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Pattern of p53 protein expression is predictive for survival in chemoradiotherapy-naive esophageal adenocarcinoma.

ABSTRACT: TP53 mutations are considered to be the driving factor in the initiation of esophageal adenocarcinoma (EAC). However, the impact of this gene and its encoded protein as a prognostic marker has not been definitely established yet.In total, 204 chemoradiotherapy (CRT)-naive patients with EAC were included for p53 protein expression evaluation by immunohistochemistry (IHC) on the resection specimens, categorized as overexpression, heterogeneous or loss of expression, and correlated with disease free survival (DFS) and overall survival (OS) using multivariable Cox regression analysis. In a subset representing all three IHC subgroups mutational status of selected candidate genes (n=33) and high throughput methylation profiling (n=16) was assessed.Compared to heterogeneous p53 expression, loss and overexpression were both independently predictive for adverse DFS and OS. TP53 mutational status significantly correlated with the IHC categories (p=0.035). Most of the EAC with loss- or overexpression harbored TP53 mutations (18/20, representing nonsense and missense mutations respectively). In contrast, 6/13 EAC with heterogeneous expression were TP53 wild type, of which two demonstrated MDM4 or MDM2 amplification. Combined genomic hypomethylation and high frequency of intra-chromosomal breaks was found in a selection of EAC without p53 overexpression.P53 expression pattern is prognostic for DFS and OS in this historical cohort of CRT-naive EAC. P53 IHC is an informative readout for TP53 mutational status in EAC with either loss- or overexpression, but not in case of a heterogeneous p53 pattern. Different EAC pathogenesis might exist, related to p53 and other candidate gene status, DNA hypomethylation and intrachromosomal breaks.

SUBMITTER: Ten Kate FJC

PROVIDER: S-EPMC5732792 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Pattern of p53 protein expression is predictive for survival in chemoradiotherapy-naive esophageal adenocarcinoma.

Ten Kate Fiebo J C FJC Suzuki Lucia L Dorssers Lambert C J LCJ Dinjens Winand N M WNM Jones David T W DTW Nieboer Daan D Doukas Michael M Van Lanschot J Jan B JJB Wijnhoven Bas P L BPL Looijenga Leendert H J LHJ Biermann Katharina K

Oncotarget 20171024 61

<h4>Introduction</h4><i>TP53</i> mutations are considered to be the driving factor in the initiation of esophageal adenocarcinoma (EAC). However, the impact of this gene and its encoded protein as a prognostic marker has not been definitely established yet.<h4>Methods</h4>In total, 204 chemoradiotherapy (CRT)-naive patients with EAC were included for p53 protein expression evaluation by immunohistochemistry (IHC) on the resection specimens, categorized as overexpression, heterogeneous or loss of ...[more]

PMID: 29262626

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Project description:BackgroundChemoradiotherapy (CRT) plays a central role in the treatment of esophageal squamous cell carcinoma (ESCC). However, no effective biomarkers have been identified for predict CRT sensitivity and prognosis of patients with ESCC. The aim of this study was to investigate cytokine profiles of epidermal growth factor (EGF) and urokinase plasminogen activator receptor (uPAR) in 68 ESCC patients, and to evaluate the clinical utility of these markers.MethodsThis pilot study enrolled 68 patients who received neoadjuvant CRT followed by radical surgery or definitive CRT between 2015 and 2017. Serum specimen was obtained from each patient before treatment and at the time of administration of total doses of 40 Gy. Cytokines expression analyses were performed in pre- and post-treatment serum using human cytokine antibody arrays which contained 120 known tumor-related cytokines.ResultsSeven differentially expressed cytokines identified by cytokine antibody arrays in pre- and post-treatment serum from 4 patients with CRT sensitivity and 4 patients with CRT resistance. Of these, up-regulation of EGF and uPAR in serum at the doses of 40 Gy were associated with adverse clinical outcomes. The predictive value of EGF and uPAR were further assessed in a second set of 60 ESCCs. A total of 68 patients enrolled in this study. The median follow-up duration of these patients was 15.87 months (range, 6.21-23.85 months). Cox multivariate survival analyses revealed that high uPAR ratio after CRT independently predicted progression-free survival (PFS) (HR =3.999, 95% CI: 1.503-10.639, P=0.006) and patients with elevated levels of EGF after CRT exhibited significantly worse overall survival (OS) (HR =2.574, 95% CI: 1.046-6.335, P=0.040). Of note, uPAR expression was significantly positive correlation with EGF expression in pre- and post-treatment serum (P=0.0001, P=0.0038). Patients with both high EGF and uPAR ratios had an inferior PFS and OS, compared to patients with a high EGF ratio only or uPAR ratio only or neither (1-year PFS rate 44.2% vs. 61.4%, 1-year OS rate 64.2% vs. 83.4%, P=0.033 and 0.029, respectively).ConclusionsThe levels of EGF and uPAR in serum are reliable and predictive biomarkers for survival in ESCC patients. Further prospective validation in larger independent cohorts is necessary to fully assess its predictive power. We present the following article in accordance with the REMARK reporting checklist.

Dataset Information

Pattern of p53 protein expression is predictive for survival in chemoradiotherapy-naive esophageal adenocarcinoma.

Publications

Pattern of p53 protein expression is predictive for survival in chemoradiotherapy-naive esophageal adenocarcinoma.

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