The Ferroptosis-Related Noncoding RNA Signature as a Novel Prognostic Biomarker in the Tumor Microenvironment, Immunotherapy, and Drug Screening of Gastric Adenocarcinoma

BACKGROUND: Ferroptosis is a new type of cell death different from apoptosis, necrosis, autophagy, and pyroptosis. This study aimed to explore the relationship between ferroptosis-related noncoding RNA (ncRNA) and gastric adenocarcinoma with regard to immunity and prognosis. METHODS: Ferroptosis-related ncRNA expression profiles and clinical pathology and overall survival information were collected from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus database. The ferroptosis-related ncRNA signature was identified by Cox regression analysis and the least absolute shrinkage and selection operator analysis. The survival analysis, receiver operating characteristic (ROC) analysis, and decision curve analysis were adopted to evaluate the prognostic prediction performance of the signature. The correlation between risk and multiple clinical characteristics was analyzed using the chi-square test. The Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analysis were used for mining functions and pathways. The CIBERSORT, ssGSEA, and ESTIMATE algorithms were used to assess immune infiltration and the tumor microenvironment. The response of immunotherapy was predicted using the Submap algorithm, and the Connectivity Map and the ridge regression model were used to screen and evaluate drugs. RESULTS: A carcinogenic risk signature was constructed using five ferroptosis-related ncRNAs. It showed an extraordinary ability to predict the prognoses of patients with gastric adenocarcinoma [area under the ROC curve (AUC) after 6 years = 0.689; GSE84426, AUC after 6 years = 0.747]. The lower ferroptosis potential level and lower tumor mutation burden were related to the poor prognoses of patients. The high-risk group had more immune cell recruitment, and the overall effect of the anti-immune checkpoint immunotherapy was not as good as that of the low-risk group. The high- and low-risk groups were enriched in tumor- and immune-related pathways, respectively. The screened antitumor drugs, such as genistein, guanabenz, and betulinic acid, improved the survival of the patients. CONCLUSIONS: The ferroptosis-related ncRNA signature is a potential carcinogenic prognostic biomarker of gastric adenocarcinoma.