IDH1 R132H Mutation Generates a Distinct Phospholipid Metabolite Profile in Glioma

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 highresolution 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. Cancer Res; 74(17); 4898-907. Ó2014 AACR.

Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198

“…WT or IDH1 R132H as described earlier (29). Constructs contain a C-terminal biotin acceptor peptide and a HIS-tag, which allows distinction from endogenous IDH1…”

Immunocytochemical markers of neuronal maturation in human diagnostic neuropathology

“…Distinct phospholipid metabolic profiles are seen in gliomas w i t h d e f e c t i v e I D H 1 , e x p r e s s e d a s d e c r e a s e d phosphoethanolamine and increased glycerophosphocholine (Esmaeili et al 2014). (3) Molecular testing, also modified for ICC, is available to demonstrate mutations in BRAF V600E, part of the RAS signalling pathway, in melanoma, in many diverse carcinomas and also in some brain tumours such as some gangliogliomas (Brown et al 2014;Pearlstein et al 2014;Fisher et al 2014;Bledsoe et al 2014;Dvorak et al 2014).…”

“…(2) Germ-line polymorphism is associated with isocitric dehydrogenase (IDH1) enzymatic mutations, many of which are also 1p-19q co-deletions and an R132H protein of IDH1 can be demonstrated immunocytochemically in tissue sections (Rodríguez et al 2014;Esmaeili et al 2014). Distinct phospholipid metabolic profiles are seen in gliomas w i t h d e f e c t i v e I D H 1 , e x p r e s s e d a s d e c r e a s e d phosphoethanolamine and increased glycerophosphocholine (Esmaeili et al 2014).…”

Progress in the application of molecular biomarkers in gliomas

“…Fractional flux, which depends on the activity of pyruvate carboxylase, is therefore increased in cells with an IDH1 mutation. Morteza et al [14] demonstrated that mutated IDH1-R132H affects phosphoethanolamine and glycerophosphocholine and subsequently alters phospholipid metabolism in glioma.…”