Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers

Abstract

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.

Keywords: DNA Methylation; Histone Modification; Long Noncoding RNA; MicroRNA.

Figure 1

A historical perspective illustrating key milestones associated with the discovery of various epigenetic alterations in colorectal cancer from 1983 to the present. Individual epigenetic alterations are listed in color-coded boxes; aberrant DNA methylation (red), non-coding RNAs including microRNAs (green), and histone modifications (yellow).

Figure 2

An illustration of various epigenetic alterations in colorectal cancer. A) This figure illustrates the concept of aberrant DNA hypermethylation in the context of a “cancer cell”. Double helix DNA represents a tumor suppressor gene, with CpG islands and CpG shores in its promoter region. Hypermethylation of CpG sites (shown as black lollipops) leading to gene silencing and closed chromatin in the cancer cells is shown. In contrast, CpG dinucleotides within introns as well as in intergenic regions are frequently hypomethylated, which may lead to the increased expression of oncogenes and oncomiRNAs, and resulting open chromatin conformation. B) This figure illustrates histone modifications in a cancer cell. The left panel depicts heterochromatin, which is a closed chromatin conformation that is often associated with DNA methylation and inactive gene transcription. In contrast, the euchromatin state is in an open conformation and associates with active gene transcription, presumably secondary to increased transcription factor binding. C) A schematic demonstrating miRNA biogenesis in cancer cells and how miRNAs inhibit and/or cause degradation of their mRNA targets. D) This figure illustrates various activities of long-noncoding RNAs (lncRNAs) in cancer cells, including i) their ability to regulate chromatin conformation; ii) induce transcription by binding to appropriate transcription factors; iii) function as decoy and inhibit gene transcription; iv) act as miRNA sponges; v) cause mRNA decay and vi) induce mRNA translation.

Figure 3

A schematic view of bench-to-bedside aspects of colorectal cancer epigenetics. This figure illustrates how a normal colonic epithelium undergoes a series of genetic and epigenetic alterations and transitions into an adenomatous polyp (via the “traditional pathway), or a serrated polyp (via the “serrated pathway’). Thereafter, these polyps acquire additional epigenetic alterations and genetic alterations and develop into primary CRCs. This normal-polyp-cancer multi-step cascade is governed by the acquisition of gene mutations and epigenetic alterations, including aberrant DNA methylation and dysregulated expression of several miRNAs. The molecular alterations during each step of colorectal cancer development can be measured in tissues (tissue-based biomarkers), as well as non-invasively in serum/plasma (blood-based biomarkers) and stool (stool-based biomarkers) and thus have potential to be diagnostic, prognostic and predictive biomarkers for colorectal cancer.