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Topic: Reviews of Recent Advances in Research and Treatment for
Gastroenterological Malignancies

Overview of genetic and epigenetic alterations in the pathogenesis
of esophagogastric junctional adenocarcinoma and esophageal
adenocarcinoma: recent fi ndings by next generation sequencing

Yu Imamura , Ryuma Tokunaga , Kenichi Nakamura , Hideo Baba , Masayuki Watanabe 1,2
2
2
1,2
2
1 Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
2 Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8555, Japan.
Correspondence to: Dr. Yu Imamura, Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer
Research, 3-8-31 Ariake, Koto, Tokyo 135-8550, Japan. E-mail: yu.imamura@jfcr.or.jp
ABSTRACT
Esophagogastric junctional adenocarcinoma is commonly treated as esophageal adenocarcinoma (EAC) and has dramatically
increased in Western countries for several decades. The similar trend has been observed in Asian countries (not in China). Barrett’s
esophagus (BE) is a widely accepted precursor of EAC. Recent advances of next-generation sequencing could provide researchers
with a better understanding of genetic and epigenetic alterations in the carcinogenesis of EAC. In this review, we have summarized
the recently reported major genetic and epigenetic alterations in both BE and EAC. Sonic hedgehog/bone morphogenetic protein
axis, which is a key signaling for esophageal development, plays an important role in BE intestinal metaplasia. Single nucleotide
polymorphisms related to esophageal organogenesis, such as FOXF1 and FOXP3, are frequently detected in BE patients. During
the progression of BE to adenocarcinoma, lacking of normal function of TP53 and CDKN2A by loss of heterozygosity (LOH),
mutation, or promoter methylation has been frequently observed. LOH at 9p (coding CDKN2A) is an earlier event to EAC
carcinogenesis compared to that at 17q (coding TP53) LOH. In order to further elucidate the pathogenesis of BE and EAC, it will
be necessary to analyze these genetic/epigenetic alterations in combination with clinical data in a large-scale cohort.
Key words: Barrett’s esophagus, carcinogenesis, epigenetic, esophageal adenocarcinoma, esophagogastric junctional
adenocarcinoma, genetic, intestinal metaplasia

Introduction is around 0.5% per year. Epidemiological studies have
[6]
revealed that adenocarcinomas occur from BE through
Esophagogastric junctional (EGJ) adenocarcinoma is multistep morphological changes, such as low-grade to
classifi ed as I to III, based on the location of the tumor high-grade dysplasia. [6,7] BE and EGJ adenocarcinoma/
[1]
center or tumor mass, by Rudiger Siewert et al. EGJ EAC share poly-genetic/epigenetic alterations. BE
[8]
cancer is considered to be an esophageal cancer, according can be described as mucosal replacement of normal
to the 7th edition of Union for International Cancer squamous epithelium with metaplastic columnar
Control tumour, node, metastasis classifi cation. EGJ mucosa, known as specialized columnar metaplasia,
[2]
adenocarcinoma/esophageal adenocarcinoma (EAC) has in response to chronic gastroesophageal refl ux
dramatically increased by 600%, mainly in Western disease (GERD). Understanding the pathogenesis
[9]
countries, over the past few decades, although the current of BE and EGJ adenocarcinoma/EAC is important
[3]
incidence rate shows only a moderate increase. Currently, in prevention and thus the development of molecular
[4]
a similar trend was reported in Asian country. EGJ targeting therapy. Here, we review the pathogenesis of
adenocarcinoma often presents at a late stages despite recent EGJ adenocarcinoma/EAC, including BE, focusing on
improvements in diagnostic technology and multidisciplinary molecular alterations. We use the term EAC and include
treatment. The 5-year survival rate is reported to be about EGJ adenocarcinoma.
20% and median survival less than one year. [3,5]
Barrett’s esophagus (BE) is a widely accepted precursor This is an open access article distributed under the terms of the Creative
of EGJ adenocarcinoma/EAC, although the reported risk Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows
others to remix, tweak, and build upon the work non-commercially, as long as
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Website: How to cite this article: Imamura Y, Tokunaga R, Nakamura K,
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Baba H, Watanabe M. Overview of genetic and epigenetic alterations
in the pathogenesis of esophagogastric junctional adenocarcinoma
and esophageal adenocarcinoma: recent fi ndings by next generation
DOI: sequencing. J Cancer Metastasis Treat 2015;1:123-9.
10.4103/2394-4722.161620
Received: 09-06-2015; Accepted: 26-06-2015.

© 2015 Journal of Cancer Metastasis and Treatment ¦ Published by Wolters Kluwer - Medknow 123