DNA Methylation as an Adjunct to Histopathology to Detect Prevalent, Inconspicuous Dysplasia and Early-Stage Neoplasia in Barrett's Esophagus

Alvi, Muhammad A.; Liu, Xinxue; O’Donovan, Maria; Newton, Richard; Wernisch, Lorenz; Shannon, Nicholas B.; Shariff, Kareem; Pietro, Massimiliano di; Bergman, Jacques J.G.H.M.; Ragunath, Krish; Fitzgerald, Rebecca C.

doi:10.1158/1078-0432.ccr-12-2880

Cited by 64 publications

(43 citation statements)

References 48 publications

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“…51,52 Cytogenetic abnormalities detected by means of fluorescence in situ hybridization (FISH) and biomarker panels that identify multiple abnormalities in DNA content, gene expression, and DNA methylation have shown promise as predictors of cancer risk, as have some risk-stratification models that incorporate a variety of clinical, histologic, and molecular features. [52][53][54][55][56] However, none of these methods have yet been validated sufficiently to justify routine application in clinical practice.…”

Section: Epidemiol Ogymentioning

confidence: 99%

Barrett's Esophagus

Spechler¹,

Souza²

2014

N Engl J Med

451

334

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I t has been estimated that 5.6% of adults in the United States have Barrett's esophagus, 1 the condition in which a metaplastic columnar mucosa that confers a predisposition to cancer replaces an esophageal squamous mucosa damaged by gastroesophageal reflux disease (GERD). 2 GERD and Barrett's esophagus are major risk factors for esophageal adenocarcinoma, a deadly tumor whose frequency in the United States has increased by a factor of more than 7 during the past four decades. 3,4 The metaplastic columnar mucosa of Barrett's esophagus causes no symptoms, and the condition has clinical importance only because it confers a predisposition to cancer. PathogenesisMetaplasia, the process wherein one adult cell type replaces another, is a consequence of chronic tissue injury. 5 In patients with chronic esophageal injury from GERD, Barrett's metaplasia develops when mucus-secreting columnar cells replace reflux-damaged esophageal squamous cells. The cells that give rise to this metaplasia are not known. It has been proposed that GERD might induce alterations in the expression of key developmental transcription factors, causing mature esophageal squamous cells to change into columnar cells (transdifferentiation) or causing immature esophageal progenitor cells to undergo columnar rather than squamous differentiation (transcommitment). 5,6 In a rat model of reflux esophagitis, metaplasia develops from bone marrow stem cells that enter the blood and settle in the reflux-damaged esophagus. 7 Studies in mouse models have suggested that metaplasia might result from upward migration of stem cells from the proximal stomach (the gastric cardia) 8 or from proximal expansion of embryonic-type cells at the gastroesophageal junction. 9 It is not clear which of these processes contribute to the pathogenesis of Barrett's esophagus in humans. Di agnosisThe diagnosis of Barrett's esophagus requires findings on endoscopy that columnar mucosa extends above the gastroesophageal junction, lining the distal esophagus, plus esophageal-biopsy results that confirm the presence of columnar metaplasia. 2 Endoscopically, the gastroesophageal junction is identified as the most proximal extent of gastric folds, and the columnar mucosa is salmon-colored and coarse, in contrast to the pale, glossy esophageal squamous mucosa (Fig. 1). The extent of esophageal columnar metaplasia determines whether long-segment or short-segment Barrett's esophagus (≥3 cm or <3 cm of columnar metaplasia, respectively) is diagnosed. 10 However, authorities disagree on the histologic type of columnar mucosa that establishes a diagnosis of Barrett's esophagus.U.S. gastroenterology societies require esophageal biopsies showing intestinal metaplasia with goblet cells (also called specialized intestinal metaplasia or specialized columnar epithelium) for a definitive diagnosis of Barrett's esophagus The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF NEWCASTLE on August 27, 2014. For personal use only. No other uses without permission.

