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Detection of “oncometabolite” 2-hydroxyglutarate by magnetic resonance analysis as a biomarker of IDH1/2 mutations in glioma

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Abstract

Somatic mutations in isocitrate dehydrogenase (IDH)1 and 2 have been identified in a subset of gliomas, rendering these tumors with elevated levels of “oncometabolite,” D-2-hydroxyglutarate (2HG). Herein, we report that 2HG can be precisely detected by magnetic resonance (MR) in human glioma specimens and used as a reliable biomarker to identify this subset of tumors. Specifically, we developed a two-dimensional correlation spectroscopy resonance method to reveal the distinctive cross-peak pattern of 2HG in the complex metabolite nuclear MR spectra of brain tumor tissues. This study demonstrates the feasibility, specificity, and selectivity of using MR detection and quantification of 2HG for the diagnosis and classification of IDH1/2 mutation-positive brain tumors. It further opens up the possibility of developing analogous non-invasive MR-based imaging and spectroscopy studies directly in humans in the neuro-oncology clinic.

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Notes

  1. During our submission the following three related studies were published: Elkhaled A et al. (2012) Magnetic resonance of 2-hydroxyglutarate in IDH1-mutated low-grade gliomas. Sci Transl Med 4(116):116ra4; Andronesi OC et al. (2012) Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy. Sci Transl Med 4(116):116ra4; and Choi C et al. (2012) 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med doi:10.1038/nm.2682.

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Acknowledgments

We thank Dr. Jeffrey Olson for the provision of brain tumor samples, Drs. Daniel Brat and Steven Hunter for neuropathological diagnosis, and Narra Sarojini Devi and Zhaobin Zhang for banking brain tumor tissue samples. We also thank the Winship Cancer Institute Tissue Procurement and Pathology core for tissue sectioning and immunohistochemistry services.

Disclosure statement

All authors concur with the content of the manuscript and assert that this report is not under consideration for publication elsewhere. No conflict of interest is noted.

Grant support

This work was supported in part by NIH grants R01 CA86335 and CA116804 (to EGVM), R21AG032104-01A1 and P50CA128301-020003 (to HM), P30 CA138292 (to the Emory Winship Cancer Institute), NINDS Training Grant 2T32NS007480-11 (to JK and Allan I. Levey), a joint Translational Research Pilot Grant from the Winship Cancer Institute and the Atlanta Clinical & Translational Science Instite (ACTSI, UL1RR025008; to HM and EGVM), the Brain Tumor Funders Collaborative (to EGVM), and the Georgia Cancer Coalition (to JK and EGVM).

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Authors and Affiliations

  1. Department of Neurosurgery, Emory University, Atlanta, GA, USA

    Juliya Kalinina & Erwin G. Van Meir

  2. Department of Radiology and Imaging Sciences, Emory Center for Systems Imaging, Emory University, 1841 Clifton Road, NE, Atlanta, GA, 30329, USA

    Anne Carroll, Liya Wang, Qiqi Yu & Hui Mao

  3. Department of Chemistry, Emory University, Atlanta, GA, USA

    Danny E. Mancheno, Shaoxiong Wu & Frank Liu

  4. Department of Human Genetics, Emory University, Atlanta, GA, USA

    Jun Ahn & Miao He

  5. Department of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, GA, USA

    Erwin G. Van Meir

  6. Winship Cancer Institute, Emory University, 1365C Clifton Rd., NE, Rm C5078, Atlanta, GA, 30322, USA

    Hui Mao & Erwin G. Van Meir

Authors
  1. Juliya Kalinina
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  2. Anne Carroll
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  10. Hui Mao
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  11. Erwin G. Van Meir
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Corresponding authors

Correspondence to Hui Mao or Erwin G. Van Meir.

Additional information

Dr. Hui Mao and Dr. Erwin G. Van Meir are co-corresponding authors and have contributed equally to this paper.

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Suppl. Figure 1

Stability analysis of 2HG in glioma samples during the HRMAS NMR analysis. a 2D COSY spectra of a representative sample (subject ID no: 0610) obtained from the first NMR experiment (left panel) and from a retest collected after 24 h (right panel) are shown. The cross-peaks from the 2HG unique J-coupling pattern (red box) and the resonances of Glx (blue box) are indicated. 2HG remains stable in glioma samples during sample re-analysis. Signal intensity color chart is shown. b The stability of a commercial 2HG preparation left for 7 days at 25°C was assessed by daily sampling and 1D NMR spectra. The unique 2HG cross-peaks are indicated. Note that the peaks marked by asterisk are impurities present in the commercial 95 % pure 2HG. (JPEG 139 kb)

High resolution image file (TIFF 19653 kb)

Suppl. Figure 2

Calibration of 2HG levels in tumor samples analyzed by HRMAS NMR. The 2HG concentrations were calculated by measuring the peak integral of the selected 2HG protons calibrated with the known concentration of the internal reference, TSP, and from a dose-dependent reference spectrum. A dose-dependent standard curve of 2HG concentration as a function of the integral of 2HG resonance (α) is shown in a. 2D COSY spectra of a non-tumoral control without (b, left panel) or titrated with 2HG (b, right panel) confirm the cross-peaks’ assignment for 2HG. The cross-peaks from the 2HG unique J-coupling pattern (red box) and the resonances of Glx (blue box) are indicated. Signal intensity color chart is shown. (JPEG 95 kb)

High resolution image file (TIFF 20797 kb)

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Kalinina, J., Carroll, A., Wang, L. et al. Detection of “oncometabolite” 2-hydroxyglutarate by magnetic resonance analysis as a biomarker of IDH1/2 mutations in glioma. J Mol Med 90, 1161–1171 (2012). https://doi.org/10.1007/s00109-012-0888-x

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  • DOI: https://doi.org/10.1007/s00109-012-0888-x

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