PNNL

Abstract

We conducted a first-of-its-kind multi-omics investigation of 99 treatment-naive GBMs including proteogenomics, post-translational modifications (PTMs) and metabolomics. Phosphoproteomic analysis identified PTPN11 and PLCG1 as the principal switches mediating RAS pathway activation, and therefore potential therapeutic targets. Additional novel targets were identified for EGFR-altered and RB1-altered tumors. We identified two immune subtypes based on differential gene and protein expression of macrophage and immune checkpoint markers. Acetylation of histone H2B is a key component of classical-like and immune-low GBM, driven largely by BRDs, CREBBP, and EP300. Additionally, lipid abundances vary across subtypes, consistent with the expression of proteins involved in lipid signaling. Metabolomic analysis also identified changes in glycolysis/TCA metabolic cascade in IDH mutants potentially driving the upregulation of oncometabolite 2-HG. Overall, this work points to new additional therapeutic avenues to stratify patients for appropriate and effective treatment.