Gastroenterology

Gastroenterology

Volume 149, Issue 5, October 2015, Pages 1204-1225.e12
Gastroenterology

Review
Genetics and Genetic Testing
Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers

https://doi.org/10.1053/j.gastro.2015.07.011Get rights and content

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. One of the fundamental processes driving the initiation and progression of CRC is the accumulation of a variety of genetic and epigenetic changes in colonic epithelial cells. Over the past decade, major advances have been made in our understanding of cancer epigenetics, particularly regarding aberrant DNA methylation, microRNA (miRNA) and noncoding RNA deregulation, and alterations in histone modification states. Assessment of the colon cancer “epigenome” has revealed that virtually all CRCs have aberrantly methylated genes and altered miRNA expression. The average CRC methylome has hundreds to thousands of abnormally methylated genes and dozens of altered miRNAs. As with gene mutations in the cancer genome, a subset of these epigenetic alterations, called driver events, are presumed to have a functional role in CRC. In addition, the advances in our understanding of epigenetic alterations in CRC have led to these alterations being developed as clinical biomarkers for diagnostic, prognostic, and therapeutic applications. Progress in this field suggests that these epigenetic alterations will be commonly used in the near future to direct the prevention and treatment of CRC.

Section snippets

Overview of DNA Methylation in Cancer

The most widely studied epigenetic alteration in cancer is aberrant DNA methylation. Although DNA hypermethylation has received the most attention recently, DNA hypomethylation was the first reported DNA methylation abnormality in human cancer (1983).5 As illustrated in Figure 1, at this time global DNA hypomethylation was identified in both colorectal adenomas and CRC.6 It was not until several years later, that Baylin and colleagues identified site-specific hypermethylation of the calcitonin (

Histone Modifications: a Potential Class of CRC Biomarkers

DNA in eukaryotic cells is found in chromatin, which is a complex of macromolecules consisting of DNA, RNA and protein. The primary functions of chromatin are to facilitate DNA compaction, to reinforce the DNA macromolecule during mitosis, to protect against DNA damage, and to control gene expression and DNA replication. The primary protein components of chromatin are histones, which regulate DNA compaction and gene expression. Histones are protein octamers that consist of two copies of four

Noncoding RNA Overview

The central dogma of molecular biology, which describes the sequential transfer of genetic information and the concept that “DNA makes RNA and RNA makes protein”, was developed in 1956 and provided a fundamental framework for modern molecular biology until recently.159 Advances in our understanding of the regulation of gene expression has been provided by the Encyclopedia of DNA Elements Consortium (ENCODE) transcriptome project, which recently revealed that protein-coding genes represent less

Conclusion and Perspectives

Advances in our understanding of the natural history of CRC and the epigenetics of colon polyps and CRC has led to the development of epigenetic biomarker assays for CRC diagnosis, prognosis, and prediction of treatment response (Figure 3). The last two decades of research have demonstrated the potential of aberrant DNA methylation and alterations in noncoding RNAs to be used as biomarkers for colon polyps and CRC. Continued investigation of these promising class of biomarkers promises to lead

Acknowledgements

We thank Drs Shusuke Toden, Wenhao Weng and Timothy Zumwalt, from the Center for Gastrointestinal Research for their advice, suggestions, and tireless efforts in editing and improving the overall quality of this article. We also thank R.A.C.E. Charities for their inspiration and support in biomarker development studies (WMG).

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    Conflicts of interest Dr Grady has limited ownership interest in a patent application for methylated MLH1. Drs Okugawa and Goel disclose no conflicts relevant to this work to report.

    Funding This work was supported by National Institutes of Health/National Cancer Institute grants R01 CA72851, CA181572, CA184792, and U01 CA187956, a Charles A Sammons Cancer Center pilot grant, the Baylor Research Institute (A.G.), NIH grants P30CA15704, UO1CA152756, R01CA194663, U54CA143862, and P01CA077852, the RACE Charities, and a Burroughs Wellcome Fund Translational Research Award for Clinician Scientist (W.M.G.).

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