Iron homeostasis landscape informs patient survival and neoadjuvant chemotherapy response in cancer

Abstract Background Cancer cells frequently alter iron metabolism by increasing uptake or decreasing export, promoting oncogenesis and proliferation. However, the quantitative relationship between iron homeostasis and cancer remains underexplored. Methods and results We simplified these alterations into measurable changes in the expression levels of iron transport-related genes. We investigated the expression of iron transport-related genes by comparing genomic data of 478 human cancer cell lines to 105 normal tissue samples, as well as analyzing clinically paired 6903 tumor to 709 normal samples. We revealed that cancer cells exhibited increased expression of transferrin receptor 1 (TFR1) or CD44 for iron uptake and decreased expression of ferroportin for iron efflux to favor iron accumulation. Using machine learning, we identified TFR1, CD44, and ferroportin as the top three features consistently associated most with patient survival. We developed a cancer-specific iron risk score (CIRS) using parametric time-to-event models based on RNA-seq data from TFR1, CD44, and ferroportin in 4723 patients spanning 15 cancers. The CIRS, cross-validated in five external datasets, significantly stratified survival risk for various cancers, and predicted chemotherapy response in two independent breast cancer pharmacogenomic datasets. Conclusions Our study enhances the understanding of the relationship between iron homeostasis, survival, and chemotherapy response, laying the groundwork for iron-targeted therapies.