title: 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 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 ppm 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.
authors.affiliation: Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Jelena
authors.initials: J
authors.lastname: Lazovic
authors.forename: Horacio
authors.initials: H
authors.lastname: Soto
authors.forename: David
authors.initials: D
authors.lastname: Piccioni
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Lou
authors.forename: Sichen
authors.initials: S
authors.lastname: Li
authors.forename: Leili
authors.initials: L
authors.lastname: Mirsadraei
authors.forename: William
authors.initials: W
authors.lastname: Yong
authors.forename: Robert
authors.initials: R
authors.lastname: Prins
authors.forename: Linda M
authors.initials: LM
authors.lastname: Liau
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Ellingson
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.forename: Albert
authors.initials: A
authors.lastname: Lai
authors.forename: Whitney B
authors.initials: WB
authors.lastname: Pope
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005910:Glioma / Q000235:genetics* / Q000378:metabolism*; D005977:Glutarates / Q000032:analysis* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D011522:Protons
chemical_list: D005977:Glutarates; D011522:Protons; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase