Abstract
The oncogenes that are expressed in gliomas reprogram particular pathways of glucose, amino acids, and fatty acid metabolism. Mutations in isocitrate dehydrogenase genes (IDH1/2) in diffuse gliomas are associated with abnormally high levels of 2-hydroxyglutarate (2-HG) levels. The aim of this study was to determine whether metabolic reprogramming associated with IDH mutant gliomas leads to additional 1H MRS-detectable differences between IDH1 and IDH2 mutations, and to identify metabolites correlated with 2-HG. A total of 21 glioma patients (age= 37 ± 11, 13 males) were recruited for magnetic resonance spectroscopy (MRS) using semi-localization by adiabatic selective refocusing pulse sequence at an ultra-high-field (7T). For 20 patients, the tumor mutation subtype was confirmed by immunohistochemistry and DNA sequencing. LCModel analysis was applied for metabolite quantification. A two-sample t-test was used for metabolite comparisons between IDH1 (n = 15) and IDH2 (n = 5) mutant gliomas. The Pearson correlation coefficients between 2-HG and associated metabolites were calculated. A Bonferroni correction was applied for multiple comparison. IDH2 mutant gliomas have a higher level of 2-HG/tCho (total choline=phosphocholine+glycerylphosphorylcholine) (2.48 ± 1.01vs.0.72 ± 0.38, Pc < 0.001) and myo-Inositol/tCho (2.70 ± 0.90 vs. 1.46 ± 0.51, Pc = 0.011) compared to IDH1 mutation gliomas. Associated metabolites, myo-Inositol and glucose+taurine were correlated with 2-HG levels. These results show the improved characterization of the metabolic pathways in IDH1 and IDH2 gliomas for precision medicine.
Highlights
The objective of our study was to demonstrate the potential of 1 H magnetic resonance spectroscopy (MRS) to distinguish neurochemical profile differences between the IDH1 and IDH2 mutations at UHF magnetic resonance imaging (MRI)
The localization accomplished by semi-localization by adiabatic selective refocusing and outer volume suppression (OVS) eliminated signals from outside the volume of interest (VOI) and resulted in artifact-free spectra with a flat baseline in the spectral range [0.5, 4.2] ppm
We found that metabolites including myo-Inositol and glucose+taurine were positively correlated with 2-HG, which is the oncometabolite of isocitrate dehydrogenase (IDH) mutations [30]
Summary
In the post-genomics era, the World Health Organization (WHO) classification of gliomas hasIn the post-genomics era, the Worldwith HealthOrganization (WHO)inclassification gliomas has become even more tightly integrated molecular parameters addition to ofhistology [1].become even more tightly integrated with molecular parameters in addition to histology IntegratedIntegrated diagnoses offer prospects for precision medicine strategies tailoring therapies for each diagnoses prospectsmore for precision strategies tailoringortherapies each individual, individual,offer by delivering effective medicine treatments, whilst avoiding reducingfor adverse outcomes.by delivering more effective treatments, whilst avoiding or reducing adverse outcomes.Mutations in Mutations in the genes encoding for isocitrate dehydrogenase (IDH) have been discovered in various the genes encoding for isocitrate dehydrogenase (IDH)have been discovered in various cancers such as cancers such as glioma, acute myeloid leukemia (AML), chondrosarcoma, cholangiocarcinoma, glioma, acute myeloid (AML), cancer chondrosarcoma, cholangiocarcinoma, paraganglioma, colon leukemia cancer, prostate and lung cancer [2]. In the post-genomics era, the World Health Organization (WHO) classification of gliomas has. In the post-genomics era, the Worldwith Health. Organization (WHO)inclassification gliomas has become even more tightly integrated molecular parameters addition to ofhistology [1]. Integrated diagnoses offer prospects for precision medicine strategies tailoring therapies for each diagnoses prospectsmore for precision strategies tailoringortherapies each individual, individual,offer by delivering effective medicine treatments, whilst avoiding reducingfor adverse outcomes. By delivering more effective treatments, whilst avoiding or reducing adverse outcomes. Have been discovered in various cancers such as cancers such as glioma, acute myeloid leukemia (AML), chondrosarcoma, cholangiocarcinoma, glioma, acute myeloid (AML), cancer chondrosarcoma, cholangiocarcinoma, paraganglioma, colon leukemia cancer, prostate and lung cancer [2]. Isocitrate paraganglioma, dehydrogenase colon is an cancer, prostate cancer and lung cancer [2]. Isocitrate dehydrogenase is an intracellular enzyme, that intracellular enzyme, that catalyzes the reversible production of alpha-ketoglutarate (α-KG) from catalyzes the reversible production of alpha-ketoglutarate (α-KG)
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