SUMOylation-Driven Subtype Heterogeneity and Prognostic Biomarkers in Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common malignancy of the urinary system, characterized by high incidence, mortality, and resistance to therapy. Its molecular heterogeneity presents challenges for effective precision treatment. RCC is highly heterogeneous, yet treatment guidelines rely predominantly on kidney renal clear cell carcinoma (KIRC) studies, neglecting other molecular subtypes, which limits therapy personalization for non-KIRC patients. This study aimed to explore the role of small ubiquitin-like modifier (SUMOylation)-associated genes in the progression and prognosis of RCC and its subtypes. We identified 298 SUMOylation-associated differentially expressed genes (DEGs), including 151 RCC-specific genes after excluding expression changes attributable to RCC subtype-specific variation. Ten core genes (PRKCG, PRKCQ, PRKCD, IRS4, SLC2A4, SLC27A1, SLC27A4, LCN2, S100A7, and S100A9) were identified, with LCN2 expression not only discriminates tumor from normal tissue but also separates KIRC from KICH/KIRP, proposing LCN2 as a potential second-step biomarker for KIRC identification on top of traditional histology. Inter-subtype RCC heterogeneity represented a key factor limiting predictive performance of the six prognostic signature genes (CREB3L1, GNA11, PFKM, PPARGC1A, PPP2R2C and PRKCG). Its 5-year AUC exceeded 0.7 for every individual RCC subtype in the TCGA training cohort, with pooled 5-year AUCs of 0.61 (TCGA training cohort) and 0.67 (independent PCAWG validation cohort). The prognostic risk model demonstrated strong predictive performance, with a C-index of 0.791 before calibration and 0.774 after calibration. Importantly, the C-index remained above 0.75 throughout the 60-month follow-up period, indicating stable and robust long-term prognostic accuracy. High-risk patients exhibited greater immune cell infiltration, indicating potential for immunotherapy. Following secondary screening, three RCC cell lines (BFTC909, CAKI1, and CAL54) and five target genes (PRKCD, SLC27A1, SLC27A4, LCN2 and GNA11) were identified as optimal candidates for subsequent mechanistic investigations. This study uncovers the prognostic and functional relevance of SUMOylation in RCC and offers a novel framework for biomarker development, therapeutic targeting, and immunotherapeutic stratification.