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

摘要

The arginine 132 (R132) mutation of isocitrate dehydro-genase -1 (IDH1~(R132)) results in production of 2-hydrox-yglutarate (2-HG) and is associated with a better prognosis compared with wild-type (WT) in glioma patients. The majority of lower-grade gliomas express IDH1~(R132), 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 IDH1~(R132) or IDH1 wild-type (IDH1~(WT)) gene in a mouse flank xenograft model. Flank tumors overexpressing IDH1~(R132) showed a resonance at 2.25 ppny corresponding to the 2-HG peak described for human IDH1~(R132) 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 T_2, apparent diffusion coefficient (ADC), or perfusion values between the mutant and IDH1~(WT) tumors. The IDH1~(R132) 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.