TitleWidespread hypomethylation occurs early and synergizes with gene amplification during esophageal carcinogenesis.
Publication TypeJournal Article
Year of Publication2011
AuthorsAlvarez, Hector, Opalinska Joanna, Zhou Li, Sohal Davendra, Fazzari Melissa J., Yu Yiting, Montagna Christina, Montgomery Elizabeth A., Canto Marcia, Dunbar Kerry B., Wang Jean, Roa Juan Carlos, Mo Yongkai, Bhagat Tushar, Ramesh K H., Cannizzaro Linda, Mollenhauer J, Thompson Reid F., Suzuki Masako, Meltzer Stephen J., Melnick Ari, Greally John M., Maitra Anirban, and Verma Amit
JournalPLoS Genet
Date Published2011 Mar
KeywordsBarrett Esophagus, Biomarkers, Tumor, Calcium-Binding Proteins, Cell Line, Tumor, Cell Transformation, Neoplastic, Chemokine CXCL1, Chemokines, Chemokines, CXC, DNA Methylation, DNA-Binding Proteins, Esophageal Neoplasms, GATA6 Transcription Factor, Gene Amplification, Gene Expression Profiling, Humans, Neoplasm Staging, Receptors, Cell Surface, Tumor Suppressor Proteins

<p>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.</p>

Alternate JournalPLoS Genet
PubMed ID21483804
PubMed Central IDPMC3069107
Grant ListR01 DK087454 / DK / NIDDK NIH HHS / United States
R01 HL082946 / HL / NHLBI NIH HHS / United States
T32 CA009173 / CA / NCI NIH HHS / United States
R01HL082946 / HL / NHLBI NIH HHS / United States