Similarity of aberrant DNA methylation in Barrett's esophagus and esophageal adenocarcinoma

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Abstract

Background

Barrett's esophagus (BE) is the metaplastic replacement of squamous with columnar epithelium in the esophagus, as a result of reflux. It is the major risk factor for the development of esophageal adenocarcinoma (EAC). Methylation of CpG dinucleotides of normally unmethylated genes is associated with silencing of their expression, and is common in EAC. This study was designed to determine at what stage, in the progression from BE to EAC, methylation of key genes occurs.

Results

We examined nine genes (APC, CDKN2A, ID4, MGMT, RBP1, RUNX3, SFRP1, TIMP3, and TMEFF2), frequently methylated in multiple cancer types, in a panel of squamous (19 biopsies from patients without BE or EAC, 16 from patients with BE, 21 from patients with EAC), BE (40 metaplastic, seven high grade dysplastic) and 37 EAC tissues. The methylation frequency, the percentage of samples that had any extent of methylation, for each of the nine genes in the EAC (95%, 59%, 76%, 57%, 70%, 73%, 95%, 74% and 83% respectively) was significantly higher than in any of the squamous groups. The methylation frequency for each of the nine genes in the metaplastic BE (95%, 28%, 78%, 48%, 58%, 48%, 93%, 88% and 75% respectively) was significantly higher than in the squamous samples except for CDKN2A and RBP1. The methylation frequency did not differ between BE and EAC samples, except for CDKN2A and RUNX3 which were significantly higher in EAC. The methylation extent was an estimate of both the number of methylated alleles and the density of methylation on these alleles. This was significantly greater in EAC than in metaplastic BE for all genes except APC, MGMT and TIMP3. There was no significant difference in methylation extent for any gene between high grade dysplastic BE and EAC.

Conclusion

We found significant methylation in metaplastic BE, which for seven of the nine genes studied did not differ in frequency from that found in EAC. This is also the first report of gene silencing by methylation of ID4 in BE or EAC. This study suggests that metaplastic BE is a highly abnormal tissue, more similar to cancer tissue than to normal epithelium.

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Most cited references 29

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ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis.

Kaila J Norton (2000)

The ubiquitously expressed family of ID helix-loop-helix (HLH) proteins function as dominant negative regulators of basic HLH (bHLH) transcriptional regulators that drive cell lineage commitment and differentiation in metazoa. Recent data from cell line and in vivo studies have implicated the functions of ID proteins in other cellular processes besides negative regulation of cell differentiation. ID proteins play key roles in the regulation of lineage commitment, cell fate decisions and in the timing of differentiation during neurogenesis, lymphopoiesis and neovascularisation (angiogenesis). They are essential for embryogenesis and for cell cycle progression, and they function as positive regulators of cell proliferation. ID proteins also possess pro-apoptotic properties in a variety of cell types and function as cooperating or dominant oncoproteins in immortalisation of rodent and human cells and in tumour induction in Id-transgenic mice. In several human tumour types, the expression of ID proteins is deregulated, and loss- and gain-of-function studies implicate ID functions in the regulation of tumour growth, vascularisation, invasiveness and metastasis. More recent biochemical studies have also revealed an emerging 'molecular promiscuity' of mammalian ID proteins: they directly interact with and modulate the activities of several other families of transcriptional regulator, besides bHLH proteins.

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Epigenetic patterns in the progression of esophageal adenocarcinoma.

C A Eads, S Kurumboor, Peter Laird … (2001)

