Identification the ferroptosis-related gene signature in patients with esophageal adenocarcinoma

Ferroptosis is a recently recognized non-apoptotic cell death that is distinct from the apoptosis, necroptosis and pyroptosis. Considerable studies have demonstrated ferroptosis is involved in the biological process of various cancers. However, the role of ferroptosis in esophageal adenocarcinoma (EAC) remains unclear. This study aims to explore the ferroptosis-related genes (FRG) expression profiles and their prognostic values in EAC.

The FRG data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate cox regressions were used to identify the prognostic FRG, and the predictive ROC model was established using the independent risk factors. GO and KEGG enrichment analyses were performed to investigate the bioinformatics functions of significantly different genes (SDG) of ferroptosis. Additionally, the correlations of ferroptosis and immune cells were assessed through the single-sample gene set enrichment analysis (ssGSEA) and TIMER database. Finally, SDG were verified in clinical EAC specimens and normal esophageal mucosal tissues.

Twenty-eight significantly different FRG were screened from 78 EAC and 9 normal tissues. Enrichment analyses showed these SDG were mainly related to the iron-related pathways and metabolisms of ferroptosis. Gene network demonstrated the TP53, G6PD, NFE2L2 and PTGS2 were the hub genes in the biology of ferroptosis. Cox regression analyses demonstrated four FRG (CARS1, GCLM, GLS2 and EMC2) had prognostic values for overall survival (OS) (all P < 0.05). ROC curve showed better predictive ability using the risk score (AUC = 0.744). Immune cell enrichment analysis demonstrated that the types of immune cells and their expression levels in the high-risk group were significant different with those in the low-risk group (all P < 0.05). The experimental results confirmed the ALOX5, NOX1 were upregulated and the MT1G was downregulated in the EAC tissues compared with the normal esophageal mucosal tissues (all P < 0.05).

We identified differently expressed ferroptosis-related genes that may involve in EAC. These genes have significant values in predicting the patients' OS and targeting ferroptosis may be an alternative for therapy. Further studies are necessary to verify these results of our study.