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Epigenetics and colorectal cancer

Abstract

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. It results from an accumulation of genetic and epigenetic changes in colon epithelial cells, which transforms them into adenocarcinomas. Over the past decade, major advances have been made in understanding cancer epigenetics, particularly regarding aberrant DNA methylation. Assessment of the colon cancer epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has hundreds to thousands of abnormally methylated genes. As with gene mutations in the cancer genome, a subset of these methylated genes, called driver genes, is presumed to have a functional role in CRC. The assessment of methylated genes in CRCs has also revealed a unique molecular subgroup of CRCs called CpG island methylator phenotype (CIMP) cancers; these tumors have a particularly high frequency of methylated genes. These advances in our understanding of aberrant methylation in CRC have led to epigenetic 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.

Key Points

  • The average colon cancer epigenome has hundreds to thousands of abnormally methylated genes, a subset of which is thought to drive colorectal cancer (CRC) pathogenesis and clinical behavior

  • Alterations in DNA methylation patterns in CRC contribute to the molecular heterogeneity of this cancer, as illustrated by the identification of a CpG island methylator phenotype (CIMP) that has a distinct epigenome

  • Clinical markers for diagnostic, prognostic and therapeutic applications are being developed using the epigenetic alterations and DNA methylation signatures in CRC

  • Although the mechanisms by which aberrant DNA methylation occurs are not yet fully understood, a mechanistic connection might exist between the altered methylation seen in CRC and the phenomena of age-related methylation and field cancerization

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Figure 1: CpG island DNA hypermethylation and global DNA hypomethylation in colorectal cancer as compared with normal colonic epithelium.
Figure 2: Commonly methylated genes (and loci) identified at the histological steps of the colorectal cancer polyp→adenocarcinoma sequence.

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Acknowledgements

This work was supported in part by funds from the FHCRC CCSG (5P30CA015704), Burroughs Wellcome Fund, NCI/EDRN (UO1CA152756) and NCI (U54CA143862, PO1CA077852) (W. M. Grady) and ASCRS (GSRRIG 10) and NIH T32 (T32DK007742-14) (V. V. Lao).

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Lao, V., Grady, W. Epigenetics and colorectal cancer. Nat Rev Gastroenterol Hepatol 8, 686–700 (2011). https://doi.org/10.1038/nrgastro.2011.173

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