Accumulation of aberrant DNA methylation during colorectal cancer development

Abstract

Despite the recent advances in the therapeutic modalities, colorectal cancer (CRC) remains to be one of the most common causes of cancer-related death. CRC arises through accumulation of multiple genetic and epigenetic alterations that transform normal colonic epithelium into adenocarcinomas. Among crucial roles of epigenetic alterations, gene silencing by aberrant DNA methylation of promoter regions is one of the most important epigenetic mechanisms. Recent comprehensive methylation analyses on genome-wide scale revealed that sporadic CRC can be classified into distinct epigenotypes. Each epigenotype cooperates with specific genetic alterations, suggesting that they represent different molecular carcinogenic pathways. Precursor lesions of CRC, such as conventional and serrated adenomas, already show similar methylation accumulation to CRC, and can therefore be classified into those epigenotypes of CRC. In addition, specific DNA methylation already occurs in the normal colonic mucosa, which might be utilized for prediction of the personal CRC risk. DNA methylation is suggested to occur at an earlier stage than carcinoma formation, and may predict the molecular basis for future development of CRC. Here, we review DNA methylation and CRC classification, and discuss the possible clinical usefulness of DNA methylation as biomarkers for the diagnosis, prediction of the prognosis and the response to therapy of CRC.

Keywords: Aberrant crypt foci; Colorectal adenoma; Colorectal cancer; Colorectal carcinogenesis; DNA methylation; Epigenotype; Genetic mutation.

Figure 1

Carcinogenetic pathway and classification of colorectal cancer. Colorectal cancer (CRC) arises through accumulation of multiple acquired genetic and epigenetic alterations. Adenomas and CRCs can be classified into several sub-groups based on the status of DNA methylation and associated genetic mutations, suggesting that the different types of CRC developed through different molecular carcinogenetic pathways. DNA methylation accumulation occurs during aberrant cell expansion and is usually completed at adenoma stage. Non-polypoid colorectal neoplasms are hypothesized to develop through de novo pathway, whereas the epigenetic features of laterally spreading tumors have not yet been fully investigated.