DNA methylation markers in esophageal cancer: an emerging tool for cancer surveillance and treatment

Abstract

Esophageal carcinoma (EC) is one of the most pervasive cancers in the world, with upwards of 500,000 new diagnoses, annually. Despite its prominence, advancements in the detection and treatment of EC have been marginal over the past 30 years and the survival rate continues to stay below 20%. This is due to the uncommonly heterogeneous presentation of EC which presents unprecedented challenges in improving patient survival and quality of care. However, distinct epigenetic alterations to the DNA methylome may provide an avenue to drastically improve the detection and treatment of EC. Specifically, the creation of novel biomarker panels that consist of EC-specific methylation markers have shown promise as a potential alternative to the more invasive, contemporary diagnostic methods. Additionally, growing insight into the biological and clinical properties of EC-specific methylation patterns have opened a window of opportunity for enhanced treatment; of growing interest is the application of "DNMT inhibitors" - a class of drugs which inhibit excessive methylation and have been shown to re-sensitize chemoresistant tumors. Here we provide a comprehensive review of the current advancements in EC DNA methylation to underscore a potential approach to its detection and treatment.

Keywords: DNA methylation; DNMT inhibitors; Esophageal carcinoma; cancer precursor lesion.

Figure 1

Aberrant DNA methylation in carcinogenesis. DNA methylation, catalyzed by DNMT family enzymes, alter gene function or activity in esophageal cancer. DNA methylation, mainly classified into hypermethylation and hypomethylation, in esophageal cancer alter different gene function or activity. After the interaction of DNMT and DNA binding sites, global hypomethylation causes the enhanced activity of the genes, such as LINE-1, and CpG-specific hypermethylation is correlated to gene expression reduction, such as MGMT and CDKN2A.

Figure 2

Methylation-based screening for esophageal carcinoma. Tissue biopsy can be obtained by endoscopic methods. After sample collection, it will be directly used for DNA extraction and bisulfite conversion, which could highlight the presence and location of DNA methylation. Several assays can be performed for methylation detection, such as sanger-sequencing or pyrosequencing.

Figure 3

Application of DNMT inhibitor therapeutics in halting progression of EAC. During the progression of esophageal carcinoma, DNA methylation, catalyzed by DNMT, was modified on several genes, causing aberrant expression and activity. DNMT inhibitor treatment could reduce the degree/extent of DNA methylation and increase the expression of tumor suppressor genes, and thus improve clinical outcomes.