Journal of Neuro-Oncology

, Volume 107, Issue 1, pp 197–205

Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy

Authors

  • Whitney B. Pope
    • Department of Radiological Sciences, David Geffen School of Medicine at UCLAUniversity of California at Los Angeles
  • Robert M. Prins
    • Department of Neurosurgery, David Geffen School of Medicine at UCLAUniversity of California at Los Angeles
  • M. Albert Thomas
    • Department of Radiological Sciences, David Geffen School of Medicine at UCLAUniversity of California at Los Angeles
  • Rajakumar Nagarajan
    • Department of Radiological Sciences, David Geffen School of Medicine at UCLAUniversity of California at Los Angeles
  • Katharine E. Yen
    • Agios Pharmaceuticals
  • Mark A. Bittinger
    • Agios Pharmaceuticals
  • Noriko Salamon
    • Department of Radiological Sciences, David Geffen School of Medicine at UCLAUniversity of California at Los Angeles
  • Arthur P. Chou
    • Department of Neurosurgery, David Geffen School of Medicine at UCLAUniversity of California at Los Angeles
  • William H. Yong
    • Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLAUniversity of California at Los Angeles
  • Horacio Soto
    • Department of Neurosurgery, David Geffen School of Medicine at UCLAUniversity of California at Los Angeles
  • Neil Wilson
    • Department of Radiological Sciences, David Geffen School of Medicine at UCLAUniversity of California at Los Angeles
  • Edward Driggers
    • Agios Pharmaceuticals
  • Hyun G. Jang
    • Agios Pharmaceuticals
  • Shinsan M. Su
    • Agios Pharmaceuticals
  • David P. Schenkein
    • Agios Pharmaceuticals
  • Albert Lai
    • Department of Neurology, David Geffen School of Medicine at UCLAUniversity of California at Los Angeles
  • Timothy F. Cloughesy
    • Department of Neurology, David Geffen School of Medicine at UCLAUniversity of California at Los Angeles
  • Harley I. Kornblum
    • Department of Psychiatry & Behavioral Sciences, David Geffen School of Medicine at UCLAUniversity of California at Los Angeles
  • Hong Wu
    • Department of Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLAUniversity of California at Los Angeles
  • Valeria R. Fantin
    • Agios Pharmaceuticals
    • Department of Neurosurgery, David Geffen School of Medicine at UCLAUniversity of California at Los Angeles
Clinical Study – Patient Study

DOI: 10.1007/s11060-011-0737-8

Cite this article as:
Pope, W.B., Prins, R.M., Albert Thomas, M. et al. J Neurooncol (2012) 107: 197. doi:10.1007/s11060-011-0737-8

Abstract

Mutations of the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are commonly found in primary brain cancers. We previously reported that a novel enzymatic activity of these mutations results in the production of the putative oncometabolite, R(−)-2-hydroxyglutarate (2-HG). Here we investigated the ability of magnetic resonance spectroscopy (MRS) to detect 2-HG production in order to non-invasively identify patients with IDH1 mutant brain tumors. Patients with intrinsic glial brain tumors (n = 27) underwent structural and spectroscopic magnetic resonance imaging prior to surgery. 2-HG levels from MRS data were quantified using LC-Model software, based upon a simulated spectrum obtained from a GAMMA library added to the existing prior knowledge database. The resected tumors were then analyzed for IDH1 mutational status by genomic DNA sequencing, Ki-67 proliferation index by immunohistochemistry, and concentrations of 2-HG and other metabolites by liquid chromatography–mass spectrometry (LC–MS). MRS detected elevated 2-HG levels in gliomas with IDH1 mutations compared to those with wild-type IDH1 (P = 0.003). The 2-HG levels measured in vivo with MRS were significantly correlated with those measured ex vivo from the corresponding tumor samples using LC–MS (r 2 = 0.56; P = 0.0001). Compared with wild-type tumors, those with IDH1 mutations had elevated choline (P = 0.01) and decreased glutathione (P = 0.03) on MRS. Among the IDH1 mutated gliomas, quantitative 2-HG values were correlated with the Ki-67 proliferation index of the tumors (r 2  = 0.59; P = 0.026). In conclusion, water-suppressed proton (1H) MRS provides a non-invasive measure of 2-HG in gliomas, and may serve as a potential biomarker for patients with IDH1 mutant brain tumors. In addition to 2-HG, alterations in several other metabolites measured by MRS correlate with IDH1 mutation status.

Keywords

2 hydroxyglutarate (2-HG) Glioma Magnetic resonance spectroscopy Brain tumor Isocitrate dehydrogenase LC-Model

Supplementary material

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Supplementary material 1 (DOC 47 kb)
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Supplementary material 2 (TIFF 7912 kb)
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Supplementary material 3 (TIFF 5791 kb)
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Supplementary material 4 (TIFF 2914 kb)
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Supplementary material 5 (TIFF 607 kb)

Copyright information

© Springer Science+Business Media, LLC. 2011