Prognostic Stratification and Subtyping of Glioblastoma Using Transient Receptor Potential Channels

Transient receptor potential (TRP) channels regulate Ca²⁺ homeostasis and tumor malignant phenotypes, whereas their prognostic relevance and therapeutic implications in glioblastoma (GBM) remain poorly characterized.

We curated a comprehensive compendium of 522 TRP-related genes from MSigDB, KEGG, and GeneCards. Differential expression analysis across clinical variables in The Cancer Genome Atlas Glioblastoma cohort (TCGA-GBM; n = 529) identified 193 TRP-associated genes significantly linked to patient outcomes. Using univariate Cox regression followed by LASSO-Cox regularization, we developed a seven-gene transient receptor potential-related prognostic risk score (TRPRS). The model was rigorously validated in three independent external cohorts. Integrated multiomics analyses encompassed genomic alterations, tumor immune microenvironment profiling, and drug sensitivity prediction. Functional validation focused on the top-ranked gene, IFNGR2, using in vitro glioma models.

TRPRS robustly stratified GBM patients into high- and low-risk groups with significantly distinct overall survival across all four datasets (AUC = 0.72-0.81). Genomically, high-TRPRS tumors were enriched for PTEN loss and 9q21.3 amplification, whereas low-TRPRS tumors frequently harbored TP53 mutations and 1q21.3 deletions. High TRPRS was associated with diminished cytotoxic T-cell infiltration and predicted resistance to multiple therapeutics-including cisplatin, carmustine, gefitinib, buparlisib, and afatinib. Notably, TIDE analysis revealed significantly reduced likelihood of response to immune checkpoint blockade in high-TRPRS GBM, a pattern consistently observed in immunotherapy-treated cohorts of melanoma, renal cell carcinoma, and bladder cancer. Functional assays demonstrated that IFNGR2 knockdown suppressed glioma cell proliferation and attenuated NF-κB signaling, underscoring its role as a key driver within the TRP network.

TRPRS provides a robust, biologically grounded tool for simultaneous prognostication and therapy guidance in GBM, highlighting TRP signaling as a therapeutic vulnerability.