Clear cell renal cell carcinoma (ccRCC) exhibits heterogeneous outcomes, and robust biomarkers predicting metastatic potential remain limited. The present study was conducted with the objective of identifying transcriptomic signatures associated with metastasis and characterizing immune-related drivers of tumor aggressiveness.

RNA-seq was performed on paired tumor and adjacent normal tissues from 33 ccRCC patients, stratified into metastatic (Meta) and non-metastatic (Non-Meta) groups. Gene expression was analyzed via differential expression, PCA, and hierarchical clustering. Functional enrichment of 343 dysregulated genes was conducted using GSEA, GO, and KEGG analyses. A protein–protein interaction (PPI) network identified 27 hub genes. ROC analysis evaluated diagnostic performance, and prognostic value was validated using TCGA-KIRC survival data.

Despite minimal separation in global expression patterns, DEG-based pathway analysis highlighted immune regulation and cell cycle involvement. Among 27 hub genes, FCGR1A and FCGR3A showed the highest tumor-specific discriminatory performance (AUC = 0.819) and were significantly overexpressed in metastatic tumors. FCGR3A correlated with poor overall and disease-specific survival (p = 0.0001), while FCGR1A was prognostic in the Meta group (p = 0.0101). Both genes are involved in Fc receptor signaling and myeloid cell activation.

FCGR1A and FCGR3A are immune-associated biomarkers distinguishing metastatic ccRCC and correlating with patient prognosis.