Journal of Molecular Medicine

, Volume 90, Issue 10, pp 1161–1171 | Cite as

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

  • Juliya Kalinina
  • Anne Carroll
  • Liya Wang
  • Qiqi Yu
  • Danny E. Mancheno
  • Shaoxiong Wu
  • Frank Liu
  • Jun Ahn
  • Miao He
  • Hui Mao
  • Erwin G. Van Meir
Original Article

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.

Keywords

Cancer 2-Hydroxyglutarate Isocitrate dehydrogenase Nuclear magnetic resonance Biomarker 

Supplementary material

109_2012_888_Fig6_ESM.jpg (139 kb)
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)

109_2012_888_MOESM1_ESM.tif (19.2 mb)
High resolution image file (TIFF 19653 kb)
109_2012_888_Fig7_ESM.jpg (95 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)

109_2012_888_MOESM2_ESM.tif (20.3 mb)
High resolution image file (TIFF 20797 kb)

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Juliya Kalinina
    • 1
  • Anne Carroll
    • 2
  • Liya Wang
    • 2
  • Qiqi Yu
    • 2
  • Danny E. Mancheno
    • 3
  • Shaoxiong Wu
    • 3
  • Frank Liu
    • 3
  • Jun Ahn
    • 4
  • Miao He
    • 4
  • Hui Mao
    • 2
    • 6
  • Erwin G. Van Meir
    • 1
    • 5
    • 6
  1. 1.Department of NeurosurgeryEmory UniversityAtlantaUSA
  2. 2.Department of Radiology and Imaging Sciences, Emory Center for Systems ImagingEmory UniversityAtlantaUSA
  3. 3.Department of ChemistryEmory UniversityAtlantaUSA
  4. 4.Department of Human GeneticsEmory UniversityAtlantaUSA
  5. 5.Department of Hematology and Medical Oncology, School of MedicineEmory UniversityAtlantaUSA
  6. 6.Winship Cancer InstituteEmory UniversityAtlantaUSA

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