title: Prevalence and prognostic value of IDH1 and IDH2 mutations in childhood AML: a study of the AML-BFM and DCOG study groups.
abstract: Mutations in the NADP(+)-dependent isocitrate dehydrogenase genes 1 and 2 (IDH1 and IDH2) have recently been found in adult acute myeloid leukemia (AML) patients with a prevalence rising up to 33%. To investigate the frequency of IDH1/2 mutations in pediatric AML, we characterized the mutational hotspot (exon 4) of these genes in diagnostic samples from 460 pediatric AML patients. Our analysis identified somatic IDH1/2 mutations in 4% of cases (IDH1 R132 n=8; IDH2 R140 n=10) and the minor allele of single-nucleotide polymorphism (SNP) rs11554137 in 47 children (10.2%). IDH mutations were associated with an intermediate age (P=0.008), FAB M1/M2 (P=0.013) and nucleophosmin1 mutations (P=0.001). In univariate analysis, IDH(mutated) compared with IDH(wildtype) patients showed a significantly improved overall survival (OS; P=0.032) but not event-free survival (EFS; P=0.14). However, multivariate analysis did not show independent prognostic significance. Children with at least one minor allele of IDH1 SNP rs11554137 had similar EFS (P=0.27) and OS (P=0.62) compared with major allele patients. Gene expression profiles of 12 IDH(mutated) were compared with 201 IDH(wildtype) patients to identify differentially expressed genes and pathways. Although only a small number of discriminating genes were identified, analysis revealed a deregulated tryptophan metabolism, and a significant downregulation of KYNU expression in IDH(mutated) cases.
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany. damm.frederik@mh-hannover.de
authors.forename: F
authors.initials: F
authors.lastname: Damm
authors.forename: F
authors.initials: F
authors.lastname: Thol
authors.forename: I
authors.initials: I
authors.lastname: Hollink
authors.forename: M
authors.initials: M
authors.lastname: Zimmermann
authors.forename: K
authors.initials: K
authors.lastname: Reinhardt
authors.forename: M M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.forename: C M
authors.initials: CM
authors.lastname: Zwaan
authors.forename: V
authors.initials: V
authors.lastname: de Haas
authors.forename: U
authors.initials: U
authors.lastname: Creutzig
authors.forename: J-H
authors.initials: JH
authors.lastname: Klusmann
authors.forename: J
authors.initials: J
authors.lastname: Krauter
authors.forename: M
authors.initials: M
authors.lastname: Heuser
authors.forename: A
authors.initials: A
authors.lastname: Ganser
authors.forename: D
authors.initials: D
authors.lastname: Reinhardt
authors.forename: C
authors.initials: C
authors.lastname: Thiede
mesh_terms: D002648:Child; D020869:Gene Expression Profiling; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000453:epidemiology / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human