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

Epigenetic changes in gastrointestinal cancers

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Hironobu Shigaki , Yoshifumi Baba , Kazuto Harada , Naoya Yoshida , Masayuki Watanabe , Hideo Baba 1
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1 Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto 860-8556, Japan.
2 Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
Correspondence to: Dr. Hideo Baba, Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University,
1-1-1 Honjo, Kumamoto 860-8556, Japan. E-mail: hdobaba@kumamoto-u.ac.jp
ABSTRACT
Epigenetic alterations, including DNA methylation, histone modifi cation, loss of genome imprinting, chromatin remodeling
and non-coding RNAs, are associated with human carcinogenesis. Among them, DNA methylation is a fundamental epigenetic
process to modulate gene expression. In cancer cells, altered DNA methylation includes hypermethylation of site-specifi c CpG
island promoter and global DNA hypo-methylation. Detection of aberrant gene promoter methylation has been applied to the
clinic to stratify risk in cancer development, detect early cancer and predict clinical outcomes. Environmental factors associated
with carcinogenesis are also signifi cantly related to aberrant DNA methylation. Importantly, epigenetic changes, including altered
DNA methylation, are reversible and thus, used as targets for cancer therapy or chemoprevention. An increasing number of
recent studies reported DNA methylation level to be a useful biomarker for diagnosis, risk assessment and prognosis prediction
for gastrointestinal (GI) cancers. This review summarized the accumulated evidence for clinical application to use aberrant DNA
methylation levels in GI cancers, including colorectal, gastric and esophageal cancer.
Key words: Colorectal cancer, DNA methylation, epigenetic alterations, esophageal cancer, gastric cancer

Introduction in its transcriptional inactivity and silence of protein
expression. Thus, hypermethylation of a gene promoter
Epigenetics refers to heritable changes in gene expression is now recognized as a means of silencing tumor
that, unlike mutations, are not attributable to alterations suppressor genes with effects similar to those of mutation
in genomic DNA sequences. Epigenetic changes, such or allelic loss in the development of cancer or other
as DNA methylation, histone modifi cations, and altered diseases. Another DNA methylation alteration in
[3]
expression of microRNAs, can regulate gene expression human cancer is genome-wide DNA hypo-methylation.
[5]
through mechanisms other than changes in genomic Genome-wide DNA hypo-methylation appears to play
DNA sequence. Among them, genomic DNA methylation an important role in genomic instability, leading to
is a major epigenetic mechanism to mediate the cancer development. [6-8] Previous experimental studies
X-chromosome inactivation, imprinting and repression demonstrated that DNA hypo-methylation of repetitive
of endogenous retroviruses. [1-4] DNA methylation is sequences, that is, short interspersed transposable
the covalent post-replicative addition of a methyl elements (SINE or Alu elements) or long interspersed
group (-CH ) to the 5-carbon of the cytosine ring in
3 transposable elements (LINEs) may predispose cells to
CpG dinucleotides. CpG dinucleotides are non-uniformly chromosomal defects and rearrangements, resulting in
distributed throughout the human genome. [2-4] Regions genetic instability. As LINE-1 constitutes a substantial
[6]
of the genome that are rich in sequences of a cytosine portion (approximately 17%) in the human genome,
preceding a guanine (CpG dinucleotide) are known as
CpG islands, which in particular, exist in the promoter levels of LINE-1 methylation are regarded to be
[9]
regions of approximately half of all coding genes. surrogate markers for global DNA methylation. Thus,
epigenetic regulation of gene expression has emerged
Altered DNA methylation in human cancers includes as a fundamental way in pathogenesis of numerous
hypermethylation of site-specifi c CpG island malignancies, including cancers of the digestive system.
promoter and global DNA hypo-methylation. [1-4] DNA
methylation in gene promoter CpG islands results This is an open access article distributed under the terms of the Creative
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Website: For reprints contact: reprints@medknow.com
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How to cite this article: Shigaki H, Baba Y, Harada K, Yoshida N,
Watanabe M, Baba H. Epigenetic changes in gastrointestinal cancers.
DOI: J Cancer Metastasis Treat 2015;1:113-22.
10.4103/2394-4722.166991
Received: 13-07-2015; Accepted: 01-09-2015.

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