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Molecular Evolution of Metaplasia to Adenocarcinoma in the Esophagus

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Abstract

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 gastroesophageal acid reflux. In a minority of individuals, BE can progress to low- and high-grade dysplasia and eventually to intra-mucosal 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, 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 Recent studies have also provided new insight into the evolutionary forces underlying the molecular alterations seen in BE and EAC and into the molecular pathogenesis of EAC.

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Acknowledgments

Support for this work was provided by National Institutes of Health (NIH) National Cancer Institute (NCI) RO1CA115513, P30CA15704, UO1CA152756, U54CA143862, and P01CA077852 (WMG) and the DeGregorio Family Foundation and Lattner Family Foundation (WMG).

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  1. Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N. D4-100, Seattle, WA, 98109, USA

    William M. Grady & Ming Yu

  2. Department of Internal Medicine, University of Washington School of Medicine, Seattle, WA, USA

    William M. Grady

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Grady, W.M., Yu, M. Molecular Evolution of Metaplasia to Adenocarcinoma in the Esophagus. Dig Dis Sci 63, 2059–2069 (2018). https://doi.org/10.1007/s10620-018-5090-8

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