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      Field cancerization in the colon: a role for aberrant DNA methylation?

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          Abstract

          Colorectal cancer is the third most common cancer worldwide and arises secondary to the progressive accumulation of genetic and epigenetic alterations in normal colon cells, which results in a polyp-to-cancer progression sequence. It is known that individuals with a personal history of colon adenomas or cancer are at increased risk for metachronous colon neoplasms. One explanation for this increased risk could be field cancerization, which is a phenomenon in which the histologically normal tissue in an organ is primed to undergo transformation. Epigenetic alterations appear to be promising markers for field cancerization. In this review, we discuss field cancerization in the colon and the data supporting the use of methylated DNA as a biomarker for this phenomenon.

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          Most cited references37

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          Cancer genes and the pathways they control.

          The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease. In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. The purposes of this review are to highlight examples of progress in these areas, indicate where knowledge is scarce and point out fertile grounds for future investigation.
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            Epigenetics and colorectal cancer.

            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.
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              Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.

              The recessive autosomal disorder known as ICF syndrome (for immunodeficiency, centromere instability and facial anomalies; Mendelian Inheritance in Man number 242860) is characterized by variable reductions in serum immunoglobulin levels which cause most ICF patients to succumb to infectious diseases before adulthood. Mild facial anomalies include hypertelorism, low-set ears, epicanthal folds and macroglossia. The cytogenetic abnormalities in lymphocytes are exuberant: juxtacentromeric heterochromatin is greatly elongated and thread-like in metaphase chromosomes, which is associated with the formation of complex multiradiate chromosomes. The same juxtacentromeric regions are subject to persistent interphase self-associations and are extruded into nuclear blebs or micronuclei. Abnormalities are largely confined to tracts of classical satellites 2 and 3 at juxtacentromeric regions of chromosomes 1, 9 and 16. Classical satellite DNA is normally heavily methylated at cytosine residues, but in ICF syndrome it is almost completely unmethylated in all tissues. ICF syndrome is the only genetic disorder known to involve constitutive abnormalities of genomic methylation patterns. Here we show that five unrelated ICF patients have mutations in both alleles of the gene that encodes DNA methyltransferase 3B (refs 5, 6). Cytosine methylation is essential for the organization and stabilization of a specific type of heterochromatin, and this methylation appears to be carried out by an enzyme specialized for the purpose.
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                Author and article information

                Journal
                Gastroenterol Rep (Oxf)
                Gastroenterol Rep (Oxf)
                gastro
                gastro
                Gastroenterology Report
                Oxford University Press
                2052-0034
                February 2014
                13 January 2014
                : 2
                : 1
                : 16-20
                Affiliations
                1Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, P.R. China, 2Gastrointestinal Institute, Sun Yat-Sen University, Guangzhou, P.R. China, 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA and 4Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
                Author notes
                *Corresponding author. Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., D4-100, Seattle, WA 98109, USA. Tel: +1-206-667-1107; Fax: +1-206-667-2917; Email: wgrady@ 123456fhcrc.org
                Article
                got039
                10.1093/gastro/got039
                3920999
                24760232
                a1b36cb8-0bd9-4374-9c9d-6482eb904ae7
                © The Author(s) 2014. Published by Oxford University Press and the Digestive Science Publishing Co. Limited.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 December 2013
                : 23 December 2013
                Page count
                Pages: 5
                Categories
                Reviews

                colorectal cancer,dna methylation,epigenetic alterations,field cancerization

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