Erythropoietin drug targets and cancer risk: A two-sample Mendelian randomization study

Erythropoiesis-stimulating agents (ESAs) are widely used to treat anemia, but their on-target effects on tumor risk via erythropoietin (EPO)/erythropoietin receptor (EPOR) signaling remain debated. This study aims to evaluate the potential causal relationship between EPO signaling and the risk of 14 site-specific cancers using a drug-target Mendelian randomization (MR) approach. We proxied EPO signaling using genetic instruments for the EPOR, derived from cis-expression quantitative trait locus data from the eQTLGen Consortium. Summary-level genetic associations for 14 cancer types were sourced from the FinnGen consortium (R12 release). We applied the inverse variance weighted method as the primary analysis, supplemented by MR-Egger, weighted median, weighted mode, and simple mode approaches. Sensitivity analyses, including Cochran Q test and pleiotropy-robust methods, were conducted to assess heterogeneity and validate result reliability. Overall, genetically proxied EPO exposure was significantly associated with an increased risk of prostate cancer (odds ratio: 1.07, 95% confidence interval: 1.02-1.12, P = 3.30 × 10-3), and this association remained statistically significant after multiple testing correction. A suggestive association was also observed for bladder cancer (odds ratio: 1.12, 95% confidence interval: 1.03-1.21, P = 6.34 × 10-3), though it did not survive strict correction for multiple comparisons. No significant associations were detected for the other 12 cancer types. Sensitivity analyses revealed no substantial heterogeneity or horizontal pleiotropy, supporting the robustness of the primary findings. This MR study provides novel genetic evidence supporting a potential causal role of EPO/EPOR signaling in prostate carcinogenesis, with a suggestive signal for bladder cancer. These findings highlight the importance of further investigating the tissue-specific oncogenic roles of EPO and underscore the need for cautious interpretation regarding the long-term safety of ESAs. In particular, the observed association with prostate cancer suggests that patients receiving ESAs for anemia management may warrant urological monitoring, although further validation is required. Future large-scale prospective studies and mechanistic investigations are warranted to validate these results and clarify their clinical relevance.