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

Journal of Neuro-Oncology volume 107, pages 197–205 (2012)Cite this article

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.

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Acknowledgments

Supported in part by grants from the National Cancer Institute (K01-CA111402 and R01-CA123396 to Dr. Prins; R01-CA112358 and R01-CA121131 to Dr. Liau), and research grants from the Neidorf Family Foundation, the Phillip R. Jonsson & Kenneth A. Jonsson Foundations, the Brad Kaminsky Foundation, and the Accelerate Brain Cancer Cure Foundation. Scientific support of Mr. Brian Burns is also gratefully acknowledged.

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Affiliations

  1. Department of Radiological Sciences, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA, 90095, USA

    Whitney B. Pope, M. Albert Thomas, Rajakumar Nagarajan, Noriko Salamon & Neil Wilson

  2. Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Gonda Building, Room 3357, 695 Charles Young Drive, Los Angeles, CA, 90095-1761, USA

    Robert M. Prins, Arthur P. Chou, Horacio Soto & Linda M. Liau

  3. Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA, 90095, USA

    William H. Yong

  4. Department of Neurology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA, 90095, USA

    Albert Lai & Timothy F. Cloughesy

  5. Department of Psychiatry & Behavioral Sciences, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA, 90095, USA

    Harley I. Kornblum

  6. Department of Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA, 90095, USA

    Hong Wu

  7. Agios Pharmaceuticals, 38 Sidney Street, Cambridge, MA, 02139, USA

    Katharine E. Yen, Mark A. Bittinger, Edward Driggers, Hyun G. Jang, Shinsan M. Su, David P. Schenkein & Valeria R. Fantin

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  1. Whitney B. Pope
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  2. Robert M. Prins
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  3. M. Albert Thomas
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  16. Albert Lai
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  19. Hong Wu
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  21. Linda M. Liau
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Corresponding author

Correspondence to Linda M. Liau.

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Whitney B. Pope, Robert M. Prins, and M. Albert Thomas contributed equally to this article.

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Pope, W.B., Prins, R.M., Albert Thomas, M. et al. Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy. J Neurooncol 107, 197–205 (2012). https://doi.org/10.1007/s11060-011-0737-8

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  • DOI: https://doi.org/10.1007/s11060-011-0737-8

Keywords

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