Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy

Abstract

Mutations of the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are commonly found in primary brain cancers. We previously reported that a novel enzymatic activity of these mutations results in the production of the putative oncometabolite, R(–)-2-hydroxyglutarate (2-HG). Here we investigated the ability of magnetic resonance spectroscopy (MRS) to detect 2-HG production in order to non-invasively identify patients with IDH1 mutant brain tumors. Patients with intrinsic glial brain tumors (n = 27) underwent structural and spectroscopic magnetic resonance imaging prior to surgery. 2-HG levels from MRS data were quantified using LC-Model software, based upon a simulated spectrum obtained from a GAMMA library added to the existing prior knowledge database. The resected tumors were then analyzed for IDH1 mutational status by genomic DNA sequencing, Ki-67 proliferation index by immunohistochemistry, and concentrations of 2-HG and other metabolites by liquid chromatography–mass spectrometry (LC–MS). MRS detected elevated 2-HG levels in gliomas with IDH1 mutations compared to those with wild-type IDH1 (P = 0.003). The 2-HG levels measured in vivo with MRS were significantly correlated with those measured ex vivo from the corresponding tumor samples using LC–MS (r2 = 0.56; P = 0.0001). Compared with wild-type tumors, those with IDH1 mutations had elevated choline (P = 0.01) and decreased glutathione (P = 0.03) on MRS. Among the IDH1 mutated gliomas, quantitative 2-HG values were correlated with the Ki-67 proliferation index of the tumors (r2 = 0.59; P = 0.026). In conclusion, water-suppressed proton (1H) MRS provides a non-invasive measure of 2-HG in gliomas, and may serve as a potential biomarker for patients with IDH1 mutant brain tumors. In addition to 2-HG, alterations in several other metabolites measured by MRS correlate with IDH1 mutation status.

Imaging genomics in cancer research: limitations and promises

“…They found that 6 of the 13 genes with increased expression in ADC tumours were isoforms of collagen-binding proteins. 35 In order to confirm this result, the authors performed immunohistochemistry in both high-and low-ADC tumours to compare the expression of decorin and collagen one, three and six isoforms. There was no significant correlation between ADC values and collagen immunoreactivity scores.…”

“…8 studies used data from The Cancer Genome Atlas (TCGA) and/or The Cancer Imaging Archive (TCIA); 1,16,23,27,32,34,38,41 2 studies were multi-institutional; 9,19 and the remaining 17 studies used local institutional data. 15,17,18,[20][21][22][24][25][26]28,30,31,33,[35][36][37]39,40 26 out of 27 studies were retrospective in design. The number of patients ranged from 10 to 104 patients, with a median of 38 patients.…”

“…However, multiple patterns of immunoreactivity, including perivascular, interstitial and cytoplastmic patterns, were associated with higher ADC. 35 Result verification A limited number of studies (5/27, 19%) used wet-lab techniques to verify significant findings from their radiogenomic analyses. 22,25,26,37,40 For example, Diehn et al 25 confirmed EGFR overexpression among imaging phenotypes of GBM with immunohistochemistry.…”

Can Diffusion Tensor Imaging Noninvasively Detect IDH1 Gene Mutations in Astrogliomas? A Retrospective Study of 112 Cases

“…10,11 Although the concentration of 2-hydroxyglutarate in serum cannot be used to judge the status of IDH1 mutations, these mutations are associated with the accumulation of R(-)-2-hydroxyglutarate within the tumor. 12,13 Pope et al 14 suggested that MR spectroscopy could detect 2-hy-droxyglutarate in patients with IDH1-mutant glioma and provide a noninvasive measurement of 2-hydroxyglutarate in gliomas. However, the measurement of 2-hydroxyglutarate through MR spectroscopy is performed by special software and is inconvenient for clinical application.…”

Microfluidics for rapid detection of isocitrate dehydrogenase 1 mutation for intraoperative application

“…Preoperative precise detection of 2-hydroxyglutarate by MR spectroscopy is still under investigation. 7,9,17,26 Our study, which is based on microfluidics and use of specific antibodies for IDH1-mutant protein, was also applicable for detection of IDH1 mutation status.…”