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 nextgeneration 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.

Plasma Circulating Tumor DNA Sequencing Predicts Minimal Residual Disease in Resectable Esophageal Squamous Cell Carcinoma

“…The mutation rate of TP53 in tumor samples was only 58.49%, which is lower than reported mutation frequency, mainly due to panel coverage (not all exons of TP53 were included) and small sample size. The mutational spectrum of TP53 is diverse in human cancers, apart from the "hotspot mutations" (23). The reported mutation rate of ESCC varies in different studies, ranging from 20% to 93%, which is mainly determined according to the sequencing panel coverage, methods used, and tumor stage (23)(24)(25)(26)(27)(28)(29).…”

“…The mutational spectrum of TP53 is diverse in human cancers, apart from the "hotspot mutations" (23). The reported mutation rate of ESCC varies in different studies, ranging from 20% to 93%, which is mainly determined according to the sequencing panel coverage, methods used, and tumor stage (23)(24)(25)(26)(27)(28)(29). We identified more variants in pre-surgical cfDNA specimens compared with tumors, indicating spatial intratumoral heterogeneity in ESCC; Hao et al also illustrated this (30).…”

“…Mutations originating from CH could lead to faulty reporting and incorrect treatment strategies when tumor-only sequencing is used ( 53 ). An increasing number of studies confirm that TP53 mutation has a prognostic value in esophageal cancer ( 23 , 54 , 55 ), attention should be paid to the CH phenomenon. cfDNA-leukocyte paired sequencing is essential to accurately identify the source of the genetic variation, and more attempts and efforts are still needed to evaluate MRD in esophageal cancer.…”

Non-Small Cell Lung Cancer Harboring Concurrent EGFR Genomic Alterations: A Systematic Review and Critical Appraisal of the Double Dilemma

“…No significant differences were assessed between the two groups, yet the shorter PFS subgroup revealed a TMB higher than eight. One could guess that an increased TMB is correlated with the existence of resistance pathways, as previous reports suggested [94]. Furthermore, among overall clinical studies, EGFR-TKIs appeared to have less activity in 67 patients harboring concomitant TP53 gene mutations.…”

“…Mutation in TP53 gene have been divided into disruptive mutations and non-disruptive ones considering the loss of function of p53 protein. Specifically, disruptive mutations produce a complete loss of function of p53, while non-disruptive alterations result in conservative mutations or non-conservative mutations (excepting stop codons) outside the L2-L3 region [91,[93][94][95]. Comprehensively, the systematic literature review identified a total of 11 reports evaluating the TP53 status in EGFR-mutant patients with lung adenocarcinoma.…”