Article

Non-invasive in vivo assessment of IDH1 mutational status in glioma

  • Nature Communications 4, Article number: 2429 (2013)
  • doi:10.1038/ncomms3429
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Abstract

Gain-of-function mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade gliomas and secondary glioblastoma. They lead to intracellular accumulation of the oncometabolite 2-hydroxyglutarate, represent an early pathogenic event and are considered a therapeutic target. Here we show, in this proof-of-concept study, that [1-13C] α-ketoglutarate can serve as a metabolic imaging agent for non-invasive, real-time, in vivo monitoring of mutant IDH1 activity, and can inform on IDH1 status. Using 13C magnetic resonance spectroscopy in combination with dissolution dynamic nuclear polarization, the metabolic fate of hyperpolarized [1-13C] α-ketoglutarate is studied in isogenic glioblastoma cells that differ only in their IDH1 status. In lysates and tumours that express wild-type IDH1, only hyperpolarized [1-13C] α-ketoglutarate can be detected. In contrast, in cells that express mutant IDH1, hyperpolarized [1-13C] 2-hydroxyglutarate is also observed, both in cell lysates and in vivo in orthotopic tumours.

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Acknowledgements

We acknowledge Sarah Woods, Dr Alessia Lodi, Pia Eriksson, Galen Reed and Aaron Robinson. This work was supported by NIH UCSF Brain Tumour SPORE P50 CA097257, NIH R01CA172845, NIH R21CA16154, NIH R01CA154915, NIH P41EB013598, a grant from the UCSF Academic Senate and a fellowship from the American Brain Tumour Association.

Author information

Affiliations

  1. Department of Radiology and Biomedical Imaging, University of California San Francisco, 1700 4th Street, San Francisco, California 94158, USA

    • Myriam M. Chaumeil
    • , Peder E. Z. Larson
    • , Hikari A. I. Yoshihara
    • , Olivia M. Danforth
    • , Daniel B. Vigneron
    • , Sarah J. Nelson
    •  & Sabrina M. Ronen
  2. Brain Tumor Research Center, University of California San Francisco, San Francisco, California 94143, USA

    • Sarah J. Nelson
    • , Russell O. Pieper
    • , Joanna J. Phillips
    •  & Sabrina M. Ronen
  3. Department of Neurological Surgery, Helen Diller Research Center, University of California San Francisco, San Francisco, California 94143, USA

    • Russell O. Pieper
    •  & Joanna J. Phillips
  4. Department of Pathology, University of California San Francisco, San Francisco, California 94143, USA

    • Joanna J. Phillips

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Contributions

M.M.C. designed and performed the experiments and wrote the paper. P.E.Z.L, J.J.P. and H.A.I.Y designed and performed experiments and contributed to writing the paper. O.M.D. performed experiments. D.B.V., S.J.N. and R.O.P. designed experiments and reviewed the paper. S.M.R. conceived the study, designed the experiments and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sabrina M. Ronen.

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