Erythropoietin receptor (EPOR) expression as an independent prognostic biomarker in clear cell renal cell carcinoma, beyond angiogenesis, hypoxia, and erythropoietin ligand.

e16520 Background: Clear cell renal cell carcinoma (ccRCC) is characterized by dysregulated hypoxia and angiogenesis signaling. While erythropoietin receptor (EPOR) expression has been implicated in tumor biology, its prognostic relevance in ccRCC and independence from erythropoietin (EPO) ligand expression remain incompletely defined. Methods: We analyzed EPOR mRNA expression and overall survival (OS) in patients with ccRCC from The Cancer Genome Atlas (TCGA-KIRC; n≈533, events≈175). EPOR expression was evaluated as a continuous z-scaled variable and dichotomized by median. Cox proportional hazards models were constructed with adjustment for age, stage, and grade. Associations between EPOR and angiogenesis, hypoxia, and erythroid differentiation signatures were assessed using correlation analyses and joint survival models. Independence from EPO ligand expression was tested using multivariable Cox models including both EPOR and EPO. External validation was performed using the GEO GSE29609 cohort (n = 39). Results: Higher EPOR expression was significantly associated with worse OS in univariable analysis (HR 1.31, 95% CI 1.15–1.48; p < 0.001) and remained independently prognostic after adjustment for age, stage, and grade (HR 1.29, 95% CI 1.14–1.47; p < 0.001; C-index≈0.79). Patients with high EPOR expression demonstrated inferior survival compared with low EPOR expression (HR 1.58, p = 0.012). EPOR expression correlated with angiogenesis and hypoxia signatures, yet remained independently associated with OS in joint models. Importantly, EPOR retained prognostic significance after adjustment for EPO ligand expression (EPOR HR 1.29, p < 0.001), while EPO itself was not significantly associated with survival. External validation demonstrated directionally consistent results, though statistical significance was limited by sample size. Conclusions: EPOR is a robust, independent prognostic biomarker in ccRCC, with effects that extend beyond angiogenesis, hypoxia, erythroid differentiation, and EPO ligand expression. These findings support a potential non-erythropoietic role for EPOR signaling in ccRCC tumor biology.