Non-disruptive mutation in TP53 DNA-binding domain is a beneficial factor of esophageal squamous cell carcinoma

Abstract

BACKGROUND: TP53 is frequently altered in esophageal squamous cell carcinoma (ESCC). However, the landscape of TP53 mutation and its effects on patients remain controversial. METHODS: Somatic mutations of TP53 in 161 patients with resectable ESCC were identified by next-generation sequencing (NGS) and verified by immunohistochemistry (IHC). Patients were stratified into seven TP53 mutations, and depending on the extent of the effect on the encoded protein, it was divided into "disruptive" and "non-disruptive" types. The association of TP53 mutation with clinicopathological properties and disease outcome was investigated. RESULTS: TP53 mutations were discovered in 85.7% patients, of which 68.9% carried mutations in the DNA-binding domain (DBD). A total of 47.8% and 37.9% patients had disruptive and non-disruptive TP53 mutations, respectively. Most patients carried only one TP53 mutation, but 15.5% had double mutations. TP53 mutations were dominant in exons 5 to 8. Missense mutation was the most frequent (97/163, 59.5%), and the top five frequently occurring variations included R273X, Y220X, H193, H179X, and R175H. Multivariable analysis revealed non-disruptive mutation in TP53 DBD as the independent prognostic predictor for progression-free survival (PFS) and overall survival (OS). The expression of p53 positively correlated with non-disruptive mutation in DBD. Patients with high p53 protein expression showed better outcomes. CONCLUSIONS: Non-disruptive mutation in TP53 DBD serves as an independent beneficial prognostic factor of prolonged survival in resectable ESCC.