Esophageal adenocarcinoma (EAC) arises after normal squamous mucosa undergoes metaplasia to specialized columnar epithelium (intestinal metaplasia or Barrett's esophagus), which can then ultimately progress to dysplasia and subsequent malignancy. Epigenetic studies of this model have thus far been limited to the DNA methylation analysis of a few genes. In this study, we analyzed a panel of 20 genes using a quantitative, high-throughput methylation assay, METHYLIGHT: We used this broader approach to gain insight into concordant methylation behavior between genes and to generate epigenomic fingerprints for the different histological stages of EAC. Our study included a total of 104 tissue specimens from 51 patients with different stages of Barrett's esophagus and/or associated adenocarcinoma. We screened 84 of these samples with the full panel of 20 genes and found distinct classes of methylation patterns in the different types of tissue. The most informative genes 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, ESR1, and MYOD1) or presence (CALCA, MGMT, and TIMP3) of methylation in normal esophageal mucosa and stomach, or the infrequent methylation of normal esophageal mucosa accompanied by methylation in all normal stomach samples (APC). The other genes were less informative, because the frequency of hypermethylation was below 5% (ARF, CDH1, CDKN2B, GSTP1, MLH1, PTGS2, and THBS1), completely absent (CTNNB1, RB1, TGFBR2, and TYMS1), or ubiquitous (HIC1 and MTHFR), regardless of tissue type. Each class undergoes unique epigenetic changes at different steps of disease progression of EAC, suggesting a step-wise loss of multiple protective barriers against CpG island hypermethylation. The aberrant hypermethylation occurs at many different loci in the same tissues, suggestive of an overall deregulation of methylation control in EAC tumorigenesis. However, we did not find evidence for a distinct group of tumors with a CpG island methylator phenotype. Finally, we found that normal and metaplastic tissues from patients with evidence of associated dysplasia or cancer had a significantly higher incidence of hypermethylation than similar tissues from patients with no further progression of their disease. The fact that the samples from these two groups of patients were histologically 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 progression.

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Is there publication bias in the reporting of cancer risk in Barrett's esophagus?

E Bozymski, Abigale M. Crosby, R Sandler … (2000)

The published risk of adenocarcinoma in the setting of Barrett's esophagus (BE) varies. Publication bias, the selective reporting of studies featuring positive or extreme results, may result in overestimation of this cancer risk in the literature. The aim of this study was to assess those publications reporting a cancer risk in BE for evidence of publication bias. A MEDLINE search for all published estimates between 1966 and 1998 of cancer risk in BE was performed. All studies reporting a cancer risk expressible in cancers per patient-year of follow-up were retrieved. Bibliographies of these studies were surveyed for additional estimates. All publications that required an initial endoscopy with histologic confirmation of BE and any cancer were included. The relationship of reported cancer risk to size of the study was assessed. Multivariable regression controlling for differences in definition of BE, as well as other study characteristics, was performed. The data were also analyzed by means of a funnel diagram, an epidemiologic method to assess publication bias. Five hundred fifty-four abstracts were reviewed. Twenty-seven publications met the stated criteria for inclusion. There was a strong correlation between cancer risk and the size of the study, with small studies reporting much higher risks of cancer than larger studies. This association persisted when differences in the definition of BE, retrospective vs. prospective nature of the study, surveillance interval, and the effect of cancer detected in the first year were considered. The funnel diagram analysis suggested publication bias. The cancer risk in BE may be overestimated in the literature due to publication bias.

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Author and article information

Journal

Journal ID (nlm-ta): Mol Cancer

Title: Molecular Cancer

Publisher: BioMed Central

ISSN (Electronic): 1476-4598

Publication date Collection: 2008

Publication date (Electronic): 2 October 2008

Volume: 7

Page: 75

Affiliations

[1 ]Discipline of Surgery, School of Medicine, The University of Adelaide, Royal Adelaide Hospital, Adelaide, South Australia, 5005, Australia

[2 ]Oncogenomics, Queensland Institute of Medical Research, Brisbane, 4006, Australia

[3 ]Division of Population Studies and Human Genetics, Queensland Institute of Medical Research, Brisbane, 4006, Australia

[4 ]School of Medicine, University of Queensland, Brisbane, Queensland, 4072, Australia

[5 ]Division of Tissue Pathology, Institute of Medical and Veterinary Science, Adelaide, South Australia, 5000, Australia

[6 ]School of Nursing and Midwifery, Flinders University, Bedford Park, South Australia, 5042, Australia

Article

Publisher ID: 1476-4598-7-75

DOI: 10.1186/1476-4598-7-75

PMC ID: 2567345

PubMed ID: 18831746

SO-VID: c695cacb-f5cf-4967-b99d-323e457fb24f

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Similarity of aberrant DNA methylation in Barrett's esophagus and esophageal adenocarcinoma

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Karger: Oncology

Most cited references 29

ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis.

Epigenetic patterns in the progression of esophageal adenocarcinoma.

Is there publication bias in the reporting of cancer risk in Barrett's esophagus?

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