  - Thol F
AD  - Hannover Medical School, Hannover, Germany.
FAU - Damm, Frederik
AU  - Damm F
FAU - Ludeking, Andrea
AU  - Ludeking A
FAU - Winschel, Claudia
AU  - Winschel C
FAU - Wagner, Katharina
AU  - Wagner K
FAU - Morgan, Michael
AU  - Morgan M
FAU - Yun, Haiyang
AU  - Yun H
FAU - Gohring, Gudrun
AU  - Gohring G
FAU - Schlegelberger, Brigitte
AU  - Schlegelberger B
FAU - Hoelzer, Dieter
AU  - Hoelzer D
FAU - Lubbert, Michael
AU  - Lubbert M
FAU - Kanz, Lothar
AU  - Kanz L
FAU - Fiedler, Walter
AU  - Fiedler W
FAU - Kirchner, Hartmut
AU  - Kirchner H
FAU - Heil, Gerhard
AU  - Heil G
FAU - Krauter, Jurgen
AU  - Krauter J
FAU - Ganser, Arnold
AU  - Ganser A
FAU - Heuser, Michael
AU  - Heuser M
LA  - eng
SI  - ClinicalTrials.gov/NCT00209833
PT  - Clinical Trial
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20110613
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (DNMT3A protein, human)
RN  - 0 (NPM1 protein, human)
RN  - 117896-08-9 (Nucleophosmin)
RN  - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases)
RN  - EC 2.1.1.37 (DNA Methyltransferase 3A)
SB  - IM
CIN - J Clin Oncol. 2011 Dec 1;29(34):4592-3; author reply 4593-4. PMID: 22042957
MH  - Adolescent
MH  - Adult
MH  - Age Factors
MH  - Biomarkers, Tumor/*genetics/metabolism
MH  - DNA (Cytosine-5-)-Methyltransferases/*genetics/metabolism
MH  - DNA Methylation
MH  - DNA Methyltransferase 3A
MH  - DNA Mutational Analysis
MH  - Disease-Free Survival
MH  - Gene Expression Regulation, Leukemic
MH  - Genetic Predisposition to Disease
MH  - Germany
MH  - Humans
MH  - Leukemia, Myeloid, Acute/enzymology/*genetics/mortality/therapy
MH  - Middle Aged
MH  - *Mutation
MH  - Nucleophosmin
MH  - Risk Assessment
MH  - Risk Factors
MH  - Survival Analysis
MH  - Survival Rate
MH  - Time Factors
MH  - Treatment Outcome
MH  - Young Adult
EDAT- 2011/06/15 06:00
MHDA- 2011/09/17 06:00
CRDT- 2011/06/15 06:00
PHST- 2011/06/15 06:00 [entrez]
PHST- 2011/06/15 06:00 [pubmed]
PHST- 2011/09/17 06:00 [medline]
AID - JCO.2011.35.4894 [pii]
AID - 10.1200/JCO.2011.35.4894 [doi]
PST - ppublish
SO  - J Clin Oncol. 2011 Jul 20;29(21):2889-96. doi: 10.1200/JCO.2011.35.4894. Epub 
      2011 Jun 13.