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Background Glioblastoma (GBM) is characterized by immune dysregulation and epigenetic alterations that contribute to tumor progression. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling has been implicated in tumor biology, the transcriptional and immunological relevance of its decoy receptors, TNF receptor superfamily member 10C and 10D (TNFRSF10C and TNFRSF10D), in gliomas remains incompletely characterized. Methods An integrative multi-omic analysis was performed using The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Chinese Glioma Genome Atlas (CGGA) datasets in combination with Gene Expression Profiling Interactive Analysis 3 (GEPIA3), University of Alabama at Birmingham Cancer database (UALCAN), Tumor Immune Estimation Resource 3.0 (TIMER3.0), Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and MEXPRESS platforms. Gene expression, promoter methylation, molecular subtype distribution, immune infiltration patterns, and clinical associations were evaluated using harmonized analytical workflows and cross-validation across datasets. Results Both receptors demonstrated progressive upregulation from normal brain to lower-grade glioma (LGG) and GBM, with higher expression observed in isocitrate dehydrogenase (IDH)-wildtype tumors. Promoter methylation analysis revealed inverse correlations between CpG methylation and gene expression, suggesting potential epigenetic associations. Immune deconvolution analyses showed consistent associations with myeloid cell populations, including macrophages, neutrophils, and dendritic cells (DCs), alongside limited correlations with T-cell subsets. Protein-protein interaction network analysis indicated that these receptors interact with multiple components of inflammatory and TNF/TRAIL signaling systems. Higher expression showed trends toward shorter progression-free intervals (PFI). Conclusions TNFRSF10C and TNFRSF10D demonstrate reproducible associations with methylation patterns and immune microenvironment characteristics in GBM. These findings highlight potential links between TRAIL decoy receptors and inflammatory tumor states and support further mechanistic investigation.
Khurana et al. (Wed,) studied this question.