Data from IDH1 R132H Mutation Generates a Distinct Phospholipid Metabolite Profile in Glioma

Abstract

<div>Abstract<p>Many patients with glioma harbor specific mutations in the isocitrate dehydrogenase gene <i>IDH1</i> that associate with a relatively better prognosis. <i>IDH1</i>-mutated tumors produce the oncometabolite 2-hydroxyglutarate. Because IDH1 also regulates several pathways leading to lipid synthesis, we hypothesized that <i>IDH1</i>-mutant tumors have an altered phospholipid metabolite profile that would impinge on tumor pathobiology. To investigate this hypothesis, we performed <sup>31</sup>P-MRS imaging in mouse xenograft models of four human gliomas, one of which harbored the <i>IDH1</i>-R132H mutation. <sup>31</sup>P-MR spectra from the <i>IDH1</i>-mutant tumor displayed a pattern distinct from that of the three <i>IDH1</i> wild-type tumors, characterized by decreased levels of phosphoethanolamine and increased levels of glycerophosphocholine. This spectral profile was confirmed by <i>ex vivo</i> analysis of tumor extracts, and it was also observed in human surgical biopsies of <i>IDH1</i>-mutated tumors by <sup>31</sup>P high-resolution magic angle spinning spectroscopy. The specificity of this profile for the <i>IDH1</i>-R132H mutation was established by <i>in vitro</i><sup>31</sup>P-NMR of extracts of cells overexpressing IDH1 or IDH1-R132H. Overall, our results provide evidence that the <i>IDH1</i>-R132H mutation alters phospholipid metabolism in gliomas involving phosphoethanolamine and glycerophosphocholine. These new noninvasive biomarkers can assist in the identification of the mutation and in research toward novel treatments that target aberrant metabolism in <i>IDH1</i>-mutant glioma. <i>Cancer Res; 74(17); 4898–907. ©2014 AACR</i>.</p></div>