Major finding: Magnetic resonance spectroscopy detects 2-hydroxyglutarate in IDH-mutant gliomas.
Clinical relevance: Gliomas with IDH1/2 mutations can be identified without surgical biopsy.
Impact: A surrogate biomarker for IDH mutation can improve glioma classification and monitoring.
Mutation of the isocitrate dehydrogenase 1 and 2 (IDH1/2) genes frequently occurs in gliomas and results in abnormal accumulation of the metabolite 2-hydroxyglutarate (2HG). It has been proposed that in vivo detection of 2HG using magnetic resonance spectroscopy (MRS) could allow noninvasive genotyping of gliomas. However, a major hurdle to detection of 2HG in tumors with conventional 1-dimensional (1D) MRS is the similarity between its chemical structure and that of other metabolites, such as glutamate and glutamine, which are equally abundant in the brain and produce overlapping spectral resonances. To address this problem, spectral editing techniques that isolate relevant spectra and facilitate the specific detection of metabolites have been considered, along with 2D MRS methods capable of separating overlapping resonances. Elkhaled, Jalbert, and colleagues used multiple MRS approaches in their ex vivo analysis of image-guided glioma biopsies, establishing that 2HG can be imaged with MRS. An 86.4% concordance was observed between the presence of 2HG, as determined by 1D and 2D high-resolution magic angle spinning spectroscopy, and IDH1 mutation status as determined by immunohistochemistry and sequencing. The authors also observed that 2HG levels were correlated with histopathologic grade due to increased tumor cellularity. The feasibility of using 2HG as a surrogate biomarker of IDH mutation was further established in vivo by Andronesi and colleagues, who used spectral editing and 2D MRS techniques to scan the brains of glioma patients with known IDH1 mutations, glioblastoma patients lacking an IDH mutation, and healthy volunteers. Only the spectra of IDH1-mutant gliomas, not glioblastomas or healthy controls, contained a peak corresponding to 2HG. Although these results are preliminary, they have the potential to guide stratification of gliomas because IDH-mutant gliomas have a better prognosis. This approach may also allow monitoring of the effects of targeted therapies that are being developed to inhibit mutant IDH enzymes.
Elkhaled A, Jalbert LE, Phillips JJ, Yoshihara HA, Parvataneni, R, Srinivasan R, et al. Magnetic resonance of 2-hydroxygluturate in IDH1-mutated low-grade gliomas. Sci Transl Med 2012;4:116ra5.
Andronesi OC, Kim GS, Gerstner E, Batchelor T, Tzika AA, Fantin VR, et al. Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy. Sci Transl Med 2012;4:116ra4.
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