Detection of 2-hydroxyglutaric acid in vivo by proton magnetic resonance spectroscopy in U87 glioma cells overexpressing isocitrate dehydrogenase-1 mutation

Abstract

The arginine 132 (R132) mutation of isocitrate dehydrogenase-1 (IDH1 R132) results in production of 2-hydroxyglutarate (2-HG) and is associated with a better prognosis compared with wild-type (WT) in glioma patients. The majority of lower-grade gliomas express IDH1R132, whereas this mutation is rare in grade IV gliomas. The aim of this study was to noninvasively investigate metabolic and physiologic changes associated with the IDH1 mutation in a mouse glioma model. Using a 7T magnet, we compared MRI and proton magnetic resonance spectroscopy (MRS) in U87 glioma cells overexpressing either the mutated IDH1R132 or IDH1 wild-type (IDH1WT) gene in a mouse flank xenograft model. Flank tumors overexpressing IDH1 R132 showed a resonance at 2.25 ppm corresponding to the 2-HG peak described for human IDH1R132 gliomas. WT tumors lacked this peak in all cases. IDH1 mutant tumors demonstrated significantly reduced glutamate by in vivo MRS. There were no significant differences in T2, apparent diffusion coefficient (ADC), or perfusion values between the mutant and IDH1WT tumors. The IDH1R132 mutation results in 2-HG resonance at 2.25 ppm and a reduction of glutamate levels as determined by MRS. Our results establish a model system where 2-HG can be monitored noninvasively, which should be helpful in validating 2-HG levels as a prognostic and/or predictive biomarker in glioma. © 2012 The Author(s).