Research Papers:

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

Fiebo J.C. Ten, Lucia Suzuki, Lambert C.J. Dorssers, Winand N.M. Dinjens, David T.W. Jones, Daan Nieboer, Michael Doukas, J. Jan B. Van Lanschot, Bas P.L. Wijnhoven, Leendert H.J. Looijenga and Katharina Biermann _

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Oncotarget. 2017; 8:104123-104135. https://doi.org/10.18632/oncotarget.22021

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Fiebo J.C. Ten Kate1, Lucia Suzuki1, Lambert C.J. Dorssers1, Winand N.M. Dinjens1, David T.W. Jones4, Daan Nieboer2, Michael Doukas1, J. Jan B. Van Lanschot3, Bas P.L. Wijnhoven3, Leendert H.J. Looijenga1 and Katharina Biermann1

1Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands

2Department of Public Health, Erasmus University Medical Center, Rotterdam, The Netherlands

3Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands

4Division of Pediatric Neurooncology, German Cancer Research Center (DFKZ), Heidelberg, Germany

Correspondence to:

Katharina Biermann, email: [email protected]

Keywords: esophageal adenocarcinoma; p53; survival; mutational profile; DNA methylation

Received: July 31, 2017    Accepted: September 22, 2017    Published: October 24, 2017


Introduction: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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