The landscape of m6A regulators in esophageal cancer: molecular characteristics, immuno-oncology features, and clinical relevance

Background: Squamous cell carcinoma (SCC) and adenocarcinoma (AC) are the two main pathological types of esophageal cancer (EC), which differ in molecular features, genetic variation, and treatment sensitivity. However, as a key process in tumorigenesis and development, the role of N6-methyladenosine (m6A) regulators in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) is not fully understood. Methods: This study systematically compared the role of m6A regulators of ESCC and EAC in terms of molecular characteristics, immuno-oncology characteristics, and clinical relevance, and validated our findings in a long-term follow-up patient cohort. Results: There were many differences in m6A regulators between ESCC and EAC in terms of expression patterns, genetic variation, association with tumor pathways, immune signatures, and immunotherapy sensitivity. Furthermore, VIRMA was identified as a factor with opposite functional and prognostic effects in ESCC and EAC. ESCC patients with high VIRMA expression and EAC patients with low VIRMA expression had a better prognosis. Single-center data showed that low expression of FTO may be associated with superior immunotherapy efficacy in ESCC patients. Conclusions: The results herein provide novel ideas for understanding the tumor characteristics, occurrence, and development of ESCC and EAC, and suggest new targets for the treatment and intervention of EC.