Biochemical and Biophysical Research Communications
ReviewDNA methylation and microRNA biomarkers for noninvasive detection of gastric and colorectal cancer
Introduction
Cancer is a major health problem in most developed nations worldwide. Within the gastrointestinal tract, gastric cancer (GC) and colorectal cancer (CRC), represent the two most frequent malignancies. Even though the incidence of GC has declined rapidly in recent decades, GC remains the fourth most common cancer and the second leading cause of cancer-related deaths in the world [1]. Likewise, CRC is the third most common cancer worldwide, with an estimated incidence of more than 1.2 million cases globally [2]. An estimated 608,000 deaths from CRC occur worldwide each year, accounting for 8% of all cancer deaths, making it the fourth most common cause of cancer-related deaths [2]. Both GC and CRC are characterized by relatively rapid progression of the disease and late clinical presentation, which is primarily the underlying reason for increased mortality and morbidity in patients suffering from these malignancies. Both diseases are largely preventable if these can be identified at early stages. However, in order to identify patients with an early stage disease, availability of robust diagnostic biomarkers could tremendously help in reducing overall mortality rates [3]. Additionally, in spite of more frequent use of highly sophisticated and sensitive imaging techniques for the diagnosis of GC and CRC, there is a significant amount of interest in developing inexpensive, highly sensitive and specific, and non-invasive biomarkers that could potentially also be useful for the prognosis and surveillance of these patients.
Cancer, which was earlier thought to be mostly a ‘genetic’ disease, is now being recognized to involve frequent and widespread ‘epigenetic’ abnormalities. It is also becoming apparent that microenvironment-mediated epigenetic perturbations play an important role in the development of neoplasia [4]. Epigenetics refers to the study of heritable changes in gene expression that are not attributed to permanent changes in DNA sequence itself, but are sufficiently powerful to regulate the dynamics of gene expression [5]. The principal processes responsible for epigenetic regulation include DNA methylation, histone modifications and posttranscriptional gene regulation through non-coding RNAs (microRNAs, long non-coding RNAs, small nucleolar RNAs etc) [6]. These mechanisms are critical components in the normal development and growth of cells and perturbations in these epigenetic expression patterns contribute to specific and diverse neoplastic phenotypes [7].
Epigenetic alterations are believed to occur early in tumor development and may precede genetic changes, thus providing a rationale for developing molecular biomarkers for the early diagnosis and disease prevention [8]. The emergence of advanced technologies that now allow detection of genome-wide epigenetic changes provide ample promise for advancing our capacity to develop such biomarkers for detecting cancers at an early stage [9]. DNA methylation, which is a result of the covalent addition of a methyl group at the 5′ position of the pyrimidine ring of cytosines within the context of CpG dinucleotides, is important in maintaining the genomic structure and regulation of gene expression [10]. Non-coding RNAs, such as microRNAs (miRNAs), regulate gene expression by inhibiting or inactivating target messenger RNAs (mRNAs). Of interest, a single miRNA can bind to several target mRNAs, making them more attractive and ideal from biomarker development viewpoint. Recent reports have shown that methylated DNA and miRNAs could be readily detected in a wide variety of tissues, as well as various body fluids, indicating that these epigenetic biomarkers could represent the next generation of biomarkers for cancer detection. In this review, we provide an overview of recent advances in epigenetics and discuss the development of DNA methylation and miRNA biomarkers for the identification of patients with GC and CRC (Fig. 1).
Section snippets
Overview of DNA methylation
The most widely studied epigenetic alteration in humans is DNA methylation. Aberrant DNA methylation contributes to cancer mainly through DNA hyper- or hypo-methylation. While DNA hypermethylation refers to the gain of methylation at a locus that was originally not methylated and usually results in stable transcriptional silencing and reduced gene expression [11], DNA hypomethylation represents the loss of DNA methylation, affecting chromosomal stability and enhanced aneuploidy [12]. Global DNA
Methods to detect DNA methylation in body fluids
The collection of body fluids is a relatively noninvasive procedure, which enables early cancer detection or monitoring of minimally recurrent disease after treatment. For gastrointestinal cancers, typical body fluids include plasma or serum from blood, as well as organ-specific fluids, such as gastric juice and fecal specimens. In contrast to rare genetic mutations, analysis of DNA methylation biomarkers in bodily fluids is a far more compelling strategy as it allows early detection of
Overview of non-coding RNAs
The central dogma of gene expression is that DNA is transcribed into mRNA, which then serves as the template for protein synthesis. [125], [126]. Extensive research over the last few decades has focused on the role of protein-coding genes in the pathogenesis of human cancer. However, recent technological advances, such as tiling arrays and RNA sequencing (RNA-seq), have made it possible to survey the transcriptomes of many organisms to an unprecedented degree, the results of which have led to
MiRNA stability and function in body fluids
The development of any biological molecules as biomarkers that can be potentially evaluated in human specimens depends on their stability and resistance to storage and handling. RNase, present in body fluids such as blood, rapidly degrades RNA molecules, particular mRNA, and thus affects their stability [133]. As a result, the development of RNA-based molecular biomarkers has been challenging in the last couple of decades. In contrast, endogenous miRNAs in serum or plasma have been shown to
Conclusions and perspectives
In recent years, the role of epigenetic alterations in carcinogenesis has received greater attention than before. After the initial elucidation of the fundamental role of epigenetic changes in human carcinogenesis, considerable efforts have been dedicated to the identification and development of epigenetic biomarkers for cancer detection, disease monitoring for tumor recurrence and prognostic outcomes [9], [181]. The presence of cell-free methylated-DNA and miRNAs in circulation provide a
Funding
The present work was supported by Grants R01 CA72851, CA181572 and CA184792 from the National Cancer Institute, National Institutes of Health, a pilot grant from the Charles A Sammons Cancer Center, and funds from the Baylor Research Institute.
