Epigenetic patterns in the progression of esophageal adenocarcinoma

Citation
Ca. Eads et al., Epigenetic patterns in the progression of esophageal adenocarcinoma, CANCER RES, 61(8), 2001, pp. 3410-3418
Citations number
48
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
0008-5472 → ACNP
Volume
61
Issue
8
Year of publication
2001
Pages
3410 - 3418
Database
ISI
SICI code
0008-5472(20010415)61:8<3410:EPITPO>2.0.ZU;2-#
Abstract
Esophageal adenocarcinoma (EAC) arises after normal squamous mucosa undergo es metaplasia to specialized columnar epithelium (intestinal metaplasia or Barrett's esophagus), which can then ultimately progress to dysplasia and s ubsequent malignancy. Epigenetic studies of this model have thus far been l imited to the DNA methylation analysis of a few genes. In this study, we an alyzed a panel of 20 genes using a quantitative, high-throughput methylatio n assay, MethyLight. Ne used this broader approach to gain insight into con cordant methylation behavior between genes and to generate epigenomic finge rprints for the different histological stages of EAC. Our study included a total of 104 tissue specimens from 51 patients with different stages of Bar rett's esophagus and/or associated adenocarcinoma. We screened 84 of these samples with the full panel of 20 genes and found distinct classes of methy lation patterns in the different types of tissue. The most informative gene s,were those with an intermediate frequency of significant hypermethylation [ranging from 15% (CDKN2A) to 60% (MGMT) of the samples]. This group could be further subdivided into three classes, according to the absence (CDKN2A , ESRI, and MYODI) or presence (CALCA, MGMT, and TIMP3) of methylation in n ormal esophageal mucosa and stomach, or the infrequent methylation of norma l esophageal mucosa accompanied by methylation in all normal stomach sample s (APC). The other genes were less informative, because the frequency of hy permethylation was below 5% (ARF, CDH1, CDKN2B, GSTP1, MLH1, PTGS2, and THB S1), completely absent (CTNNB1, RBI, TGFBR2, and TYMS1), or ubiquitous (H1C 1 and MTHFR), regardless of tissue type. Each class undergoes unique epigen etic changes at different steps of disease progression of EAC, suggesting a step-wise loss of multiple protective barriers against CpG island hypermet hylation. The aberrant hypermethylation occurs at many different loci in th e same tissues, suggestive of an overall deregulation of methylation contro l in EAC tumorigenesis. However, we did not find evidence for a distinct gr oup of tumors with a CpG island methylator phenotype. Finally,we found that normal and metaplastic tissues from patients with evidence of associated d ysplasia or cancer had a significantly higher incidence of hypermethylation than similar tissues from patients with no further progression of their di sease. The fact that the samples from these two groups of patients were his tologically indistinguishable, yet molecularly distinct, suggests that the occurrence of such hypermethylation may provide a clinical tool to identify patients with premalignant Barrett's who are at risk for further progressi on.