Systematic Analyses Reveals the Functional Roles of Ferroptosis Across Cancers

Background: Ferroptosis is a newly discovered type of cell death that is closely related to cancer, however, the characteristics of ferroptosis and its regulators in cancers are still largely unknown. Methods: Based on the cancer omics data in The Cancer Genome Atlas, we comprehensively analyzed the alterations of ferroptosis regulator genes (FRGs) and computationally established the ferroptosis potential index (FPI) to reveal the functional roles of ferroptosis in cancer. Findings: We found that the mutation rates of FRGs were generally low, but most FRGs were differentially expressed in tumors among various cancer types. Frequent copy number alterations (CNA) and differential DNA methylation of FRGs contributed greatly to their aberrant expression. In most cancers, the FPI was higher in tumors than in the adjacent normal tissues and was associated with histological/molecular subtypes and clinical features. We observed that the FPI was negatively correlated with a number of metabolism pathways such as terpenoid backbone biosynthesis, but positively associated with metastasis-related pathways such as epithelial-mesenchymal transition (EMT), WNT beta-catenin signaling and angiogenesis. The FPI was also correlated immune microenvironment since it was positively correlated with pathways such as IL6 JAK-STAT signaling, inflammatory response, complement. Furthermore, it was observed that high FPI predicted significantly worse overall survival in glioblastoma multiforme, renal clear/papillary cell carcinoma, hepatocellular carcinoma, and lung adenocarcinoma, while FPI and FRGs were intensively correlated with cancer drug sensitivity. Interpretation: Our study presents a systematical analysis of ferroptosis and its regulatory genes across cancers, and highlights the potential of ferroptosis-based cancer therapy. Funding Statement: This work was supported by grants from National Key RD and Science and Technology Program of Guangdong (2019B020227002 to RH.X.). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Not required.