Widespread hypomethylation occurs early and synergizes with gene amplification during esophageal carcinogenesis

PLoS Genet. 2011 Mar;7(3):e1001356. doi: 10.1371/journal.pgen.1001356. Epub 2011 Mar 31.

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 types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Barrett Esophagus / genetics*
  • Barrett Esophagus / pathology
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / pathology
  • Chemokine CXCL1 / genetics
  • Chemokine CXCL1 / metabolism
  • Chemokines / genetics*
  • Chemokines / metabolism
  • Chemokines, CXC / genetics
  • Chemokines, CXC / metabolism
  • DNA Methylation*
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / pathology
  • GATA6 Transcription Factor / genetics
  • GATA6 Transcription Factor / metabolism
  • Gene Amplification*
  • Gene Expression Profiling
  • Humans
  • Neoplasm Staging
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism

Substances

  • Biomarkers, Tumor
  • CXCL1 protein, human
  • CXCL3 protein, human
  • Chemokine CXCL1
  • Chemokines
  • Chemokines, CXC
  • DMBT1 protein, human
  • GATA6 Transcription Factor
  • GATA6 protein, human
  • Receptors, Cell Surface