Detection of 2-Hydroxyglutarate in IDH -Mutated Glioma Patients by In Vivo Spectral-Editing and 2D Correlation Magnetic Resonance Spectroscopy

Abstract

Mutations of arginine 132 (R132) in the enzyme isocitrate dehydrogenase-1 (IDH1) are present in up to 86% of grade II and III gliomas and secondary glioblastoma. R132 mutations in IDH1 result in excess production of the metabolite 2-hydroxyglutarate (2HG), which could be used as a biomarker for this subset of gliomas. Here, we use optimized spectral-editing and two-dimensional (2D) correlation magnetic resonance spectroscopy (MRS) methods to unambiguously detect 2HG non-invasively in glioma patients with IDH1 mutations. By comparison, fitting of conventional 1D MR spectra can provide false-positive readouts owing to spectral overlap of 2HG and chemically similar brain metabolites, such as glutamate and glutamine. 2HG has been found also by 2D high-resolution magic angle spinning MRS performed ex vivo on a separate set of glioma biopsy samples. 2HG detection by in vivo or ex vivo MRS enabled detailed molecular characterization of a clinically important subset of human gliomas. This has implications for diagnosis as well as monitoring of treatments targeting IDH mutations.

Isocitrate Dehydrogenase 1 (IDH1) Mutation in Breast Adenocarcinoma Is Associated With Elevated Levels of Serum and Urine 2-Hydroxyglutarate

“…However, up to the time of preparation for this manuscript, elevations in serum and urine 2-HG have not been reported in IDH-mutant solid tumors. Levels of intratumoral 2-HG have been shown to be elevated in IDH1-mutant glioma tissue [18,31] using both in vitro and in vivo techniques [32,33]. Nevertheless, an earlier small study of IDH1-mutant gliomas failed to detect an elevation in circulating 2-HG levels in sera of affected patients [34].…”

Oncometabolites: linking altered metabolism with cancer

“…Using MRS sequence optimization and spectral fitting techniques, Maher and colleagues examined 30 patients with glioma and showed that the detection of 2HG correlated 100% with the presence of IDH1 or IDH2 mutations (102). Andronesi et al further demonstrated that two-dimensional correlation spectroscopy could effectively distinguish 2HG from chemically similar metabolites present in the brain (103).…”

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

“…Recently, reliable detection of D-2HG using in vivo 1H MRS was demonstrated in glioma patients (29,30). Andronesi et al reported the unambiguous detection of D-2HG in mutant IDH1 glioma in vivo using 2D correlation spectroscopy (COSY) and J-difference spectroscopy (29).…”

“…Andronesi et al reported the unambiguous detection of D-2HG in mutant IDH1 glioma in vivo using 2D correlation spectroscopy (COSY) and J-difference spectroscopy (29). In 2D COSY the overlapping signals are resolved along a second orthogonal chemical shift dimension (31,32), and in the case of D-2HG, the cross-peaks resulting from the scalar coupling of Hα-Hβ protons show up in a region that is free of the contribution of other metabolites in both healthy and wild-type tumors.…”