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DNA alkylation and DNA methylation: cooperating mechanisms driving the formation of colorectal adenomas and adenocarcinomas?
  1. William M Grady1,
  2. Cornelia M Ulrich2
  1. 1Clinical Research Division, Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington Medical School, Seattle, Washington, USA, and R&D Service, VA Puget Sound Health Care System, USA
  2. 2Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Department of Epidemiology, University of Washington, Seattle, Washington, USA
  1. Correspondence to:
    Dr William M Grady
    Fred Hutchinson Cancer Research Center 1100 Fairview Ave N, D4-100, Seattle, WA 98109, USA; wgrady{at}fhcrc.org

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Defining our understanding of the association between DNA alkylation and colon carcinogenesis

Colorectal cancer has been called a disease of the somatic genome based on the fact that numerous somatic mutations have been identified in colorectal cancer, and these mutations have been shown to play a functional role in driving the formation of these cancers.1,2 More recently, a wealth of studies have implicated alterations in the epigenome, particularly aberrant CpG island DNA methylation, as also being important in cancer formation.3–5 Hence colorectal cancer is a disease that directly results from the serial accumulation of genetic alterations (for example, mutations in genes such as APC, KRAS and TP53) and epigenetic alterations (for example, aberrant methylation of MLH1 and CDKN2A, etc.) in an evolving clone of colon epithelial cells, which in aggregate leads to the initiation and progression of neoplasms along a polyp to cancer progression sequence.6

In order to appreciate the significance of the epigenetic alterations in colorectal cancer, it is helpful to understand the nature of epigenetics. Epigenetics refers to heritable modifications to DNA that regulate gene expression. These heritable modifications are essentially amendments or chemical modifications to the DNA that include methylation of cytosine in CpG dinucleotides that are located in CpG islands, which are regions of DNA that have a high content of cytosines and guanines. The epigenetic status of the gene determines whether or not the gene can be expressed. Epigenetic regulation of genes normally plays a role in controlling cell differentiation, X chromosome inactivation and imprinting but is aberrant in cancer.

With regard to the factors that induce the genetic and epigenetic alterations observed in colorectal cancers, both endogenous cellular processes and environmental exposures play a role. The environmental factors that induce the formation of cancer have been the …

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