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World J Gastroenterol. Jan 28, 2014; 20(4): 978-987
Published online Jan 28, 2014. doi: 10.3748/wjg.v20.i4.978
Accumulation of aberrant DNA methylation during colorectal cancer development
Eiji Sakai, Atsushi Nakajima, Atsushi Kaneda
Eiji Sakai, Atsushi Nakajima, Department of Gastroenterology, Yokohama City University School of Medicine, Yokohama 236-0027, Japan
Eiji Sakai, Atsushi Kaneda, Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 113-8654, Japan
Atsushi Kaneda, Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
Atsushi Kaneda, CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan
Author contributions: Sakai E and Kaneda A wrote the manuscript; Nakajima A and Kaneda A supervised the study.
Correspondence to: Atsushi Kaneda, MD, PhD, Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba-City 260-8670, Japan. kaneda@chiba-u.jp
Telephone: +81-43-2262039 Fax: +81-43-2262039
Received: September 28, 2013
Revised: November 12, 2013
Accepted: December 12, 2013
Published online: January 28, 2014
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: Colorectal cancer, Colorectal adenoma, Aberrant crypt foci, Genetic mutation, Epigenotype, DNA methylation, Colorectal carcinogenesis

Core tip: Colorectal cancer (CRC) is a heterogeneous disease which involves several distinct molecular carcinogenetic pathways. Recent comprehensive genome-wide analyses clarify detailed DNA methylation statuses of cancer-related genes in CRC. We and others have investigated the association between DNA methylation and genetic alterations, and performed classification of CRC/their precursors, including conventional adenomas, serrated adenomas, non-polypoid colorectal neoplasms and aberrant crypt foci. In addition, we also evaluated the usefulness of DNA methylation markers as surrogate biomarkers for diagnosis, prognosis and therapeutic application of CRC. Here, we review the DNA methylation status and classification of CRC to understand the roles of DNA methylation in colorectal carcinogenesis.