Proteogenomic study of high-grade glioma among adolescents and young adults

To unravel the molecular mechanisms underlying high-grade glioma (HGG) in adolescent and young adult (AYA) patients, we conducted acomprehensive proteogenomic analysis for 34 AYA (age 15-40) and 59 pediatric (age 0-15) HGG cases. Our approach involved whole genomesequencing, methylation profiling, RNA sequencing, and a suite of mass spectrometry-based proteomic experiments, including global proteomic,phosphoproteomic, and glycoproteomic profiling. The proteomics study successfully identified and quantified approximately 11,000 proteins, 33,000phosphosites, and 3000 glycopeptides with a 50% missing filtering threshold. To identify the unique characteristics of AYA HGG in contrast to bothpediatric and adult HGG, we further integrated a proteogenomic dataset of 99 adult GBM tumors previously published by CPTAC and collaborators(PMID: 33577785).
Our study unveiled a collection of mutations, copy number variations, epigenetic modifications and gene fusions that exhibited different frequenciesacross tumors from pediatric, AYA, and adult patients. Moreover, the influence of these genetic variations on RNA/protein activities also varied acrossdifferent age groups. Clustering analysis using age-dependent molecular profiles revealed striking differences in RNA/protein/phosphosite activitiesbetween patients aged 15-26 and 26-40. Additionally, significantly better overall survival (OS) was observed in the 26-40 age group compared to allother age groups, highlighting distinct biological characteristics within the AYA category that differentiate adolescents from young adults.Byleveraging proteogenomic datasets from normal brain tissues (PMID: 30518843), we identified genes, proteins, and pathways with differential age-dependent molecular profiles between tumor and normal brain tissues. Notably, this analysis highlighted significant alterations in proteins from theoxidative phosphorylation, tricarboxylic acid (TCA) cycle, and myelin sheath pathways in tumors compared to normal tissues, some of which werefound to be sex-specific.To search for prognostic markers, we introduced a novel approach called Trans-Population Survival Analysis throughInterpolation of Age-Dependent Tumor Molecular Profiles. Applying this method on the kinase activity scores derived from the phosphoproteomicdata, we identified 150 kinases whose activities were significantly associated with OS among AYA patients. Additionally, employing a causal networkanalysis tool, we pinpointed six kinases causally linked to OS, suggesting their potential as treatment targets. This study not only characterizes themolecular landscape of AYA HGG but also explores the disease trajectory across the lifespan. Our findings shed light on the intricate interplay ofvarious factors influencing glioma etiology and patient outcomes, paving the way for a deeper understanding of HGG in the AYA population.