IDH1 R132H Mutation Generates a Distinct Phospholipid Metabolite Profile in Glioma

Morteza Esmaeili,Tone F. Bathen,Remco van Horssen,William P. Leenders,Anna C. Navis,Bob C. Hamans,Ingrid S. Gribbestad,Arend Heerschap

doi:10.1158/0008-5472.can-14-0008

Abstract

Many patients with glioma harbor specific mutations in the isocitrate dehydrogenase gene IDH1 that associate with a relatively better prognosis. IDH1-mutated tumors produce the oncometabolite 2-hydroxyglutarate. Because IDH1 also regulates several pathways leading to lipid synthesis, we hypothesized that IDH1-mutant tumors have an altered phospholipid metabolite profile that would impinge on tumor pathobiology. To investigate this hypothesis, we performed (31)P-MRS imaging in mouse xenograft models of four human gliomas, one of which harbored the IDH1-R132H mutation. (31)P-MR spectra from the IDH1-mutant tumor displayed a pattern distinct from that of the three IDH1 wild-type tumors, characterized by decreased levels of phosphoethanolamine and increased levels of glycerophosphocholine. This spectral profile was confirmed by ex vivo analysis of tumor extracts, and it was also observed in human surgical biopsies of IDH1-mutated tumors by (31)P high-resolution magic angle spinning spectroscopy. The specificity of this profile for the IDH1-R132H mutation was established by in vitro (31)P-NMR of extracts of cells overexpressing IDH1 or IDH1-R132H. Overall, our results provide evidence that the IDH1-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 IDH1-mutant glioma.

Highlights

Diffuse gliomas are the most common malignant brain-born tumors and are incurable with present therapeutic strategies [1]
We tested the hypothesis that IDH1 mutations affect the phospholipid metabolite profile of tumors by using IDH1-R132H E478 xenografts [41]
Our major finding is that gliomas with an IDH1 mutation have a phospholipid profile, which differs from that in gliomas with wild-type IDH1

Summary

Introduction

Diffuse gliomas are the most common malignant brain-born tumors and are incurable with present therapeutic strategies [1]. The current median survival from the time of diagnosis for GBMs is only 14.6 months and for lower grades between 4 and 15 years [2, 3]. This highly variable survival calls for reliable prognostic biomarkers for rational decision making in clinical management. Such biomarkers have become available with the discovery that in more than 70% of grade 2 and 3 gliomas and in.

Methods

Results

Conclusion