Integrated Multi-Omics Characterization of WASHC2C Reveals Cancer-Specific Molecular, Clinical, Immune, and Cellular Associations

WASHC2C encodes a WASH-complex scaffold implicated in actin remodeling, endosomal organization, and intracellular trafficking, yet its cancer-specific molecular and clinical relevance remains insufficiently defined, particularly in the context of the closely related paralogue WASHC2A. We performed an integrated pan-cancer multi-omics analysis incorporating transcriptomic and protein-level evidence, clinicopathological and survival associations, genomic and epigenetic alterations, pathway activity, gene-set enrichment, immune features, immunotherapy-related observations, and single-cell functional states. Primary RNA analyses extracted both paralogues from the same GDC STAR files across eight cancer types, while covariate-adjusted Cox models evaluated LUAD, BLCA, and LIHC. A locked 50-gene co-expression signature was additionally assessed in independent GEO cohort, GSE31210. The harmonized expression analysis comprised 4365 primary tumors and 429 normal specimens and revealed pronounced lineage-specific variation together with strong WASHC2A–WASHC2C co-expression. Although HNSC showed platform-dependent directional differences between STAR and GSCA, the integrated analyses identified LIHC as the clearest prognostic context: higher WASHC2C expression was associated with poorer overall survival in the primary adjusted model (340 patients; 115 deaths; HR = 1.61 per unit log2[TPM + 1], 95% CI 1.18–2.21; FDR = 0.035), although the magnitude of association varied with model specification. Favorable unadjusted observations in LUAD and BLCA were not retained after covariate adjustment, and primary BLCA OS/DSS models were non-estimable. Across cancers, copy-number variation showed a consistent positive relationship with transcript abundance, whereas pathway, immune, methylation, and single-cell associations demonstrated marked tumor-context specificity. In GSE31210, 48 measurable genes from the locked signature were associated with favorable survival in 204 patients, supporting the relevance of the broader co-expression program, although neither WASHC2C nor WASHC2A contributed directly to that score. Collectively, this study establishes a rigorous multi-omic framework for WASHC2C, highlights its lineage-dependent molecular and prognostic relevance, and prioritizes specific cancer contexts—particularly LIHC—for mechanistic and translational investigation. These findings provide a strong foundation for future paralogue-resolved functional studies and independent clinical validation.