Comprehensive Genomic and Transcriptomic Analyses Reveal Prognostic Stratification for Esophageal Squamous Cell Carcinoma

Background Recent large-scale multi-omics studies have characterized the heterogeneity of esophageal squamous cell carcinoma (ESCC), but inconsistent clinical management has hindered the identification of prognostic markers and patient stratification. Methods We conducted genomic and transcriptomic profiling of 203 patients from the ECTOP-2002 study with full clinical information. Results Mutation in the mucin family, as well as APOBEC signature, were associated with poor prognosis. In contrast, activation of the epithelial-keratinization (EpK) pathway was strongly linked to favorable prognosis and lower post-chemotherapy recurrence rates. Independent validation supported S100A8/A9 complex as a key marker of EpK pathway. Furthermore, we developed a prognostic stratification strategy, where the EpK-activated, CAFs-enriched, and immune-desert subtypes were identified and found to represent distinct molecular characteristics and clinical outcomes. Conclusion Our study provides a valuable resource and insights to better understand ESCC in the era of precision medicine and targeted therapies.