Dataset Information

Evolutionary Action Score of TP53 Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer.

ABSTRACT: TP53 is the most frequently altered gene in head and neck squamous cell carcinoma, with mutations occurring in over two-thirds of cases, but the prognostic significance of these mutations remains elusive. In the current study, we evaluated a novel computational approach termed evolutionary action (EAp53) to stratify patients with tumors harboring TP53 mutations as high or low risk, and validated this system in both in vivo and in vitro models. Patients with high-risk TP53 mutations had the poorest survival outcomes and the shortest time to the development of distant metastases. Tumor cells expressing high-risk TP53 mutations were more invasive and tumorigenic and they exhibited a higher incidence of lung metastases. We also documented an association between the presence of high-risk mutations and decreased expression of TP53 target genes, highlighting key cellular pathways that are likely to be dysregulated by this subset of p53 mutations that confer particularly aggressive tumor behavior. Overall, our work validated EAp53 as a novel computational tool that may be useful in clinical prognosis of tumors harboring p53 mutations.

SUBMITTER: Neskey DM

PROVIDER: S-EPMC4383697 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Evolutionary Action Score of TP53 Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer.

Neskey David M DM Osman Abdullah A AA Ow Thomas J TJ Katsonis Panagiotis P McDonald Thomas T Hicks Stephanie C SC Hsu Teng-Kuei TK Pickering Curtis R CR Ward Alexandra A Patel Ameeta A Yordy John S JS Skinner Heath D HD Giri Uma U Sano Daisuke D Story Michael D MD Beadle Beth M BM El-Naggar Adel K AK Kies Merrill S MS William William N WN Caulin Carlos C Frederick Mitchell M Kimmel Marek M Myers Jeffrey N JN Lichtarge Olivier O

Cancer research 20150129 7

TP53 is the most frequently altered gene in head and neck squamous cell carcinoma, with mutations occurring in over two-thirds of cases, but the prognostic significance of these mutations remains elusive. In the current study, we evaluated a novel computational approach termed evolutionary action (EAp53) to stratify patients with tumors harboring TP53 mutations as high or low risk, and validated this system in both in vivo and in vitro models. Patients with high-risk TP53 mutations had the poore ...[more]

PMID: 25634208

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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.

Project description:BackgroundTP53 mutations are frequent in non-small cell lung cancer (NSCLC). Different categories of TP53 mutations may be associated with survival in advanced NSCLC, but their effect on prognosis is diverse. To date, a comprehensive comparison of the relationship between different classes of TP53 alterations and survival in advanced NSCLC has rarely been performed. Moreover, the prognostic significance of a novel approach called the evolutionary action of TP53 (EAp53) in advanced NSCLC is unclear.MethodsA total of 210 patients with NSCLC harboring TP53 mutation data were enrolled. Genomic and clinical data for the Memorial Sloan Kettering Cancer Center (MSKCC) cohort with advanced NSCLC were obtained from cBioPortal. Relationship between clinical characteristics and TP53 mutations was performed by Fisher's exact test or χ2 test. Overall survival (OS) analysis was evaluated using Kaplan-Meier method and Cox proportional hazards regression model.ResultsTP53 mutations were identified in 51.4% of NSCLC patients and were mainly located in exons 5, 7, and 8. The distribution patterns of missense and truncating mutations of TP53 were remarkably different. Among patients with advanced NSCLC who never received immune checkpoint inhibitor treatments, EAp53 high-risk mutations were significantly associated with poor OS in both our cohort and the MSKCC cohort. Moreover, marked differences were observed in the mutational landscape between patients with EAp53 high-risk mutations (HR group) and other patients (OT group). The HR group displayed higher mutation frequencies in the RTK, cell cycle, and DNA damage repair (DDR) pathways than the OT group. In addition, the tumor mutation burden in the HR group was significantly higher than that in the OT group.ConclusionsThis study provided important insights into the molecular-clinical profile of TP53-mutated NSCLC patients. Moreover, the data revealed that EAp53 high-risk mutations were an independent prognostic factor for worse OS in advanced NSCLC.

Dataset Information

Evolutionary Action Score of TP53 Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer.

Publications

Evolutionary Action Score of TP53 Identifies High-Risk Mutations Associated with Decreased Survival and Increased Distant Metastases in Head and Neck Cancer.

Similar Datasets

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