Erythropoietin receptor (EPOR) expression to identify a biologically aggressive tumor phenotype in clear cell renal cell carcinoma.

e16521 Background: Clear cell renal cell carcinoma (ccRCC) demonstrates substantial biologic heterogeneity and variable clinical outcomes. Erythropoietin receptor (EPOR) signaling has been implicated in tumor biology, yet its relationship to canonical therapy-resistance and immune-associated programs in ccRCC remains incompletely characterized. Methods: RNA sequencing and clinical data from The Cancer Genome Atlas kidney renal clear cell carcinoma cohort (TCGA-KIRC; n = 533) were analyzed. EPOR expression was z-scaled. Pre-specified gene signatures representing angiogenesis, mTOR/PI3K/AKT signaling, immune activation, epithelial–mesenchymal transition (EMT), metabolic reprogramming, and DNA damage repair were quantified using mean gene-level z-scores. Associations between EPOR and pathway signatures were evaluated using Spearman correlation with false discovery rate (FDR) correction. Overall survival (OS) was assessed using multivariable Cox regression adjusted for age, stage, and grade. Results: Higher EPOR expression was independently associated with worse OS (hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.14–1.47, p < 0.001). EPOR expression demonstrated strong positive correlations with mTOR/PI3K/AKT signaling (ρ = 0.31, FDR < 0.001) and angiogenesis (ρ = 0.26, FDR < 0.001), and was also significantly associated with cytolytic immune activity, EMT, MYC targets, DNA damage repair, and oxidative phosphorylation programs (all FDR < 0.05). EPOR-high tumors showed significant enrichment of angiogenic, mTOR, and cytolytic immune signatures compared with EPOR-low tumors (all FDR < 0.001). Importantly, inclusion of these pathway-level signatures in multivariable survival models did not attenuate the prognostic impact of EPOR expression. Conclusions: EPOR expression identifies a biologically aggressive ccRCC tumor phenotype characterized by coordinated activation of angiogenic, mTOR-driven, immune, and invasive programs, while retaining independent prognostic significance. These findings support EPOR as an integrative biomarker of high-risk disease biology in ccRCC and provide a rationale for further investigation of EPOR-associated pathways in therapeutic resistance.