Genome-wide methylation analysis shows similar patterns in Barrett's esophagus and esophageal adenocarcinoma

Carcinogenesis. 2013 Dec;34(12):2750-6. doi: 10.1093/carcin/bgt286. Epub 2013 Aug 29.

Abstract

Barrett's esophagus (BE) is a precursor of esophageal adenocarcinoma (EAC). To identify novel tumor suppressors involved in esophageal carcinogenesis and potential biomarkers for the malignant progression of BE, we performed a genome-wide methylation profiling of BE and EAC tissues. Using Illumina's Infinium HumanMethylation27 BeadChip microarray, we examined the methylation status of 27 578 CpG sites in 94 normal esophageal (NE), 77 BE and 117 EAC tissue samples. The overall methylation of CpG sites within the CpG islands was higher, but outside of the CpG islands was lower in BE and EAC tissues than in NE tissues. Hierarchical clustering analysis showed an excellent separation of NE tissues from BE and EAC tissues; however, the clustering of BE and EAC tissues was less clear, suggesting that methylation occurs early during the progression of EAC. We confirmed many previously reported hypermethylated genes and identified a large number of novel hypermethylated genes in BE and EAC tissues, particularly genes encoding ADAM (A Disintegrin And Metalloproteinase) peptidase proteins, cadherins and protocadherins, and potassium voltage-gated channels. Pathway analysis showed that a number of channel and transporter activities were enriched for hypermethylated genes. We used pyrosequencing to validate selected candidate genes and found high correlations between the array and pyrosequencing data (rho > 0.8 for each validated gene). The differentially methylated genes and pathways may provide biological insights into the development and progression of BE and become potential biomarkers for the prediction and early detection of EAC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / genetics
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Barrett Esophagus / genetics*
  • Barrett Esophagus / pathology
  • Cadherins / genetics
  • CpG Islands / genetics
  • DNA Methylation / genetics*
  • Disease Progression
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / pathology
  • Esophagus / pathology
  • Genome-Wide Association Study / methods
  • Humans
  • Potassium Channels, Voltage-Gated / genetics
  • Signal Transduction / genetics

Substances

  • Cadherins
  • Potassium Channels, Voltage-Gated
  • ADAM Proteins

Supplementary concepts

  • Adenocarcinoma Of Esophagus