title: Recurrent DNMT3A mutations in patients with myelodysplastic syndromes.
abstract: Alterations in DNA methylation have been implicated in the pathogenesis of myelodysplastic syndromes (MDS), although the underlying mechanism remains largely unknown. Methylation of CpG dinucleotides is mediated by DNA methyltransferases, including DNMT1, DNMT3A and DNMT3B. DNMT3A mutations have recently been reported in patients with de novo acute myeloid leukemia (AML), providing a rationale for examining the status of DNMT3A in MDS samples. In this study, we report the frequency of DNMT3A mutations in patients with de novo MDS, and their association with secondary AML. We sequenced all coding exons of DNMT3A using DNA from bone marrow and paired normal cells from 150 patients with MDS and identified 13 heterozygous mutations with predicted translational consequences in 12/150 patients (8.0%). Amino acid R882, located in the methyltransferase domain of DNMT3A, was the most common mutation site, accounting for 4/13 mutations. DNMT3A mutations were expressed in the majority of cells in all tested mutant samples regardless of myeloblast counts, suggesting that DNMT3A mutations occur early in the course of MDS. Patients with DNMT3A mutations had worse overall survival compared with patients without DNMT3A mutations (P=0.005) and more rapid progression to AML (P=0.007), suggesting that DNMT3A mutation status may have prognostic value in de novo MDS.
authors.affiliation: Department of Internal Medicine, Division of Oncology, Washington University, St Louis, MO 63110, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Walter
authors.forename: L
authors.initials: L
authors.lastname: Ding
authors.forename: D
authors.initials: D
authors.lastname: Shen
authors.forename: J
authors.initials: J
authors.lastname: Shao
authors.forename: M
authors.initials: M
authors.lastname: Grillot
authors.forename: M
authors.initials: M
authors.lastname: McLellan
authors.forename: R
authors.initials: R
authors.lastname: Fulton
authors.forename: H
authors.initials: H
authors.lastname: Schmidt
authors.forename: J
authors.initials: J
authors.lastname: Kalicki-Veizer
authors.forename: M
authors.initials: M
authors.lastname: O'Laughlin
authors.forename: C
authors.initials: C
authors.lastname: Kandoth
authors.forename: J
authors.initials: J
authors.lastname: Baty
authors.forename: P
authors.initials: P
authors.lastname: Westervelt
authors.forename: J F
authors.initials: JF
authors.lastname: DiPersio
authors.forename: E R
authors.initials: ER
authors.lastname: Mardis
authors.forename: R K
authors.initials: RK
authors.lastname: Wilson
authors.forename: T J
authors.initials: TJ
authors.lastname: Ley
authors.forename: T A
authors.initials: TA
authors.lastname: Graubert
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003062:Codon / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005091:Exons / Q000235:genetics; D005260:Female; D042381:Granulocyte Precursor Cells / Q000201:enzymology; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D003062:Codon; D004273:DNA, Neoplasm; C000717967:DNMT3A protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A