Journal article
DNMT3A mutations in acute myeloid leukemia
The New England journal of medicine, Vol.363(25), pp.2424-2433
12/16/2010
DOI: 10.1056/NEJMoa1005143
PMCID: PMC3201818
PMID: 21067377
Abstract
The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia (AML) are unknown.
Using massively parallel DNA sequencing, we identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in the genome of cells from a patient with AML with a normal karyotype. We sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define recurring mutations.
A total of 62 of 281 patients (22.1%) had mutations in DNMT3A that were predicted to affect translation. We identified 18 different missense mutations, the most common of which was predicted to affect amino acid R882 (in 37 patients). We also identified six frameshift, six nonsense, and three splice-site mutations and a 1.5-Mbp deletion encompassing DNMT3A. These mutations were highly enriched in the group of patients with an intermediate-risk cytogenetic profile (56 of 166 patients, or 33.7%) but were absent in all 79 patients with a favorable-risk cytogenetic profile (P<0.001 for both comparisons). The median overall survival among patients with DNMT3A mutations was significantly shorter than that among patients without such mutations (12.3 months vs. 41.1 months, P<0.001). DNMT3A mutations were associated with adverse outcomes among patients with an intermediate-risk cytogenetic profile or FLT3 mutations, regardless of age, and were independently associated with a poor outcome in Cox proportional-hazards analysis.
DNMT3A mutations are highly recurrent in patients with de novo AML with an intermediate-risk cytogenetic profile and are independently associated with a poor outcome. (Funded by the National Institutes of Health and others.).
Details
- Title: Subtitle
- DNMT3A mutations in acute myeloid leukemia
- Creators
- Timothy J Ley - Department of Genetics, Genome Center, Washington University, St Louis, MO 63110, USA. timley@wustl.eduMichael H TomassonLi DingMatthew J WalterMichael D McLellanTamara LamprechtDavid E LarsonCyriac KandothJacqueline E PaytonJack BatyJohn WelchChristopher C HarrisCheryl F LichtiR Reid TownsendRobert S FultonDavid J DoolingDaniel C KoboldtHeather SchmidtQunyuan ZhangJohn R OsborneLing LinMichelle O'LaughlinJoshua F McMichaelKim D DelehauntySean D McGrathLucinda A FultonVincent J MagriniTammi L VickeryJasreet HundalLisa L CookJoshua J ConyersGary W SwiftJerry P ReedPatricia A AlldredgeTodd WylieJason WalkerJoelle KalickiMark A WatsonSharon HeathWilliam D ShannonNobish VargheseRakesh NagarajanPeter WesterveltDaniel C LinkTimothy A GraubertJohn F DiPersioElaine R MardisRichard K Wilson
- Resource Type
- Journal article
- Publication Details
- The New England journal of medicine, Vol.363(25), pp.2424-2433
- DOI
- 10.1056/NEJMoa1005143
- PMID
- 21067377
- PMCID
- PMC3201818
- ISSN
- 0028-4793
- eISSN
- 1533-4406
- Grant note
- P41RR000954 / NCRR NIH HHS U54 HG003079 / NHGRI NIH HHS UL1 RR024992 / NCRR NIH HHS P01 CA101937 / NCI NIH HHS P01CA101937 / NCI NIH HHS P41 RR000954 / NCRR NIH HHS
- Language
- English
- Date published
- 12/16/2010
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094538802771
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