title: Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia.
abstract: OBJECTIVE
  To determine the frequency of DNMT3A mutations, their associations with clinical and molecular characteristics and outcome, and the associated gene- and microRNA-expression signatures in primary cytogenetically normal acute myeloid leukemia (CN-AML).
  
  
  METHODS
  Four hundred fifteen previously untreated adults were analyzed for DNMT3A mutations and established prognostic gene mutations and expression markers. Gene- and microRNA-expression profiles were derived using microarrays.
  
  
  RESULTS
  Younger (< 60 years; n = 181) and older (≥ 60 years; n = 234) patients had similar frequencies of DNMT3A mutations (35.3% v 33.3%). Missense mutations affecting arginine codon 882 (R882-DNMT3A) were more common (n = 92; 62%) than those affecting other codons (non-R882-DNMT3A). DNMT3A-mutated patients did not differ regarding complete remission rate, but had shorter disease-free survival (DFS; P = .03) and, by trend, overall survival (OS; P = .07) than DNMT3A-wild-type patients. In multivariable analyses, DNMT3A mutations remained associated with shorter DFS (P = .01), but not with shorter OS. When analyzed separately, the two DNMT3A mutation types had different significance by age group. Younger patients with non-R882-DNMT3A mutations had shorter DFS (P = .002) and OS (P = .02), whereas older patients with R882-DNMT3A mutations had shorter DFS (P = .005) and OS (P = .002) after adjustment for other clinical and molecular prognosticators. Gene- and microRNA-expression signatures did not accurately predict DNMT3A mutational status.
  
  
  CONCLUSIONS
  DNMT3A mutations are frequent in CN-AML, and their clinical significance seems to be age dependent. DNMT3A-R882 mutations are associated with adverse prognosis in older patients, and non-R882-DNMT3A mutations are associated with adverse prognosis in younger patients. Low accuracy of gene- and microRNA-expression signatures in predicting DNMT3A mutation status suggested that the role of these mutations in AML remains to be elucidated.
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA. guido.marcucci@osumc.edu
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Metzeler
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schwind
authors.forename: Heiko
authors.initials: H
authors.lastname: Becker
authors.forename: Kati
authors.initials: K
authors.lastname: Maharry
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mrózek
authors.forename: Michael D
authors.initials: MD
authors.lastname: Radmacher
authors.forename: Jessica
authors.initials: J
authors.lastname: Kohlschmidt
authors.forename: Deedra
authors.initials: D
authors.lastname: Nicolet
authors.forename: Susan P
authors.initials: SP
authors.lastname: Whitman
authors.forename: Yue-Zhong
authors.initials: YZ
authors.lastname: Wu
authors.forename: Bayard L
authors.initials: BL
authors.lastname: Powell
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Carter
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.forename: Meir
authors.initials: M
authors.lastname: Wetzler
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carroll
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
authors.forename: Joseph O
authors.initials: JO
authors.lastname: Moore
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D055815:Young Adult
chemical_list: C000717967:DNMT3A protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A