Widespread Hypomethylation Occurs Early and Synergizes with Gene Amplification during Esophageal Carcinogenesis

• DOI: 10.1371/journal.pgen.1001356
• Publication Date: 2011-03-31T21:14:58Z
• Authors: Hector Alvarez; Joanna Opalinska; Li Zhou; Davendra Sohal; Melissa J. Fazzari; Yiting Yu; Christina Montagna; Elizabeth A. Mont...; 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 Meltzer; Ari Melnick; John M. Greally; Anirban Maitra; Amit Verma
• Keywords: Barrett's esophagus; CpG site; Neoplastic transformation; Epigenomics

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