SDK1 as an Independent Prognostic Biomarker in Primary Glioma: A Multi-Cohort Validation Study with Functional Characterization

Glioma prognosis is shaped by molecular markers such as IDH mutation, WHO grade, and MGMT methylation, yet heterogeneity persists within defined subgroups. Sidekick Cell Adhesion Molecule 1 (SDK1), an immunoglobulin superfamily member mediating homophilic adhesion, has been documented in glioma tissue but lacks systematic prognostic evaluation. I assessed SDK1’s prognostic value using the Chinese Glioma Genome Atlas (CGGA, N = 503) and The Cancer Genome Atlas (TCGA, N = 572) through multivariate Cox regression, subgroup analyses, differential gene expression, pathway enrichment, ssGSEA-based immune profiling, and molecular subtype association. High SDK1 expression was independently associated with poor overall survival in both cohorts (CGGA: adjusted HR = 1.48, 95% CI 1.16–1.89, p = 0.002; TCGA: HR = 1.76, 95% CI 1.19–2.61, p = 0.005; pooled HR = 1.55, I2 = 0%). Effect estimates varied across subgroups, with significant associations in WHO grade IV and IDH-wildtype strata but not in grade II or older patients. Cross-validated differentially expressed genes were enriched in extracellular matrix organization and focal adhesion pathways. Notably, SDK1 expression showed weak but statistically significant correlations with COL1A1-associated mesenchymal program scores (CGGA: R = 0.12, p = 0.008; TCGA: R = 0.15, p < 0.001) and oncostream-related gene signatures (CGGA: R = 0.16, p < 0.001; TCGA: R = 0.086, p = 0.039), suggesting a modest association with mesenchymal invasion programs. SDK1-high tumors showed elevated M2 macrophage and Treg signatures with upregulated immune checkpoints, though cohort-dependent differences were observed. Multivariate Cox analysis demonstrated that the prognostic significance of SDK1 is independent of tumor mutational burden (TMB), with no significant correlation or interaction observed between them (p > 0.05). SDK1 is a candidate prognostic biomarker in glioma co-occurring with ECM remodeling and immunosuppressive features, warranting experimental validation for clinical translation.