Leukemic mutations in the methylation-associated genes DNMT3A and IDH2 are rare events in pediatric AML: a report from the Children's Oncology Group

Abstract

Background: Mutations in the DNMT3A, TET2, IDH1, and IDH2 genes carry prognostic significance and occur frequently in adult acute myeloid leukemia (AML). Leukemic mutations in all four genes have recently been implicated in aberrant DNA methylation, a hallmark of neoplasia. We previously reported that IDH1 mutations were absent, whereas TET2 mutations were present in 6%, of pediatric AML patients; in the present study, we determined the prevalence of DNMT3A and IDH2 mutations in pediatric AML.

Methods: We screened for DNMT3A and IDH2 mutations by direct sequencing of diagnostic specimens from 180 children treated on the Children's Oncology Group clinical trial AAML03P1. Clinical characteristics, the presence of other leukemic mutations, and survival outcome was determined for mutation-positive patients.

Results: No disease-associated DNMT3A mutations were detected. IDH2 mutations were detected in 4/180 patients (2.2%), affecting codons R140 (n = 3) and R172 (n = 1). Two patients with IDH2 mutations harbored t(8;21), one patient harbored an MLL translocation, and one patient had a concomitant NPM1 mutation. FLT3, CEBPA, and WT1 mutations did not occur together with IDH2 mutations in our study.

Conclusion: DNMT3A and IDH2 mutations are uncommon in pediatric AML. The low prevalence of methylation-associated mutations in our study highlights the differences in the pathogenesis of pediatric versus adult AML, at the genetic as well as potentially at the epigenetic level. The age-specific characteristics of AML underscore the importance of studying the molecular biology of both childhood and adult forms of this leukemia in parallel, as the development of novel therapeutics should account for these biologic differences.

Fig. 1

Prevalence of Leukemia-Associated Mutations in Pediatric vs. Adult AML. Prevalence of mutations in pediatric patients treated on COG AML trials is compared to corresponding reported mutation prevalence in adult AML. Results from the present study are indicated with an asterisk. WT1^, and FLT3/ALM^, mutations occurred at similar frequencies between the two cohorts, while FLT3/ITD,^, NPM1,^, and CEBPA^, mutations occurred more commonly in adult AML. Although TET2^, mutations were nearly as prevalent in childhood as compared to adult AML, functional mutations of the other methylation-associated genes–IDH1 or IDH2 (combined mutation prevalence of 17% in adult AML) and DNMT3A (22% in adult AML)–were notably less common (rare or absent) in pediatric patients.

Fig. 2

Role of the leukemia-associated genes DNMT3A, TET2, IDH1, and IDH2 in DNA methylation DNMT3A encodes a DNA methyltransferase gene responsible for methylation at the 5 position of cytosine, resulting in 5-methylcytosine (5mc). TET2 catalyzes the conversion of 5mc to 5-hydroxymethylcytosine (5hmc), a reaction which may ultimately result in the demethylation of DNA. The TET2 enzyme requires the substrate alpha-ketoglutarate, which is the product of the oxidative decarboxylation of isocitrate by IDH1 or IDH2. Function-altering mutations of all four genes have been implicated in AML and may be involved in the deregulation of DNA methylation/demethylation.