Iron Status, Erythropoietin, and Cancer Incidence in the General Population

Iron is essential for cellular function and cancer growth. While iron imbalance has been implicated in cancer development, epidemiological evidence remains inconsistent. Erythropoietin (EPO) may influence tumour progression. We aimed to investigate the associations between iron status, EPO levels, and cancer incidence in the general population.

Data were obtained from 6109 participants (mean age 52 ± 12 years; 49% male) in the Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort. Iron biomarkers, including ferritin, transferrin saturation, soluble transferrin receptor (sTfR), hepcidin and EPO levels, were measured at baseline.

Over a median 18.5 year follow-up, 1090 participants developed cancer. Multivariable Cox regression revealed that higher EPO (HR 1.26; 95% CI 1.07-1.47; p = 0.005) was associated with increased overall cancer risk, while elevated hepcidin levels were associated with a lower risk (HR 0.88; 95% CI 0.80-0.96; p = 0.006). Higher sTfR (HR 1.35; 95% CI 1.01-1.80; p = 0.043) was suggestive for an increased risk of overall cancer. After excluding early diagnoses, the increased risk associated with higher EPO levels and decreased risk associated with higher hepcidin levels remained significant. Lower transferrin saturation was associated with increased haematological cancer risk, while higher hepcidin was associated with reduced gastrointestinal cancer risk, especially in women and those with BMI < 25 kg/m². In non-smokers, higher sTfR and EPO were associated with increased overall and kidney cancer.

These findings underscore the putative roles of iron metabolism and EPO in cancer, with consistently decreased risks associated with elevated hepcidin levels, particularly among women and individuals with lower BMI.