MPC-11 IDH1/2 MUTATIONS ARE ASSOCIATED WITH SEIZURE ONSET AND VETRY IMAGING IN PATIENTS WITH DIFFUSE GLIOMA VISUALIZING 2-HYDROXYGLUTARATE BY MASS SPECTRUM

BACKGROUND: Mutations in isocitrate dehydrogenase 1 or 2 genes (IDH1/2) frequently occur in lower-grade gliomas. Mutant IDH1/2 proteins gain a new ability to produce 2-hydroxyglutarate (2HG). IDH1/2 mutations have shown to be related with seizure through the structural similarity of 2HG to glutamate. We, therefore, sought to investigate the relationship between seizure and IDH1/2 mutations and to visualize tissue 2HG distribution in patients with diffuse gliomas. METHODS: We assessed 149 patients with diffuse glioma, and measured tissue 2HG concentrations in 104 patients by using liquid chromatography-tandem mass spectrometry. The matrix-assisted laser desorption/ionization high resolution mass spectrometry imaging (MALDI-HR-MSI) was used to visualize tissue 2HG distribution for 12 tissue samples. RESULTS: Seizure onset was observed in 34 among 56 (60.7%) patients with IDH1/2 mutant tumor, whereas in 18 among 93 (19.4%) patients with IDH1/2 wild-type tumor (p<0.0001). The tissue 2HG concentration was significantly higher in IDH1/2 mutant tumor than in IDH1/2 wild-type tumor (median: 4862 ng/mg vs 75 ng/mg) (p<0.0001). Multivariate analysis, including tissue 2HG concentration, IDH1/2 status, histology, grade, and location, showed that IDH1/2 mutations was significantly correlated with seizure onset. The MALDI-HR-MSI showed that 2HG spread in various concentration independent of cellularity and also in extracellular space in IDH1/2 mutant tumor tissue. CONCLUSIONS: We demonstrated the association between IDH1/2 mutations and seizure, and the heterogeneous 2HG distribution not only in cellular area but also in extracellular space. These findings suggest the potential role of 2HG as an intercellular mediator to tumor environment, resulting in epileptogenesis formation.