The Hypoxic Landscape Stratifies Gastric Cancer Into 3 Subtypes With DistinctM6a Methylation and Tumor Microenvironment Infiltration Characteristics.

Abstract

The interaction between hypoxia and RNA N6-methyladenosine (m6A) is an emerging focus of investigation. However, alterations in m6A modifications at distinct hypoxia levels remain uncharacterized in gastric cancer (GC). Unsupervised hierarchical clustering was performed to stratify samples into different clusters. Differentially expressed gene analysis, univariate Cox proportional hazards regression analysis, and hazard ratio calculations were used to establish an m6A score to quantify m6A regulator modification patterns. After using an algorithm integrating Least absolute shrinkage and selection operator (LASSO) and bootstrapping, we identified the best candidate predictive genes. Thence, we established an m6A-related hypoxia pathway gene prognostic signature and built a nomogram to evaluate its predictive ability. The area under the curve (AUC) value of the nomogram was 0.811, which was higher than that of the risk score (AUC=0.695) and stage (AUC=0.779), suggesting a high credibility of the nomogram. Furthermore, the clinical response of anti-PD-1/CTLA-4 immunotherapy between high- and low-risk patients showed a significant difference. Our study successfully explored a brand-new GC pathological classification based on hypoxia pathway genes and the quantification of m6A modification patterns. Comprehensive immune analysis and validation demonstrated that hypoxia clusters were reliable, and our signature could provide a new approach for clinical decision-making and immunotherapeutic strategies for GC patients.