QLIF-03. MUTANT IDH1 PROMOTES TUMOR-ASSOCIATED EPILEPSY IN GLIOMA PATIENTS

Seizures are a major quality-of-life issue for patients with infiltrative gliomas. Over 50% will experience at least one seizure during the course of their disease, and over 30% will develop tumor-associated epilepsy (TAE), defined as multiple seizures. Lower-grade gliomas are more likely to cause TAE than glioblastomas (GBMs), though the reasons for this are unclear. Grade II-III gliomas are far more likely to contain mutations in isocitrate dehydrogenase 1 (IDH1mut) than grade IV GBMs. The product of IDH1mut, D-2-hydroxyglutarate (D2HG), is released by tumor cells into the microenvironment. D2HG is structurally similar to a powerful excitatory neurotransmitter, glutamate, which triggers neuronal depolarization by opening NMDA channels. Therefore, we hypothesized that IDH1mut increases seizure risk through the activity of D2HG on neurons within and around the tumor. In 3 cohorts from separate institutions (total N=712), seizures were a part of the presenting symptoms in 18-34% of IDH1 wild-type (IDH1wt) patients and in 59-74% of IDH1mut patients (P<0.0001). Multiple logistic regression modeling, including 1p/19q codeletion and temporal lobe location, showed that IDH1mut was the only significant independent correlate with seizures in all 3 cohorts (OR=2.5-10.4). Although clinical presentation with seizures has previously been reported as a predictor of longer survival, Cox proportional hazards modeling suggest that this is due to its link with IDH1mut (RR=0.78 for seizures, P=0.39; RR=0.027 for IDH1mut, P<0.001). Exogenous D2HG increased the firing rate of cultured rat cortical neurons in a dose-dependent manner, up to 374% in 10 mM D2HG. This was completely blocked by the selective NMDA antagonist, AP5. These data show, for the first time, a direct mechanism of action by D2HG on neurons, supported by data from 3 large cohorts of glioma patients. This has translational implications for the personalized management of TAE, as targeted IDH1mut inhibitors may improve antiepileptic therapy in IDH1mut patients.