title: Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy.
abstract: Mutations in the gene isocitrate dehydrogenase 1 (IDH1) are present in up to 86% of grade II and III gliomas and secondary glioblastoma. Arginine 132 (R132) mutations in the enzyme IDH1 result in excess production of the metabolite 2-hydroxyglutarate (2HG), which could be used as a biomarker for this subset of gliomas. Here, we use optimized in vivo spectral-editing and two-dimensional (2D) correlation magnetic resonance spectroscopy (MRS) methods to unambiguously detect 2HG noninvasively in glioma patients with IDH1 mutations. By comparison, fitting of conventional 1D MR spectra can provide false-positive readouts owing to spectral overlap of 2HG and chemically similar brain metabolites, such as glutamate and glutamine. 2HG was also detected using 2D high-resolution magic angle spinning MRS performed ex vivo on a separate set of glioma biopsy samples. 2HG detection by in vivo or ex vivo MRS enabled detailed molecular characterization of a clinically important subset of human gliomas. This has implications for diagnosis as well as monitoring of treatments targeting mutated IDH1.
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. ovidiu@nmr.mgh.harvard.edu
authors.forename: Ovidiu C
authors.initials: OC
authors.lastname: Andronesi
authors.forename: Grace S
authors.initials: GS
authors.lastname: Kim
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gerstner
authors.forename: Tracy
authors.initials: T
authors.lastname: Batchelor
authors.forename: Aria A
authors.initials: AA
authors.lastname: Tzika
authors.forename: Valeria R
authors.initials: VR
authors.lastname: Fantin
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.forename: A Gregory
authors.initials: AG
authors.lastname: Sorensen
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004827:Epilepsy / Q000473:pathology; D005260:Female; D005910:Glioma / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D019047:Phantoms, Imaging; D055815:Young Adult
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human