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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.

SUBMITTER: Huang M

PROVIDER: S-EPMC7186752 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Non-disruptive mutation in <i>TP53</i> DNA-binding domain is a beneficial factor of esophageal squamous cell carcinoma.

Huang Minran M Jin Jiaoyue J Zhang Fanrong F Wu Yingxue Y Xu Chenyang C Ying Lisha L Su Dan D

Annals of translational medicine 20200301 6

<h4>Background</h4><i>TP53</i> is frequently altered in esophageal squamous cell carcinoma (ESCC). However, the landscape of <i>TP53</i> mutation and its effects on patients remain controversial.<h4>Methods</h4>Somatic mutations of <i>TP53</i> in 161 patients with resectable ESCC were identified by next-generation sequencing (NGS) and verified by immunohistochemistry (IHC). Patients were stratified into seven <i>TP53</i> mutations, and depending on the extent of the effect on the encoded protein ...[more]

PMID: 32355760

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Project description:For TP53-mutated head and neck squamous cell carcinomas (HNSCCs), the codon and specific amino acid sequence change resulting from a patient's mutation can be prognostic. Thus, developing a framework to predict patient survival for specific mutations in TP53 would be valuable. There are many bioinformatics and functional methods for predicting the phenotypic impact of genetic variation, but their overall clinical value remains unclear. Here, we assess the ability of 15 different methods to predict HNSCC patient survival from TP53 mutation, using TP53 mutation and clinical data from patients enrolled in E4393 by the Eastern Cooperative Oncology Group (ECOG), which investigated whether TP53 mutations in surgical margins were predictive of disease recurrence. These methods include: server-based computational tools SIFT, PolyPhen-2, and Align-GVGD; our in-house POSE and VEST algorithms; the rules devised in Poeta et al. with and without considerations for splice-site mutations; location of mutation in the DNA-bound TP53 protein structure; and a functional assay measuring WAF1 transactivation in TP53-mutated yeast. We assessed method performance using overall survival (OS) and progression-free survival (PFS) from 420 HNSCC patients, of whom 224 had TP53 mutations. Each mutation was categorized as "disruptive" or "non-disruptive". For each method, we compared the outcome between the disruptive group vs. the non-disruptive group. The rules devised by Poeta et al. with or without our splice-site modification were observed to be superior to others. While the differences in OS (disruptive vs. non-disruptive) appear to be marginally significant (Poeta rules + splice rules, P = 0.089; Poeta rules, P = 0.053), both algorithms identified the disruptive group as having significantly worse PFS outcome (Poeta rules + splice rules, P = 0.011; Poeta rules, P = 0.027). In general, prognostic performance was low among assessed methods. Further studies are required to develop and validate methods that can predict functional and clinical significance of TP53 mutations in HNSCC patients.

Dataset Information

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

Publications

Non-disruptive mutation in <i>TP53</i> DNA-binding domain is a beneficial factor of esophageal squamous cell carcinoma.

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