title: 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 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.
authors.affiliation: Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. m.esmaeili@ntnu.no.
authors.forename: Morteza
authors.initials: M
authors.lastname: Esmaeili
authors.affiliation: Department of Radiology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Bob C
authors.initials: BC
authors.lastname: Hamans
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Navis
authors.affiliation: Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands. Department of Clinical Chemistry and Hematology, St. Elisabeth Hospital, Tilburg, the Netherlands.
authors.forename: Remco
authors.initials: R
authors.lastname: van Horssen
authors.affiliation: Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: Tone F
authors.initials: TF
authors.lastname: Bathen
authors.affiliation: Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors.forename: Ingrid S
authors.initials: IS
authors.lastname: Gribbestad
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: William P
authors.initials: WP
authors.lastname: Leenders
authors.affiliation: Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. Department of Radiology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Arend
authors.initials: A
authors.lastname: Heerschap
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D004983:Ethanolamines / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D010743:Phospholipids / Q000235:genetics* / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D004983:Ethanolamines; D010743:Phospholipids; C005448:phosphorylethanolamine; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human