DNA methylation in breast and colorectal cancers

Abstract

DNA methylation is one of several epigenetic changes observed in cells. Aberrant methylation of tumor suppressor genes, proto-oncogenes, and vital cell cycle genes has led many scientists to investigate the underlying cellular mechanisms of DNA methylation under normal and pathological conditions. Although DNA methylation is necessary for normal mammalian embryogenesis, both hypo-and hypermethylation of DNA are frequently observed in carcinogenesis and other pathological disorders. DNA hypermethylation silences the transcription of many tumor suppressor genes, resulting in immortalization of tumor cells. The reverse process, demethylation and restoration of normal functional expression of genes, is augmented by DNA methylation inhibitors. Recent studies suggest that DNA hypomethylation may also control gene expression and chromosomal stability. However, the roles of and relationship between hypomethylation and hypermethylation are not well understood. This review provides a brief overview of the mechanism of DNA methylation, its relationship to extrinsic stimulation including dietary intake and aging, and of abnormally methylated DNA in breast and colorectal cancers, which could be used as prognostic and diagnostic markers.

CpG island methylator phenotype-low (CIMP-low) colorectal cancer shows not only few methylated CIMP-high-specific CpG islands, but also low-level methylation at individual loci

“…Transcriptional inactivation of tumor suppressor genes by promoter CpG island methylation is an important mechanism in human carcinogenesis. 2,[34][35][36][37][38] To measure the degree of DNA methylation, we used quantitative PCR assays (MethyLight), 20 which is essential to reproducibly differentiate low-level methylation from high-level methylation. 21,24 Our resource of a large number of samples of colorectal cancer (relatively unbiased samples compared to retrospective or single-hospital-based samples), derived from two large prospective cohorts, has enabled us to precisely estimate the frequency of low-level CpG island methylation in colorectal cancers at a population level.…”

WRN promoter methylation possibly connects mucinous differentiation, microsatellite instability and CpG island methylator phenotype in colorectal cancer

“…[12][13][14][15] A number of tumor suppressor genes are silenced by promoter methylation in colorectal cancers. 12,13 A subset of colorectal cancers exhibit widespread promoter CpG island methylation, which is referred to as the CpG island methylator phenotype (CIMP).…”

“…[12][13][14][15] A number of tumor suppressor genes are silenced by promoter methylation in colorectal cancers. 12,13 A subset of colorectal cancers exhibit widespread promoter CpG island methylation, which is referred to as the CpG island methylator phenotype (CIMP). 16 CIMP-high colorectal tumors have a distinct clinical, pathologic, and molecular profile, such as associations with proximal tumor location, female sex, poor differentiation, microsatellite instability (MSI), and high BRAF and low TP53 mutation rates.…”

Methylation of specific CpG sites in the P2 promoter ofparathyroid hormone-related proteindetermines the invasive potential of breast cancer cell lines

“…DNA methylation changes play an important role during breast tumorigenesis and a large number of targets for abnormal DNA methylation patterns have been identified including both genes whose promoters get hypermethylated during carcinogenesis as well as genes that display hypomethylation. 36,37 It is not known how epigenetic modifications influence PTHrP expression in normal cells and how this may change in cancers derived from specific cell types. We investigated whether location or extent of increased DNA methylation was related to promoter usage and whether the gene methylation status of PTHrP correlated with promoter usage during progression of breast tumorigenesis using a well described model system.…”