Epigenetics and Colorectal Cancer Pathogenesis

Abstract

Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.

Long non-coding RNAs in colorectal cancer: implications for pathogenesis and clinical application

“…[40][41][42] This disease-specific focus has identified novel oncogenic drivers, and the genes contributing to functional change, 43 importantly, revealed that different molecular features contribute to individual differences that occurred in clinicopathological characteristics, disease behavior, prognosis, and response to treatments, which thus helped to establish definitions of molecular subtypes and identified new biomarkers on the basis of omic alterations. [44][45][46] It is now well known that some CRC cases are linked to some factors, such as environment, 47 inflammation, 48,49 immunity, 50 and epigenetic alterations 51,52 rather than heritable genetic changes. An interesting thing is that these factors can influence each other, for instance, epigenetic aberrations induced by environmental factors contribute to cancer processes; 53 interaction of drug and molecular characteristics can influence lncRNAs and clinical outcome; 46,54,55 and epigenetic factors such as lncRNAs can also coordinate cellular responses to environment in turn.…”

Colorectal cancer in the young, many questions, few answers

“…Since RAS proteins control signaling in cell differentiation and apoptosis, disruption of such pathways will lead to neoplastic transformation. CINassociated tumours comprise 75% to 80% of all tumours found in Western populations [54] .…”

Methylation status of the APC and RASSF1A promoter in cell-free circulating DNA and its prognostic role in patients with colorectal cancer

“…There is, therefore, an urgent requirement for non-invasive, novel molecular biomarkers that could be useful in diagnosis and could also improve prognosis and treatment prediction. The accumulation of in vitro and in vivo evidence suggests that epigenetics exerts a fundamental role in CRC pathogenesis (4). The best known and more frequent epigenetic alteration is DNA methylation, which affects tumor suppressor genes that may be involved in cell cycle control, DNA repair, metabolism of carcinogens, cell-cell interaction, apoptosis and angiogenesis (5).…”