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

Hector Alvarez, Joanna Opalinska, Li Zhou, Davendra Sohal, Melissa J. Fazzari, Yiting Yu, Christina Montagna, Elizabeth A. Montgomery, Marcia Canto, Kerry B. Dunbar, Jean Wang, Juan Carlos Roa, Yongkai Mo, Tushar Bhagat, K. H. Ramesh, Linda Cannizzaro, J. Mollenhauer, Reid F. Thompson, Masako Suzuki, Stephen MeltzerAri Melnick, John M. Greally, Anirban Maitra, Amit Verma

Research output: Contribution to journalArticle

84 Scopus citations

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.

Original languageEnglish (US)
Article numbere1001356
JournalPLoS genetics
Volume7
Issue number3
DOIs
StatePublished - Mar 2011

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Alvarez, H., Opalinska, J., Zhou, L., Sohal, D., Fazzari, M. J., Yu, Y., Montagna, C., Montgomery, E. A., Canto, M., Dunbar, K. B., Wang, J., Roa, J. C., Mo, Y., Bhagat, T., Ramesh, K. H., Cannizzaro, L., Mollenhauer, J., Thompson, R. F., Suzuki, M., ... Verma, A. (2011). Widespread hypomethylation occurs early and synergizes with gene amplification during esophageal carcinogenesis. PLoS genetics, 7(3), [e1001356]. https://doi.org/10.1371/journal.pgen.1001356