title: Noninvasive Quantification of 2-Hydroxyglutarate in Human Gliomas with IDH1 and IDH2 Mutations.
abstract: Mutations in the isocitrate dehydrogenase genes (IDH1/2) occur often in diffuse gliomas, where they are associated with abnormal accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Monitoring 2-HG levels could provide prognostic information in this disease, but detection strategies that are noninvasive and sufficiently quantitative have yet to be developed. In this study, we address this need by presenting a proton magnetic resonance spectroscopy ((1)H-MRS) acquisition scheme that uses an ultrahigh magnetic field (≥ 7T) capable of noninvasively detecting 2-HG with quantitative measurements sufficient to differentiate mutant cytosolic IDH1 and mitochondrial IDH2 in human brain tumors. Untargeted metabolomics analysis of in vivo (1)H-MRS spectra discriminated between IDH-mutant tumors and healthy tissue, and separated IDH1 from IDH2 mutations. High-quality spectra enabled the quantification of neurochemical profiles consisting of at least eight metabolites, including 2-HG, glutamate, lactate, and glutathione in both tumor and healthy tissue voxels. Notably, IDH2 mutation produced more 2-HG than IDH1 mutation, consistent with previous findings in cell culture. By offering enhanced sensitivity and specificity, this scheme can quantitatively detect 2-HG and associated metabolites that may accumulate during tumor progression, with implications to better monitor patient responses to therapy.
authors.affiliation: The FMRIB Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. uzay.emir@ndcn.ox.ac.uk.
authors.forename: Uzay E
authors.initials: UE
authors.lastname: Emir
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Larkin
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom. Department of Neurosurgery, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
authors.forename: Nick
authors.initials: N
authors.lastname: de Pennington
authors.affiliation: The FMRIB Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Natalie
authors.initials: N
authors.lastname: Voets
authors.affiliation: Department of Neurosurgery, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
authors.forename: Puneet
authors.initials: P
authors.lastname: Plaha
authors.affiliation: Department of Neurosurgery, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Stacey
authors.affiliation: Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Khalid
authors.initials: K
authors.lastname: Al-Qahtani
authors.affiliation: Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Mccullagh
authors.affiliation: Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
authors.affiliation: The FMRIB Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Stuart
authors.initials: S
authors.lastname: Clare
authors.affiliation: The FMRIB Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Jezzard
authors.affiliation: Department of Neurosurgery, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Cadoux-Hudson
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
authors.forename: Olaf
authors.initials: O
authors.lastname: Ansorge
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D005910:Glioma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human