COL22A1 expression identifies aggressive glioma and independently predicts survival through integrated multiomics and clinical validation.

Background: Gliomas, especially IDH‑wildtype astrocytomas, remain lethal despite multimodal therapy. Collagen type XXII alpha-1 (COL22A1) exhibits oncogenic activity in other cancers but remains underexplored in brain tumors. We asked whether its expression, cellular origin, and spatial context add prognostic and translational value in diffuse glioma.

Methods: We reprocessed TCGA/CGGA RNA‑seq to transcripts‑per‑million and re‑annotated tumours under the WHO 2021 taxonomy. Differential expression, Kaplan-Meier, and multivariable Cox models assessed survival associations; gene‑set enrichment profiled pathway context. Cell‑type sources were mapped by deconvolution and single‑cell datasets (GSE131928, GSE89567), and spatial distribution was examined using Ivy GAP and 10 × Visium. Protein abundance was validated by quantitative immunohistochemistry in 75 surgical specimens, with orthogonal proteomic corroboration from the TCGA Proteomic Data Commons.

Results: COL22A1 mRNA was up‑regulated in glioma and increased with grade. High expression predicted shorter overall survival and remained an independent hazard factor after adjusting for age, grade, Karnofsky score, radiotherapy, and temozolomide. Transcriptome deconvolution and Single‑cell analyses localized COL22A1 predominantly to mesenchymal-like tumour subpopulations with negligible signal in lymphoid, reactive-glial, or myeloid compartments. Spatial transcriptomics showed marked enrichment in peri‑necrotic and microvascular proliferation niches. Gene Set Enrichment Analysis (GSEA) linked COL22A1‑high tumours to epithelial-mesenchymal transition, cell-cycle, and inflammatory (IL6/JAK-STAT3, TNF-NFκB) programmes, consistent with a proliferative and hypoxic phenotype. Immunohistochemistry confirmed higher protein abundance in tumours versus normal brain, a stepwise increase with grade, and a trend association with Ki‑67; mass‑spectrometry data corroborated increased protein abundance and adverse survival at high expression. A parsimonious nomogram combining COL22A1 with clinical covariates improved the prediction of 1-, 3-, and 5-year survival.

Conclusions: Across bulk, single‑cell, and spatial layers, COL22A1 integrates molecular, cellular, and microenvironmental hallmarks of glioma aggressiveness. Its tumour‑centric expression, peri‑necrotic localisation, and independent prognostic value support COL22A1 as a robust biomarker and a tractable candidate for imaging or therapeutic strategies in treatment‑refractory disease.