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

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.

Detection of oncogenic IDH1 mutations using magnetic resonance spectroscopy of 2-hydroxyglutarate

“…HRMAS preserves the integrity of the samples that can be further analyzed with immunohistochemistry, genomics, or other metabolic profiling tools such as mass spectrometry. Detection of D-2HG in mutant IDH1 glioma was confirmed by ex vivo HRMAS experiments (29,54,55). In addition to D-2HG, ex vivo HRMAS studies can detect quantitative and qualitative changes for a large number of metabolites in IDH mutated tumors (54,55).…”

Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas

“…It is known that 2HG can be present at millimolar levels in IDH-MUT tumors (58). Therefore, there is a strong possibility that 2HG may also impact nontumor cells such as microglia, macrophages, and T cells in the tumor microenvironment.…”

Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China

“…Identification of other markers, including metabolites, may greatly widen the AML stratification toolkit. The 2-HG detected in tumor by using magnetic resonance spectroscopy were recently described as a biomarker in gliomas (25), whereas very recent reports were in support of the value of serum 2-HG as a biomarker of AML (21). Moreover, efforts are underway to explore drugs inhibiting the aberrant activities of IDH1/2, and identification of cases in both hematological malignancies and solid tumors with high 2-HG levels could be eventually helpful for the clinical trials of these drugs.…”