Research ArticleBrain Imaging

Magnetic Resonance of 2-Hydroxyglutarate in IDH1-Mutated Low-Grade Gliomas

Science Translational Medicine  11 Jan 2012:
Vol. 4, Issue 116, pp. 116ra5
DOI: 10.1126/scitranslmed.3002796

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Gliomas Make the Grade

Tumors of the central nervous systems can be classified, or “graded,” on a scale of I to IV, according to their capacity to proliferate and invade surrounding tissue (with I being benign). Although determining the grade of brain tumor malignancy is important for doctors to predict survival and prescribe treatment, it cannot sufficiently explain the variation in clinical outcome. Some have attempted to classify brain tumors on the basis of acquired mutations, which has provided further insight into the characteristic diversity observed in survival. For example, one mutation in the gene isocitrate dehydrogenase (IDH) has demonstrated prolonged life expectancy for patients with low-grade brain tumors. Now, Elkhaled, Jalbert, and colleagues have shown that accumulation of a metabolite resulting from this mutation can be detected using magnetic resonance imaging techniques.

Under normal conditions, the IDH enzyme converts the metabolite isocitrate to α-ketoglutarate. When IDH is mutated, its enzyme product further converts α-ketoglutarate to an otherwise scarce metabolite, 2-hydroxyglutarate (2HG). Because improved patient outcome has been associated with IDH mutations, the accumulation of 2HG might therefore be able to predict favorable genotypes. Elkhaled, Jalbert, and colleagues used an imaging method based on proton high-resolution magic angle spinning (1H HR-MAS) nuclear magnetic resonance (NMR) spectroscopy to determine whether the presence of 2HG was detectable. A total of 104 tissue (biopsy) samples from 52 patients with recurrent grade II gliomas (some of which had converted to grades III or IV) were evaluated for the presence of 2HG and the IDH1 mutation. 2HG proved to be detectable by spectroscopic analysis and showed approximately 86% concordance with the status of IDH1 mutation, as determined by antibody staining and genetic sequencing. Furthermore, 2HG abundance was shown to be similar across all brain tumor grades when normalized by cellularity, suggesting that its relative production per cell remains the same even after lesions have converted to higher histologic grades. This finding bears considerable significance for clinical evaluation of the malignancy grade and extent of tumor lesions.

Finally, 2HG levels were determined to negatively correlate with normal vascularity. Given the current hypotheses in the literature regarding the influence of 2HG on vascular endothelial growth factor (VEGF), this result may be of interest for designing anti-angiogenic strategies for treating tumors with IDH mutations. This ex vivo study—along with its in vivo companion by Andronesi et al.—shows that the use of magnetic resonance imaging technology, already routine in the clinic, could significantly improve the management of brain tumors.


  • * These authors contributed equally to this work.