Prognostic Significance of Positive Margin-Informed Tumor Status in Esophageal Squamous Cell Carcinoma Using Next-Generation Sequencing

Abstract

BACKGROUND: Reliable prognostic biomarkers are urgently needed for operable esophageal squamous cell carcinoma (ESCC), as conventional histopathology often fails to detect minimal residual disease and accurately predict patient outcomes. PATIENTS AND METHODS: This study investigated the mutational patterns in ESCC and the prognostic value of shared mutations between tumors and margins (margin-informed tumor, MiT) using next-generation sequencing. We analyzed tumor, margin, and normal tissues from a total of 70 patients with operable ESCC, including 48 from a retrospective cohort and 22 from a prospective cohort. RESULTS: TP53 mutations were more prevalent in tumors than in margins or normal tissues (retrospective, p < 0.0001; prospective, p = 0.02), while NOTCH1 mutations were more frequent in normal or margin tissues (retrospective, p = 0.0002; prospective, p = 0.07). Positive MiT was observed in 16.7% of the retrospective cohort and 45.5% of the prospective cohort, respectively, with all patients exhibiting over 50% shared mutations experiencing disease progression. Patients with identical TP53 mutations in both tumor and margin tissues (TP53-MiT) exhibited significantly worse survival (retrospective, hazard ratio [HR] = 3.32, 95% confidence interval [CI]: 1.11-9.91, p = 0.03; prospective, HR = 4.35, 95% CI: 0.87-21.63, p = 0.05). TP53 mutations were associated with tumorigenic pathways and low immune infiltration fraction. CONCLUSION: Our findings underscore the clinical importance of MiT, particularly TP53-MiT, in postoperative prognosis. Integrating TP53-MiT assessment into postoperative evaluations could refine risk stratification and guide adjuvant management better.