Promoter CpG island methylation in colorectal cancer: Biology and clinical applications

Sarah Derks, Manon van Engeland

Research output: Chapter in Book / Report / Conference proceedingChapterAcademicpeer-review

1 Citation (Scopus)

Abstract

Introduction Colorectal cancer (CRC) is the third leading cause of cancer death in both the USA and Europe and incidence and mortality rates are still on the rise (Parkin et al., 2005). Colorectal cancers are thought to arise from pluripotent stem cells located in intestinal crypts which can develop into aberrant crypt foci (ACF) (Humphries and Wright, 2008) and premalignant adenomas of which about 5–6% will develop into a carcinoma with invasive and metastatic potential (Hermsen et al., 2002). Steps that transform normal epithelium into adenomas and carcinomas were first described in the model of Fearon and Vogelstein in 1988 (Fearon and Vogelstein, 1990). In this model CRC was considered mainly a genetic disease characterized by accumulating abnormalities such as TP53 (Baker et al., 1989), KRAS (Bos et al., 1987), and APC (Nakamura et al., 1991) mutations and allelic deletions of chromosomes 5, 17, and 18 (Fearon and Vogelstein, 1990). In the following years it became apparent that CRC is a heterogeneous disease. About 85% of CRCs can be characterized by a condition of aneuploidy and an increased rate of loss of heterozygosity (LOH) which occurs in a non-random pattern of associated genomic changes (Hermsen et al., 2002; Douglas et al., 2004). The remaining 15% of CRCs are characterized by a defective mismatch repair (MMR) which is commonly achieved by DNA hypermethylation of the DNA mismatch repair gene MHL1 in sporadic CRCs (Cunningham et al., 1998; Herman et al., 1998). Defective mismatch repair leads to accumulating frameshift mutations at simple repeated nucleotide sequences affecting genes such as TGFβRII, IGFIIR, and BAX, thereby leading to a mutator phenotype (Parsons et al., 1995; Malkhosyan et al., 1996; Souza et al., 1996; Rampino et al., 1997).

Original languageEnglish
Title of host publicationEpigenomics
Subtitle of host publicationFrom Chromatin Biology to Therapeutics
PublisherCambridge University Press
Pages306-322
Number of pages17
ISBN (Electronic)9780511777271
ISBN (Print)9781107003828
DOIs
Publication statusPublished - 1 Jan 2012

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