Proteomics separates adult-type diffuse high-grade gliomas in metabolic subgroups independent of 1p/19q codeletion and across IDH mutational status

• Published in: Cell reports. Medicine Vol. 4; no. 1; p. 100877
• Main Authors: Bader, Jakob Maximilian, Deigendesch, Nikolaus, Misch, Martin, Mann, Matthias, Koch, Arend, Meissner, Felix
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.01.2023; Elsevier
• Subjects: 1p/19q codeletion; Adult; Brain Neoplasms - genetics; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; glioblastoma; glioma; Glioma - genetics; Glioma - pathology; Humans; IDH; isocitrate dehydrogenase; Mutation; Proteome - genetics; Proteomics; glioma; glioblastoma; isocitrate dehydrogenase; proteomics; IDH; 1p/19q codeletion
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2022.100877

High-grade adult-type diffuse gliomas are malignant neuroepithelial tumors with poor survival rates in combined chemoradiotherapy. The current WHO classification is based on IDH1/2 mutational and 1p/19q codeletion status. Glioma proteome alterations remain undercharacterized despite their promise for a better molecular patient stratification and therapeutic target identification. Here, we use mass spectrometry to characterize 42 formalin-fixed, paraffin-embedded (FFPE) samples from IDH-wild-type (IDHwt) gliomas, IDH-mutant (IDHmut) gliomas with and without 1p/19q codeletion, and non-neoplastic controls. Based on more than 5,500 quantified proteins and 5,000 phosphosites, gliomas separate by IDH1/2 mutational status but not by 1p/19q status. Instead, IDHmut gliomas split into two proteomic subtypes with widespread perturbations, including aerobic/anaerobic energy metabolism. Validations with three independent glioma proteome datasets confirm these subgroups and link the IDHmut subtypes to the established proneural and classic/mesenchymal subtypes in IDHwt glioma. This demonstrates common phenotypic subtypes across the IDH status with potential therapeutic implications for patients with IDHmut gliomas. [Display omitted] •The tumor proteomes of IDHmut gliomas do not segregate by 1p/19q codeletion•IDHmut gliomas show two aerobic/anaerobic energy metabolism subgroups•Metabolic IDHmut subgroups resemble proneural and mesenchymal/classic IDHwt glioma•Protein level perturbations of oncogenes and tumor suppressors in glioma Bader et al. use liquid chromatography-mass spectrometry to characterize the proteomes of diffuse glioma brain tumors. The study reveals that Isocitrate dehydrogenase-mutant gliomas segregate into two metabolic subtypes resembling proneural and classic/mesenchymal subtypes in Isocitrate dehydrogenase wild-type gliomas. This has broad implications for clinical patient stratification and therapy.