P04.13 Detection and quantitative analysis of oncometabolite 2-hydroxyglutarate by 1H-magnetic resonance spectroscopy and LCModel in gliomas
Authors: S. Kume, M. Gomyo, K. Kobayashi, K. Saito, S. Shimizu, K. Suzuki, K. Maruyama, K. Tsuchiya, Y. Shiokawa, M. Nagane
Journal: Neuro-Oncology (2017)

Backgrounds: Mutations of the isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) genes are present in most WHO grade II/III gliomas and secondary glioblastoma (GBM), thus being of essential importance in the diagnosis and decision for therapeutic options Mutant IDH (mut-IDH) 1 or 2 catalyzes production of 2-hydroxyglutarate (2-HG), which acts as an “oncometabolite” leading to gliomagenesis through activation of cardinal biological pathways. LCModel is a software which can detect and conduct quantitative analysis of metabolites including 2-HG using data from proton-magnetic resonance spectroscopy (H-MRS). Here we report our experience using this method focusing on its sensitivity, specificity, and accuracy in detection of 2-HG in a variety of intracerebral lesions mostly of gliomas. Methods: Patients with brain tumor that was examined with 3T MRS (single voxel, PRESS sequence) from December, 2014 to November, 2016 were eligible. The acquired MRS data were analyzed with LCModel, which then were compared with pathological diagnosis and gene mutation profiles of the lesions. There were 147 patients, 65 males and 82 females, and their mean age was 53 years (range, 6–91 years) Mutations of IDH1/2 genes were identified by Sanger sequencing. Accuracy of the metabolite concentration measurement was determined with standard deviation rate (%SD) provided by LCModel analysis and a threshold for exclusion was set at 50% or greater of %SD. Results: IDH mutation was found in 39 gliomas while IDH was wild-type (wt-IDH) in 29 gliomas. There were 22 other neoplastic lesions including meningiomas and primary nervous system lymphomas, and additional 57 without histopathological confirmation. Those with mut-IDH were significantly younger (p=0.002). IDH mutation was significantly associated with methylation in promoter region of O6-methylguanine-DNA methyltransferase (MGMT) gene (p=0.027). Among a total of 276 H-MRS analyses (132 mut-IDHs, 44 wt-IDHs, 29 other tumors and 71 unconfirmed lesions), 2-HG was detectable in 23 analyses where mean 2-HG concentration was 6.01 mmol/L (range 1.831–15.203). Among 23 2-HG detected lesions, 9 were found to be positive for IDH mutation, while 2-HG levels were 0 mmol/L in all 64 wt-IDH gliomas and other brain tumors, giving rise to sensitivity of 11%, specificity 86%, and accuracy of 66%. Of note, 2-HG detected lesions with IDH mutation contained significantly higher concentration of aspartic acid (Asp) than those without IDH mutation (1.49 vs. 0.56 mmol/L, p=0.046). Conclusions: 2-HG could be detected in human glioma lesions with mut-IDH using MRS-LCModel system, but the sensitivity was insufficient for reliable non-invasive diagnosis. Given that Asp is synthesized from oxaloacetate in the citric acid cycle, association of increased Asp level with 2-HG might provide a potential usefulness in enhancing accuracy of this method, although further exploration is warranted.