The prognostic role of a novel TP53 mutation classifier in resectable esophageal squamous-cell carcinoma.

Abstract

e14749 Background: TP53 is the most recurrently mutated gene in esophageal squamous-cell carcinoma (ESCC). However, the effect of TP53 mutation status on the prognosis for patients with ESCC remains controversial. Also, there has been no consensus on the minimal genomic region necessary for clinical TP53 genetic testing. Methods: We retrospectively examined somatic mutations in all coding exons of the TP53 gene in 161 resectable ESCC patients by next-generation sequencing. We then stratified patients by multiple TP53 mutation classifiers based on different mutant features and analyzed its association with clinicopathological features and disease outcome by univariable and multivariable analysis. Results: We detected TP53 mutations in 138 of the 161 patients (85.7%), among which 61 patients harbored a non-disruptive mutation in the DNA-binding domain (DBD). The presence of TP53 mutation, hotspot mutant, and the mutation number alone was not predictive of any disease features and prognosis. We identified a prognostic effect of harboring the non-disruptive and DBD mutation of TP53 with an HR 0.362 (95% CI: 0.212–0.620, P < 0.001) and 0.486 (95% CI: 0.277–0.853, P = 0.012) for 5-year progression-free (PFS) and overall survival (OS), respectively. Multivariable analysis revealed it as an independent prognostic predictor for PFS (HR: 0.414, 95% CI: 0.230–0.746, P = 0.003) and OS (HR: 0.414, 95% CI: 0.207–0.825, P = 0.012). In particular, this TP53 mutation classifier defined a patient subset more beneficial from peri-operative radiotherapy with improved 5-year PFS (P = 0.020) and OS (P = 0.036). Conclusions: It is of clinical importance to examine and identify the non-disruptive somatic mutation in DBD of the TP53 gene for resectable ESCC.