AUTHOR=Krauze Andra Valentina , Sierk Michael , Nguyen Trinh , Chen Qingrong , Yan Chunhua , Hu Ying , Jiang William , Tasci Erdal , Zgela Theresa Cooley , Sproull Mary , Mackey Megan , Shankavaram Uma , Meerzaman Daoud , Camphausen Kevin 

TITLE=Glioblastoma survival is associated with distinct proteomic alteration signatures post chemoirradiation in a large-scale proteomic panel

JOURNAL=Frontiers in Oncology

VOLUME=Volume 13 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1127645

DOI=10.3389/fonc.2023.1127645

ISSN=2234-943X

ABSTRACT=Background: Glioblastomas (GBM) are rapidly progressive, nearly uniformly fatal brain tumors. Proteomic analysis represents an opportunity for noninvasive GBM classification and biological understanding of treatment response. 
Purpose: We analyzed differential proteomic expression pre vs. post completion of concurrent chemoirradiation (CRT) in patient serum samples to explore proteomic alterations and classify GBM by integrating clinical and proteomic parameters.    
Materials and methods: 82 patients with GBM (serum obtained pre and post CRT) were clinically annotated, and serum samples were screened using the aptamer-based SomaScan® proteomic assay. Post uni- and multivariate Cox models for overall survival (OS), significant traits were designated independent prognostic factors, and principal component analysis (PCA) was carried out. Differential expression of protein signals was calculated using paired t-tests, with KOBAS used to identify associated KEGG pathways. GSEA pre-ranked analysis was employed on the overall list of differentially expressed proteins (DEPs) against the MSigDB Hallmark, GO Biological Process and Reactome databases with weighted gene correlation network analysis (WGCNA) and Enrichr used to validate pathway hits internally.
Results: 3 clinical clusters of patients with differential survival were identified. 389 significantly DEPs pre vs. post-treatment, 284 upregulated, 105 downregulated emerged including several pathways relevant to cancer metabolism and progression. The worst survival group (median OS 13.2 months) was associated with DEPs affiliated with proliferative pathways and distinct oppositional response (including RT) as compared to better-performing groups (intermediate, median OS 22.4 months; highest, median OS 28.7 months). Opposite signaling patterns across multiple analyses in several pathways (notably fatty acid metabolism, NOTCH, TNF via NF-κB, Myc target V1 signaling, UV response, unfolded protein response, peroxisome, and interferon response) were distinct between clinical survival groups and supported by WGCNA. 23 proteins were statistically signficant for OS with 5 (NETO2, CST7, SEMA6D, CBLN4, NPS) supported by KM. 
Conclusions: Distinct proteomic alterations with hallmarks of cancer, including progression, resistance, stemness, and invasion were identified in serum samples obtained from GBM patients pre vs. post CRT, and corresponded with clinical survival. The proteome can potentially be employed for glioma classification and biological interrogation of cancer pathways.