High tissue 2HG level may increase preoperative seizure risk in those with mutant tumors

Higher tissue 2-hydroxyglutarate concentration appeared to increase risk for preoperative seizures in isocitrate dehydrogenase 1/2 mutant tumors, according to study results published in Neurology.

“Seizures are common manifestations in patients with gliomas and are one of the major problems affecting patient quality of life,” Makoto Ohno, MD, PhD, of the department of neurosurgery and neuro-oncology at National Cancer Center Hospital in Japan, and colleagues wrote. “Seizures occur in 60% to 85% of patients with lower-grade gliomas and 30% to 60% of patients with glioblastomas. It is important to understand the mechanisms and risk factors of glioma-related epilepsy to optimize treatment and improve patient quality of life.”

The investigators used clinical samples to examine the association between tissue 2-hydroxyglutarate (2HG) concentration and preoperative seizures. They analyzed data of 104 consecutive patients with diffuse glioma who underwent surgery between August 2008 and May 2016, with known clinical presentation and isocitrate dehydrogenase 1/2 (IDH1/2) status. They used patient charts to assess the presence of preoperative seizures, tumor location, histopathological diagnosis, IDH1/2 status and 1p/19q codeletion.

Via liquid chromatography-tandem mass spectrometry, they measured tissue 2HG concentration. Further, in surgically resected samples from 12 patients, they applied matrix-assisted laser desorption/ionization high-resolution mass spectrometry imaging (MALDI-MSI) to assess 2HG distribution without artefactual tissue disruption.

Results showed higher tissue 2HG concentration among IDH1/2 mutant tumors compared with IDH1/2 wildtype tumors, with a median of 4,860 ng/mg vs. 75 ng/mg, respectively (P < .0001). MALDI-MSI was able to detect 2HG signals in IDH mutant tumors but not IDH wildtype tumors. The researchers reported preoperative seizures among 64.3% of patients with IDH mutant tumors and 21% of patients with IDH wildtype tumors (P < .0001). Calculations based on the receiver operating characteristic curve showed an optimal cutoff value of tissue 2HG concentration of 1,190 ng/mg for predicting preoperative seizures.

Ohno and colleagues only observed increased preoperative seizure risk in tumors with 2HG concentration above the cutoff value among IDH mutant tumors. Multivariate analysis showed an association only between increased tissue 2HG concentration and preoperative seizures (OR = 5.86; 95% CI, 1.02-48.5).

“IDH1/2 mutant tumors might have different capacities of producing 2HG, and this heterogeneity might have a different clinical effect on IDH1/2 mutant tumors,” the researchers wrote. “Nevertheless, this patient-based study improves our understanding of underlying mechanisms of tumor-related seizures in IDH1/2 mutant tumors.”