Pan-gastrointestinal adenocarcinoma analysis uncovers the prognostic and immune correlates of ferroptosis-related genes

Background: Gastrointestinal adenocarcinomas (GIACs) are common malignant tumors with poor prognosis in the world. Ferroptosis, characterized by the accumulation of intracellular iron and lipid reactive oxygen species, emerges as a pivotal process in tumorigenesis and cancer advancement. However, the implications of ferroptosis-related genes in GIAC remain to be elucidated. This study aimed at exploring the potential role of ferroptosis-related genes on the prognosis and treatment of GIAC. Methods: In our study, comprehensive clinical, transcriptomic, and/or genomic data were acquired from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), Genomics of Drug Sensitivity in Cancer (GDSC), and Gene Expression Omnibus (GEO). We formulated a ferroptosis-score within the TCGA cohort through gene set variation analysis (GSVA) and subsequently validated in 4 GEO datasets (GSE84437, GSE17536, GSE103479, and GSE19417). Drug sensitivity and immunotherapy efficacy were analyzed in the GDSC dataset and the PRJEB25780 cohort, respectively. Results: The ferroptosis-score was significantly associated with favorable overall survival both in the training cohort [TCGA: P=0.003; hazard ratio (HR), 0.67, 95% confidence interval (95% CI): 0.52-0.87] and across the four validation cohorts (GSE17536: P=0.03; HR, 0.57, 95% CI: 0.34-0.96; GSE19417: P=0.047; HR, 0.53, 95% CI: 0.28-1.01; GSE84437: P=0.004; HR, 0.68, 95% CI: 0.51-0.90; GSE103479: P=0.03; HR, 0.55, 95% CI: 0.32-0.96). Furthermore, the ferroptosis-score was correlated with activation of the DNA damage repair pathway and resistance to cisplatin. Notably, GIACs with low ferroptosis-scores exhibited heightened expression of immune checkpoint molecules such as programmed death-(ligand) 1 and cytotoxic T lymphocyte antigen-4, elevated densities of tumor-infiltrating CD8+ T cells, and a favorable response to pembrolizumab monotherapy. Conclusions: Our findings delineated the clinical relevance of ferroptosis-related genes in GIACs and demonstrated the potential utility of the ferroptosis-score in predicting prognosis and immunotherapy effectiveness.