Widespread hypomethylation occurs early and synergizes with gene amplification during esophageal carcinogenesis Academic Article uri icon

Overview

MeSH Major

  • Barrett Esophagus
  • Biomarkers, Tumor
  • Cell Transformation, Neoplastic
  • Chemokines
  • DNA Methylation
  • Esophageal Neoplasms
  • Gene Amplification

abstract

  • Although a combination of genomic and epigenetic alterations are implicated in the multistep transformation of normal squamous esophageal epithelium to Barrett esophagus, dysplasia, and adenocarcinoma, the combinatorial effect of these changes is unknown. By integrating genome-wide DNA methylation, copy number, and transcriptomic datasets obtained from endoscopic biopsies of neoplastic progression within the same individual, we are uniquely able to define the molecular events associated progression of Barrett esophagus. We find that the previously reported global hypomethylation phenomenon in cancer has its origins at the earliest stages of epithelial carcinogenesis. Promoter hypomethylation synergizes with gene amplification and leads to significant upregulation of a chr4q21 chemokine cluster and other transcripts during Barrett neoplasia. In contrast, gene-specific hypermethylation is observed at a restricted number of loci and, in combination with hemi-allelic deletions, leads to downregulatation of selected transcripts during multistep progression. We also observe that epigenetic regulation during epithelial carcinogenesis is not restricted to traditionally defined "CpG islands," but may also occur through a mechanism of differential methylation outside of these regions. Finally, validation of novel upregulated targets (CXCL1 and 3, GATA6, and DMBT1) in a larger independent panel of samples confirms the utility of integrative analysis in cancer biomarker discovery.

publication date

  • March 2011

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3069107

Digital Object Identifier (DOI)

  • 10.1371/journal.pgen.1001356

PubMed ID

  • 21483804

Additional Document Info

start page

  • e1001356

volume

  • 7

number

  • 3