Abstract / Summary
Kidney renal clear cell carcinoma (KIRC) is a major subtype of renal cell carcinoma with substantial molecular heterogeneity and variable clinical outcomes. Tetraspanins (TSPANs) are membrane proteins involved in cell adhesion, signaling, migration, tumor progression, and interactions with the tumor microenvironment (TME); however, their collective significance in KIRC remains insufficiently characterized. The expression profile of the TSPAN gene family was evaluated in the TCGA-KIRC cohort using GEPIA2. Differentially expressed TSPANs were further investigated through protein–protein interaction network (PPIN) and univariate survival analyses. Prognostically significant TSPANs were assessed for genomic alterations, promoter methylation, and associations with tumor-infiltrating immune cells. Feed-forward-loop (FFL) was constructed and visualized using Cytoscape. Thereafter, the findings were evaluated in an independent KIRC dataset. Several TSPANs displayed significant differential expression between KIRC and normal renal tissues. TSPAN1 and TSPAN6 were significantly associated with overall survival (OS), with higher expression corresponding to more favorable outcomes. Notably, higher TSPAN6 expression was associated with improved OS but a higher estimated risk of relapse indicating an endpoint-dependent and potentially complex prognostic relationship. Promoter methylation of TSPAN1 and TSPAN6 showed associations with selected clinicopathological characteristics, while both genes demonstrated significant relationships with specific immune-cell populations. Network analysis identified a ZNF260–miR-6794-5p–TSPAN6 FFL subnetwork motif, prioritizing TSPAN6 as the hub TSPAN. TSPAN6 was additionally detected among differentially expressed genes (DEGs) in an independent GEO cohort. This study identifies TSPAN6 as a promising candidate biomarker in KIRC and provides a multi-dimensional framework linking TSPAN dysregulation with prognosis, epigenetic regulation, immune infiltration, and regulatory networks. Experimental and clinical validation is warranted.