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Section: Epidemiol Ogymentioning

confidence: 99%

Barrett's Esophagus

Spechler¹,

Souza²

2014

N Engl J Med

451

334

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“…They also found numerous previously undescribed hypermethylated genes in BE and EAC tissues, including genes encoding ADAM (A Disintegrin And Metalloproteinase) peptidase proteins, cadherins and protocadherins, and potassium voltage-gated channels. Alvi et al also used the HumanMethylation27 BeadChips to compare methylation patterns, focusing on imprinted and X chromosome genes, from 24 BE and 22 EAC samples (55) and validated their findings in retrospective and prospective cohorts to assess the ability of methylated genes to classify individuals as having prevalent BE, dysplastic BE, or EAC. They found four genes ( SLC22A18, PIGR, GJA12 , and RIN2 ) had the greatest area under curve (AUC=0.988) to distinguish between BE and dysplasia/EAC in their retrospective cohort.…”

Section: Epigenetic Alterations In Barrett’s Esophagus Barrett’mentioning

confidence: 99%

Genetic and Epigenetic Alterations in Barrett’s Esophagus and Esophageal Adenocarcinoma

Kaz

Grady

Stachler

et al. 2015

Gastroenterology Clinics of North America

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Esophageal adenocarcinoma (EAC) develops from Barrett’s esophagus (BE), a condition where the normal squamous epithelia is replaced by specialized intestinal metaplasia in response to chronic gastro-esophageal acid reflux. In a minority of individuals, BE can progress to low- and high-grade dysplasia (LGD and HGD) and eventually to intramucosal and then invasive carcinoma. BE provides researchers with a unique model to characterize the process by which a carcinoma arises from its precursor lesion. Molecular studies of BE have demonstrated that it is not simply a metaplastic tissue, but rather it harbors frequent alterations that are also present in dysplastic BE and in EAC. Both BE and EAC are characterized by loss of heterozygosity (LOH), aneuploidy, specific genetic mutations, and clonal diversity. Epigenetic abnormalities, primary alterations in DNA methylation, are also frequently seen in BE and EAC. Candidate gene and array-based approaches have demonstrated that numerous tumor-suppressor genes exhibit aberrant promoter methylation, and some of these altered genes are associated with the neoplastic progression of BE. It has also been shown that the BE and EAC epigenomes are characterized by hypomethylation of intragenic and non-coding regions. Given the limitations of histopathology for the diagnosis of BE and particularly dysplastic BE, genomic and epigenomic analyses have the potential to improve the precision of risk stratification. Assays to detect molecular alterations that are associated with neoplastic progression could one day be used to improve the pathological assessment of BE/EAC and to select high-risk patients for more intensive surveillance.

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“…25–27 For each of these studies, the selection of the biomarkers was based on the biology underlying cancer development, as determined by basic and translational research studies. A few of the more promising predictive biomarkers for cancer progression in Barrett’s esophagus have been validated in large studies; most with retrospective validation, while some studies include both a retrospective validation followed by prospective evaluation in a cohort of patients.…”

Section: Use Of Biomarker Panels To Assess Cancer Risk In Barrett’s Ementioning

confidence: 99%

“…25 Genes with differential methylation were identified and applied to cohort of samples including 60 non-dysplastic Barrett’s esophagus, 9 esophageal adenocarcinomas, and 28 dysplastic Barrett’s esophagus. From this retrospective validation, the investigators identified a 4-gene panel that was able to discriminate between non-dysplastic Barrett’s esophagus and Barrett’s-associated neoplasia with a high area-under-the-curve (AUC) of 0.988.…”

Section: Use Of Biomarker Panels To Assess Cancer Risk In Barrett’s Ementioning

confidence: 99%

Beyond Dysplasia Grade

Dunbar

Souza

2017

Gastrointestinal Endoscopy Clinics of North America

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SYNOPSIS Gastroenterology society guidelines recommend endoscopic surveillance as a means to detect early stage cancer in Barrett’s esophagus. However, the incidence of esophageal adenocarcinoma in Western countries continues to rise, suggesting that this strategy may be inadequate. Current surveillance methods rely on the endoscopist’s ability to identify suspicious areas of Barrett’s esophagus to biopsy, random biopsies, and on the histopathologic diagnosis of dysplasia. This review highlights the challenges of using dysplasia to stratify cancer risk, and addresses the development and use of molecular biomarkers and in vivo molecular imaging to detect early neoplasia in Barrett’s esophagus.

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DNA Methylation as an Adjunct to Histopathology to Detect Prevalent, Inconspicuous Dysplasia and Early-Stage Neoplasia in Barrett's Esophagus

Cited by 64 publications

References 48 publications

Barrett's Esophagus

Barrett's Esophagus

Genetic and Epigenetic Alterations in Barrett’s Esophagus and Esophageal Adenocarcinoma

Beyond Dysplasia Grade

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