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2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas

Nature Medicine volume 18, pages 624–629 (2012)Cite this article

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Abstract

Mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) have been shown to be present in most World Health Organization grade 2 and grade 3 gliomas in adults. These mutations are associated with the accumulation of 2-hydroxyglutarate (2HG) in the tumor. Here we report the noninvasive detection of 2HG by proton magnetic resonance spectroscopy (MRS). We developed and optimized the pulse sequence with numerical and phantom analyses for 2HG detection, and we estimated the concentrations of 2HG using spectral fitting in the tumors of 30 subjects. Detection of 2HG correlated with mutations in IDH1 or IDH2 and with increased levels of D-2HG by mass spectrometry of the resected tumors. Noninvasive detection of 2HG may prove to be a valuable diagnostic and prognostic biomarker.

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Figure 1: Theoretical and experimental spectra of 2HG.
Figure 2: In vivo 1H spectra and analysis.
Figure 3: Validation of 2HG PRESS measurements.
Figure 4: Spectroscopic imaging of 2HG.

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Change history

  • 31 January 2012

     In the version of this article initially published online, Craig R. Malloy’s name was incorrectly listed as Craig M. Malloy. Figure 2c was incorrectly labeled as a grade 4 oligodendroglioma; the correct labeling should be grade 2 oligodendroglioma. In reference 13, Ernest, R.R. should have been Ernst, R.R. In the Acknowledgments, one grant was missing: US National Institutes of Health grant RR0584. These errors have been corrected for all versions of this article.

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Acknowledgements

This work was supported by US National Institutes of Health grants RC1NS0760675, R21CA159128 and RR02584 and by the Cancer Prevention Research Institute of Texas grant RP101243-P04. We thank C. Sheppard for expert management of the patient database and for coordinating research scans and tissue samples; S. McNeil for expert human subject care during scanning; C. Foong for expert assistance with pathological analysis of tumor; and R.L. Boriack for expert assistance with 2HG measurements by mass spectrometry.

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Authors and Affiliations

  1. Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Changho Choi, Sandeep K Ganji, Zoltan Kovacs & Craig R Malloy

  2. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Changho Choi, Sandeep K Ganji & Craig R Malloy

  3. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Ralph J DeBerardinis, Isaac Marin-Valencia & Juan M Pascual

  4. McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Ralph J DeBerardinis

  5. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Ralph J DeBerardinis, Kimmo J Hatanpaa, Xiao-Li Yang, Tomoyuki Mashimo, Jack M Raisanen, Christopher J Madden, Bruce E Mickey, Robert M Bachoo & Elizabeth A Maher

  6. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Kimmo J Hatanpaa, Dinesh Rakheja & Jack M Raisanen

  7. Annette Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Kimmo J Hatanpaa, Xiao-Li Yang, Tomoyuki Mashimo, Jack M Raisanen, Christopher J Madden, Bruce E Mickey, Robert M Bachoo & Elizabeth A Maher

  8. Children’s Medical Center, Dallas, Texas, USA

    Dinesh Rakheja

  9. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Xiao-Li Yang, Tomoyuki Mashimo, Craig R Malloy, Robert M Bachoo & Elizabeth A Maher

  10. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Juan M Pascual, Robert M Bachoo & Elizabeth A Maher

  11. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Juan M Pascual

  12. Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Christopher J Madden & Bruce E Mickey

  13. Veterans Affairs North Texas Health Care System, Dallas, Texas, USA

    Craig R Malloy

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  1. Changho Choi
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  14. Craig R Malloy
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  16. Elizabeth A Maher
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Contributions

C.C. developed the MRS methodology for 2HG detection, designed and performed the magnetic resonance experiments and data analysis, supervised the MRS study, prepared figures and wrote the manuscript. E.A.M. led all aspects of the human study, contributed to data analysis, preparation of the figures and writing of the manuscript. S.K.G. carried out magnetic resonance data acquisition and contributed to data analysis. D.R. performed mass spectrometry analysis on resected tumors and contributed to manuscript preparation. Z.K. synthesized 2HG and prepared a figure. R.J.D. and C.R.M. contributed to the conceptual approach, review of the data and manuscript preparation. K.J.H. and J.M.R. contributed to tumor sample collection and validation, neuropathological evaluation and diagnosis, evaluation of immunohistochemical stains and manuscript preparation. X.-L.Y. and T.M. performed the tissue evaluation of IDH mutations. I.M.-V. and J.M.P. contributed to conceptual analysis. B.E.M. recruited subjects and contributed to clinical data analysis and manuscript preparation. C.J.M. recruited subjects and contributed to manuscript preparation. R.M.B. contributed to the conceptual approach, led the tumor analysis workup, and contributed to data analysis and manuscript preparation.

Corresponding authors

Correspondence to Changho Choi or Elizabeth A Maher.

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The authors declare no competing financial interests.

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Choi, C., Ganji, S., DeBerardinis, R. et al. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med 18, 624–629 (2012). https://doi.org/10.1038/nm.2682

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