Review
DNA methylation and microRNA biomarkers for noninvasive detection of gastric and colorectal cancer

https://doi.org/10.1016/j.bbrc.2014.08.001Get rights and content

Highlights

  • Gastric and colorectal cancers are the leading causes of cancer-related deaths.

  • Mortality with these cancers is primarily due to late detection of disease.

  • Availability of early detection biomarkers is desirable in reducing mortality rates.

  • Non-invasive biomarkers are gaining attention for surveillance of these cancers.

  • We provide current state of knowledge on epigenetic-based non-invasive biomarkers.

Abstract

Cancer initiation and progression is controlled by both genetic and epigenetic events. Epigenetics refers to the study of mechanisms that alter gene expression without permanently altering the DNA sequence. Epigenetic alterations are reversible and heritable, and include changes in histone modifications, DNA methylation, and non-coding RNA-mediated gene silencing. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Aberrant epigenetic modifications occur at the earliest stages of neoplastic transformation and are now believed to be essential players in cancer initiation and progression. Recent advances in epigenetics have not only offered a deeper understanding of the underlying mechanism(s) of carcinogenesis, but have also allowed identification of clinically relevant putative biomarkers for the early detection, disease monitoring, prognosis and risk assessment of cancer patients. At this moment, DNA methylation and non-coding RNA including with microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) represent the largest body of available literature on epigenetic biomarkers with the highest potential for cancer diagnosis. Following identification of cell-free nucleic acids in systematic circulation, increasing evidence has demonstrated the potential of cell-free epigenetic biomarkers in the blood or other body fluids for cancer detection. In this article, we summarize the current state of knowledge on epigenetic biomarkers – primarily DNA methylation and non-coding RNAs – as potential substrates for cancer detection in gastric and colorectal cancer, the two most frequent cancers within the gastrointestinal tract. We also discuss the obstacles that have limited the routine use of epigenetic biomarkers in the clinical settings and provide our perspective on approaches that might help overcome these hurdles, so that these biomarkers can be readily developed for clinical management of cancer patients.

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.

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