title: Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association.
abstract: Recently, DNA methyltransferase 3A (DNMT3A) mutations have been identified in acute myeloid leukemia (AML), the highest frequency being found within cytogenetically normal (CN) AML. In this study, diagnostic samples from 123 adults younger than 60 years with primary CN-AML homogeneously treated in the Acute Leukemia French Association-9801 and -9802 trials were screened for mutations in DNMT3A-conserved domains by direct sequencing. Patients were also assessed for the presence of FLT3 (fms-like tyrosine kinase receptor-3), NPM1 (nucleophosmin), CEBPA, WT1 (Wilms tumor 1), IDH1 (isocitrate dehydrogenase 1) and IDH2 mutations. Thirty-eight mutations were detected in 36 patients (29%): 36 nucleotide substitutions, mostly affecting amino-acid residue R882 and two frameshift deletions. DNMT3A mutations were significantly associated with the French-American-British subtypes M4/M5 and the presence of NPM1 mutations. In the whole cohort, DNMT3A mutated patients had a shorter event-free survival (5-year EFS: 13% vs 32%, P = 0.02) and overall survival (5-year OS: 23% vs 45%, P = 0.02) compared with DNMT3A wild-type patients. In multivariate analysis including age, white blood cell count, NPM1/FLT3-internal tandem duplication/CEBPA risk group and DNMT3A mutational status, the presence of a DNMT3A mutation remained an independent adverse prognostic factor for EFS and OS, suggesting that testing for DNMT3A mutations could help further improve risk stratification in CN-AML.
authors.affiliation: Laboratory of Hematology, Biology and Pathology Center, CHRU of Lille, Lille, France.
authors.forename: A
authors.initials: A
authors.lastname: Renneville
authors.forename: N
authors.initials: N
authors.lastname: Boissel
authors.forename: O
authors.initials: O
authors.lastname: Nibourel
authors.forename: C
authors.initials: C
authors.lastname: Berthon
authors.forename: N
authors.initials: N
authors.lastname: Helevaut
authors.forename: C
authors.initials: C
authors.lastname: Gardin
authors.forename: J-M
authors.initials: JM
authors.lastname: Cayuela
authors.forename: S
authors.initials: S
authors.lastname: Hayette
authors.forename: O
authors.initials: O
authors.lastname: Reman
authors.forename: N
authors.initials: N
authors.lastname: Contentin
authors.forename: D
authors.initials: D
authors.lastname: Bordessoule
authors.forename: C
authors.initials: C
authors.lastname: Pautas
authors.forename: S de
authors.initials: Sd
authors.lastname: Botton
authors.forename: T de
authors.initials: Td
authors.lastname: Revel
authors.forename: C
authors.initials: C
authors.lastname: Terre
authors.forename: P
authors.initials: P
authors.lastname: Fenaux
authors.forename: X
authors.initials: X
authors.lastname: Thomas
authors.forename: S
authors.initials: S
authors.lastname: Castaigne
authors.forename: H
authors.initials: H
authors.lastname: Dombret
authors.forename: C
authors.initials: C
authors.lastname: Preudhomme
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics*; D020732:Cytogenetic Analysis; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000090243:Nucleophosmin; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011446:Prospective Studies; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C000717967:DNMT3A protein, human; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3