TY - JOUR
T1 - Widespread hypomethylation occurs early and synergizes with gene amplification during esophageal carcinogenesis
AU - Alvarez, Hector
AU - Opalinska, Joanna
AU - Zhou, Li
AU - Sohal, Davendra
AU - Fazzari, Melissa J.
AU - Yu, Yiting
AU - Montagna, Christina
AU - Montgomery, Elizabeth A.
AU - Canto, Marcia
AU - Dunbar, Kerry B.
AU - Wang, Jean
AU - Roa, Juan Carlos
AU - Mo, Yongkai
AU - Bhagat, Tushar
AU - Ramesh, K. H.
AU - Cannizzaro, Linda
AU - Mollenhauer, J.
AU - Thompson, Reid F.
AU - Suzuki, Masako
AU - Meltzer, Stephen
AU - Melnick, Ari
AU - Greally, John M.
AU - Maitra, Anirban
AU - Verma, Amit
PY - 2011/3
Y1 - 2011/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79953737588&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1001356
DO - 10.1371/journal.pgen.1001356
M3 - Article
C2 - 21483804
AN - SCOPUS:79953737588
SN - 1553-7390
VL - 7
JO - PLoS genetics
JF - PLoS genetics
IS - 3
M1 - e1001356
ER -