References (194)
- et al.
Epigenetic alterations as cancer diagnostic, prognostic, and predictive biomarkers
Adv. Genet.
(2010) - et al.
DNA methylation
Blood
(1999) - et al.
Methylation of promoter proximal-transcribed sequences of an embryonic globin gene inhibits transcription in primary erythroid cells and promotes formation of a cell type-specific methyl cytosine binding complex
J. Biol. Chem.
(2002) - et al.
How does DNA methylation repress transcription?
Trends Genet.
(1997) - et al.
A model for gastric cancer epidemiology
Lancet
(1975) - et al.
Profile of aberrant CpG island methylation along the multistep pathway of gastric carcinogenesis
Lab. Invest.
(2003) - et al.
Promoter hypermethylation of multiple genes in early gastric adenocarcinoma and precancerous lesions
Hum. Pathol.
(2009) - et al.
Lessons from hereditary colorectal cancer
Cell
(1996) - et al.
Genetics supersedes epigenetics in colon cancer phenotype
Cancer Cell
(2003) - et al.
Hypomethylation of ras oncogenes in primary human cancers
Biochem. Biophys. Res. Commun.
(1983)
Epigenetic biomarkers of colorectal cancer: focus on DNA methylation
Cancer Lett.
Mutant KRAS in aberrant crypt foci (ACF): initiation of colorectal cancer?
Biochim. Biophys. Acta
CpG island methylation in aberrant crypt foci of the colorectum
Am. J. Pathol.
CpG island methylator phenotypes in aging and cancer
Semin. Cancer Biol.
Improving early breast cancer detection: focus on methylation
Ann. Oncol.
Gastric cancer
Lancet
Hypermethylated DNA as potential biomarkers for gastric cancer diagnosis
Clin. Biochem.
Aberrant methylation of the CpG island of HLTF gene in gastric cardia adenocarcinoma and dysplasia
Clin. Biochem.
Sensitive and specific detection of early gastric cancer with DNA methylation analysis of gastric washes
Gastroenterology
Recent patterns in gastric cancer: a global overview
Int. J. Cancer
Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008
Int. J. Cancer
MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review
EMBO Mol. Med.
An operational definition of epigenetics
Genes Dev.
Epigenetics and human disease: translating basic biology into clinical applications
CMAJ
Epigenetic aberrations and cancer
Mol Cancer
Epigenetics and cancer
J. Appl. Physiol.
Gene-promoter hypermethylation as a biomarker in lung cancer
Nat. Rev. Cancer
Biochemistry and biology of mammalian DNA methyltransferases
Cell. Mol. Life Sci.
Epigenetic events in gastrointestinal cancer
Am. J. Gastroenterol.
Induction of tumors in mice by genomic hypomethylation
Science
Alu and Satalpha hypomethylation in Helicobacter pylori-infected gastric mucosae
Int. J. Cancer
The fundamental role of epigenetic events in cancer
Nat. Rev. Genet.
DNA methylation patterns and epigenetic memory
Genes Dev.
Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation
Nature
Comprehensive analysis of CpG islands in human chromosomes 21 and 22
Proc. Natl. Acad. Sci. USA
Analysis of promoter CpG island hypermethylation in cancer: location, location, location!
Clin. Cancer Res.
Cancer epigenetics reaches mainstream oncology
Nat. Med.
Epigenetics in cancer
N. Engl. J. Med.
Transcription of IAP endogenous retroviruses is constrained by cytosine methylation
Nat. Genet.
How epigenetics integrates nuclear functions. Workshop on epigenetics and chromatin: transcriptional regulation and beyond
EMBO Rep.
An evaluation of new criteria for CpG islands in the human genome as gene markers
Bioinformatics
DNA methylation landscapes: provocative insights from epigenomics
Nat. Rev. Genet.
The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. an attempt at a histo-clinical classification
Acta Pathol. Microbiol. Scand.
Hereditary diffuse gastric cancer: a manifestation of lost cell polarity
Cancer Sci.
Epigenetic mechanisms in gastric cancer
Epigenomics
Helicobacter pylori and EBV in gastric carcinomas: methylation status and microsatellite instability
World J. Gastroenterol.
Global DNA hypomethylation is an early event in Helicobacter pylori-related gastric carcinogenesis
J. Clin. Pathol.
High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk
Clin. Cancer Res.
DNA methylation as a marker for the past and future
J. Gastroenterol.
Helicobacter pylori and epigenetic mechanisms underlying gastric carcinogenesis
Dig. Dis.
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2021, Food BioscienceCitation Excerpt :CRC affects the lower gastrointestinal tract and involves two major sites; the malignancy in the inner wall of the colon (CC) that constitutes the most of all CRC cases, and rectal cancer (RC) located within 12 cm or less from the anal verge (Dong et al., 2014). Late clinical symptoms and rapid progression are two important characteristics of CRC, which both are responsible for increased morbidity and mortality in patients with CRC (Toiyama et al., 2014). There are different factors contributed to CRC risk, including non-modifiable risk factors like; age and hereditary factors, and modifiable risk factors (environmental risk factors) like; nutritional factors (high fat, high red and processed meat and low fiber diet), low physical activity, obesity, cigarette smoking and heavy alcohol consumption (Chen, C. C. et al., 2012).