Interclonal and Intraclonal Heterogeneity in Patients with IDH1/2 Mutation

• Published in: Blood 2016-12, Vol.128 (22), p.1689-1689
• Main Authors: Ma, Wanlong, Thangavelu, Maya, De Dios, Ivan, Funari, Vincent, Albitar, Maher
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V128.22.1689.1689

Background: DNA methylation in AML/MDS plays a major role in the pathogenesis of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The major genes involved in DNA methylation in AML/MDS are IDH1 and 2, TET2 and DNMT3A. Mutations in IDH1/2 result in the production of an aberrant metabolite, 2-hydroxyglutarate, which acts as a competitive inhibitor of a-ketoglutarate and inhibits TET2 oxidation of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Mutations in TET2 or IDH1/2 are associated with reduced levels of 5hmC and genomic hypermethylation. TET2 mutations and IDH1/IDH2 mutations are believed to be mutually exclusive. In addition, DNMT3A as a DNA methyltransferase enzyme is commonly mutated in AML/MDS and its mutation is believed to lead to hypomethylation. Understanding the interaction between these genes may influence therapy with IDH1/2 inhibitors. Toward better understanding of interaction between these genes, we analyzed the mutation profile of these genes in patients with AML/MDS. Methods: A total of 1182 bone marrow (BM) aspirate samples were tested by the commercially available TruSight Myeloid Next Generation Sequencing Panel (Illumina, San Diego, CA). We extracted DNA from bone marrow aspirate using the QIAamp DNA Mini Kit. This NGS panel covers hot spot mutations in 54 genes. The average depth of sequencing was 10,000X. Results: IDH1/2 mutations were detected in 201 of the 1182 (17%). IDH1 was detected in 87 (7.4%) and IDH2 was detected in 120 (10.1%). This included 6 patients who had mutations in both IDH1 and IDH2. Variant (mutant) allele frequency (VAF) was significantly higher (P=0.01) in IDH2 as compared to IDH1 (median of 43.35% vs 35.0%, respectively). Thirteen patients (6.5%) had mutant VAF >50% suggesting homozygosity, 11 of which had IDH2 mutation. Two of the 6 patients with both IDH1 and IDH2 mutations had VAF 50% in 6 of these patient and in DNMT3A in 3 patients. Twenty four patients had TP53 mutation, of w