Special reports and reviewsCpG island methylation in gastroenterologic neoplasia: A maturing field
Section snippets
DNA methylation in cancer
DNA methylation changes in paradoxical directions in neoplastic cells.4 Global decreases in 5-methylcytosine content (hypomethylation) have been associated with tumorigenesis,5 including colon cancer.6 These decreases have been proposed to lead to genetic instability,7 and mouse models show tissue-specific increased tumor formation associated with profound hypomethylation.8, 9 It is not clear whether this degree of hypomethylation is relevant to human tumorigenesis, where decreases of 10%–20%
Aging and methylation
In the colon, studies of methylation in cancer unexpectedly revealed a hitherto unknown aspect of DNA aging. Careful quantitative studies showed that many genes highly methylated in cancer also have a low but measurable degree of methylation in apparently normal colon mucosa, and this methylation increases linearly with age.18, 19 This has led to the proposal that, in colon tumors, methylated genes fall in 2 categories termed type A and type C.20 Methylation of type A genes such as ERα, N33,
New genes and pathways inactivated in association with CpG island methylation
With the realization of the important role of methylation-associated silencing in cancer, a number of groups have isolated new genes and pathways inactivated by this mechanism in gastroenterologic (GI) cancers. Using either methylation-based screening techniques such as methylated CpG island amplification31, 32 or gene expression/reactivation-based techniques,33, 34, 35 over 20 genes have recently been identified as silenced in GI cancers. These include transcription factors, genes involved in
Methylation and exposures
There is both direct and indirect evidence supporting a role for lifestyle and environmental exposures in the development of epigenetic alterations in normal and neoplastic tissues. The tissue specificity of the process described above suggests a potential role for tissue-specific exposures in modulating methylation patterns. Indeed, marked geographic variation in the rate of DNA methylation in hepatocellular cancer could be traced to differences in exposures (viruses, aflatoxin, alcohol, and
CpG island methylator phenotype
Recently, a distinct pathway of colorectal carcinogenesis was described,20 termed CpG island methylator phenotype (CIMP). This pathway was uncovered through a series of observations that included (1) association between microsatellite instability and hypermethylation of multiple genes in colorectal60 and gastric cancer,15 (2) concordance between the methylation status of different genes in colorectal cancer20 (and other cancers61) that was unrelated to gene function or chromosomal location, and
CpG island methylation in precursors of GI cancers
Colorectal adenomas are precursors of most adenocarcinomas, and methylation in colorectal adenomas has been reported.20, 72 Methylation was more common in larger adenomas and adenomas with villous histology. Aberrant crypt foci are the “putative” earliest morphologic lesions identified in the colorectum. Methylation was present in aberrant crypt foci and was more common in sporadic aberrant crypt foci than familial adenomatous polyposis-associated aberrant crypt foci.88, 89 Colorectal
Methylation and genetic alterations
DNA methylation and genetic changes have intricate associations in malignancies of the GI tract. A straightforward association revolves around epigenetic inactivation of DNA repair genes, resulting in characteristic genetic changes. For example, MLH1 silencing in colorectal cancer results in mismatch repair deficiency104 and characteristic mutations in TGFBRII and other genes. O6-methylguanine DNA methyltransferase, a DNA repair protein that removes alkyl groups and adducts at the O6 position
The methylation and chromatin waltz
DNA methylation was suggested several decades ago to affect gene expression through altering chromatin states, but it has only been recently that the molecular mechanisms involved have been clarified. A seminal observation was the finding that dense DNA methylation results in local histone deacetylation through recruitment of a protein complex that includes histone deacetylases and other chromatin modifiers.109, 110, 111 This recruitment is targeted to hypermethylated promoters by
Clinical applications
The field of epigenetic alterations in cancer has raised significant clinical questions that are being tested in GI malignancies. DNA methylation markers have been proposed for risk assessment, early detection, determination of prognosis, and as therapeutic targets.128
For risk assessment, the hypothesis has been that measuring DNA methylation in normal tissues (e.g., colorectal biopsies) could predict for the risk of developing colorectal adenomas or cancer.125, 129 Support for this comes from
Conclusions
Research into epigenetic changes in GI malignancies has opened fascinating new windows related to the etiology and molecular pathways that lead to neoplastic transformation. The concept that epigenetic changes could be a parallel and potentially equal pathway to genetic changes in driving clonal selection has profound epidemiologic and clinical implications45 and, not unexpectedly, has generated controversy.83, 116 Healthy arguments notwithstanding, some of these clinical applications are in
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Methylator phenotype in colorectal cancer: A prognostic factor or not?
2016, Critical Reviews in Oncology/HematologyAge at onset should be a major criterion for subclassification of colorectal cancer
2014, Journal of Molecular DiagnosticsHelicobacter pylori causes epigenetic dysregulation of FOXD3 to promote gastric carcinogenesis
2013, GastroenterologyCitation Excerpt :Although aberrant promoter methylation modulates gene expression, hypomethylation of the global genome, mainly in the repetitive sequences, can induce genomic instability.12,37 The epigenetic abnormalities in distinct genomic compartments of different cell types are believed to collectively promote Helicobacter-associated gastric carcinogenesis.11,12 In our analysis of primary human tissues, there was a significant increase in the FOXD3 methylation level along Correa's cascade of gastric carcinogenesis.
In Silico Gene Prioritization Highlights the Significance of Bone Morphogenetic Protein 4 (BMP4) Promoter Methylation across All Methylation Clusters in Colorectal Cancer
2023, International Journal of Molecular SciencesRecognition of DNA Methylation Molecular Features for Diagnosis and Prognosis in Gastric Cancer
2021, Frontiers in Genetics
Research in the author’s laboratory was supported by NIH grants CA41108 and CA89245 (to J.P.J.I.).