NcoI TNF-β gene polymorphism and TNF expression are associated with an increased risk of developing Barrett's esophagus and esophageal adenocarcinoma

Abstract

Objective. Esophageal cancer development is a sequence that starts with reflux esophagitis (RE), followed by Barrett's esophagitis (BE), dysplasia, and finally esophageal adenocarcinoma (EAC). Tumor necrosis factor (TNF) is a potent anti-neoplastic agent, hence DNA polymorphisms that reduce TNF levels potentially enhance the development of BE and EAC. The aim of the study was to determine the impact of TNF gene variation on the RE–BE–EAC cascade. Methods. DNA from 887 Caucasian participants (197 controls, 305 RE, 257 BE, 128 EAC) was tested for the gene polymorphism TNF-β NcoI, and TNF production was determined by TNF-α specific immunohistochemistry on esophageal biopsies from these BE (n = 31) and EAC (n = 4) patients. Results. As compared with healthy controls, the TNF-β NcoI A/A genotype was significantly more prevalent in BE (p = 0.04) and EAC patients (p = 0.02), but not in RE patients (p = 0.1). While TNF-α protein levels were invariably high in esophageal biopsies from EAC patients, most esophageal BE samples showed low to moderate TNF levels. Conclusions. Chronic inflammation, like in BE, markedly increase the risk of malignant transformation. In this study, the significantly higher frequency of the TNF-β NcoI A/A genotype and the local TNF expression indicate that the pro-inflammatory cytokine TNF plays a role in the development of BE and EAC.

Key Words::

• Barrett's esophagus
• chronic inflammation
• esophageal adenocarcinoma
• reflux esophagitis
• tumor necrosis factor (TNF)

Acknowledgements

The authors would like to thank the investigators of the pro-inflammatory genotype study [23] for their permission to include the RE and BE patient materials in this study. We also like to acknowledge Dr. H. van Dekken for the histology of the tissue samples, Dr. Honkoop and Dr. Wolters for the collection of materials from the EAC patients, and J. Francke, A. Heijens, and M. Ouwendijk for their assistance with the processing of the materials.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.