Integrated Multi‐Omics and Radiogenomic Analysis Identifies S100B and ITGB5 as Complementary Candidate Biomarkers of Glioblastoma Heterogeneity
TL;DR
These exploratory findings support S100B and ITGB5 as complementary candidate biomarkers of GBM heterogeneity and provide a basis for future experimental, multicenter, and prospective validation.
Abstract
Glioblastoma (GBM) is characterized by marked intratumoral heterogeneity, diffuse invasion, and a profoundly immunosuppressive tumor microenvironment. In this study, we applied an integrative multi‐omics and radiogenomic framework to identify candidate biomarkers reflecting complementary dimensions of GBM heterogeneity. Public bulk transcriptomic datasets were integrated to define GBM‐related differentially expressed genes, which were intersected with curated microbiota‐associated gene sets as a hypothesis‐generating screening strategy. Machine‐learning models with SHAP interpretation were used for candidate‐gene prioritization, followed by survival‐association analysis, pan‐cancer comparison, Human Protein Atlas immunohistochemistry, CPTAC proteomics, immune infiltration analysis, single‐cell transcriptomics, spatial transcriptomics, in silico perturbation analysis, and MRI‐based radiogenomics. GBM samples showed enrichment of extracellular matrix organization, proliferative programs, immune‐related signaling, and vascular or endothelial pathways, with relative reductions in neural, synaptic, and myelin‐associated signatures. S100B and ITGB5 emerged as survival‐associated candidate markers with different biological contexts. Multi‐omics analyses suggested that S100B may reflect broadly distributed glial‐lineage and malignant‐state programs, whereas ITGB5 was more closely associated with focal extracellular matrix remodeling, stromal‐vascular interactions, and immunoregulatory niches. Radiogenomic analysis further suggested distinct MRI‐derived associations for the two genes, with the ITGB5‐related model retaining a broader radiomic signature and showing a more heterogeneous habitat pattern than the S100B‐related model. These exploratory findings support S100B and ITGB5 as complementary candidate biomarkers of GBM heterogeneity and provide a basis for future experimental, multicenter, and prospective validation.