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

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.

Notch Pathway Is Activated via Genetic and Epigenetic Alterations and Is a Therapeutic Target in Clear Cell Renal Cancer

“…We used a Zeiss stereomicroscope under 60ϫ magnification for the microdissection. Genomic DNA was isolated using the dialysis tubing method, as performed and described previously (13). RNA was extracted using Qiagen RNeasy mini kits.…”

“…cancer can be accomplished via gene amplifications, as well as by aberrant epigenetic modifications (13). Analysis of our integrative CCRCC data set revealed that even though hypermethylation was the predominant epigenetic abnormality in CCRCC (8), JAG1 was one of the select genes that was aberrantly hypomethylated in CCRCC (supplemental Table S1).…”

High Resolution Methylome Analysis Reveals Widespread Functional Hypomethylation during Adult Human Erythropoiesis

“…Genome-wide DNA Methylation Analysis Using the HELP Assay-Genomic DNA was isolated by phenol chloroform extraction, as performed before (9). HELP was carried out as described previously (10).…”

Genomics, Epigenetics and Molecular Considerations in Esophageal Adenocarcinoma: What You Need to Know?

“…Notably, methylation panels of the aforementioned genetic loci are currently being clinically used as biomarkers of EAC in certain high volume centers [23]. Interestingly, hypomethylation of noncoding DNA regions have been correlated with disease progression as well [24]. Last but not least, investigations regarding the role of microRNAs (miRNAs) in EC are also gaining traction.…”