Article

Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy.

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Science translational medicine (Impact Factor: 14.41). 01/2012; 4(116):116ra4. DOI: 10.1126/scitranslmed.3002693
Source: PubMed

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.

3 Followers
 · 
128 Views
  • Source
    Evolution of the Molecular Biology of Brain Tumors and Therapeutic Implications, Edited by Terry Lichtor, 02/2013: chapter The distribution and significance of IDH mutations in gliomas: pages 299-342; INTECH.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in isocitrate dehydrogenase (IDH) 1 have been reported in over 70% of low-grade gliomas and secondary glioblastomas. IDH1 is the enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate while mutant IDH1 catalyzes the conversion of α-ketoglutarate into 2-hydroxyglutarate. These mutations are associated with the accumulation of 2-hydroxyglutarate within the tumor and are believed to be one of the earliest events in the development of low-grade gliomas. The goal of this work was to determine whether the IDH1 mutation leads to additional magnetic resonance spectroscopy (MRS)-detectable changes in the cellular metabolome. Two genetically engineered cell models were investigated, a U87-based model and an E6/E7/hTERT immortalized normal human astrocyte (NHA)-based model. For both models, wild-type IDH1 cells were generated by transduction with a lentiviral vector coding for the wild-type IDH1 gene while mutant IDH1 cells were generated by transduction with a lentiviral vector coding for the R132H IDH1 mutant gene. Metabolites were extracted from the cells using the dual-phase extraction method and analyzed by 1H-MRS. Principal Component Analysis was used to analyze the MRS data. Principal Component Analysis clearly discriminated between wild-type and mutant IDH1 cells. Analysis of the loading plots revealed significant metabolic changes associated with the IDH1 mutation. Specifically, a significant drop in the concentration of glutamate, lactate and phosphocholine as well as the expected elevation in 2-hydroxyglutarate were observed in mutant IDH1 cells when compared to their wild-type counterparts. The IDH1 mutation leads to several, potentially translatable MRS-detectable metabolic changes beyond the production of 2-hydroxyglutarate.
    PLoS ONE 02/2015; 10(2):e0118781. DOI:10.1371/journal.pone.0118781 · 3.53 Impact Factor
  • Source
    Tumor Cell Metabolism. Pathways, Regulation and Biology, Edited by Sybille Mazurek, Maria Shosha, 01/2015: chapter 14: pages 315-348; Springer., ISBN: 978-3-7091-1823-8