Gastroenterology

Gastroenterology

Volume 127, Issue 5, November 2004, Pages 1578-1588
Gastroenterology

Special reports and reviews
CpG island methylation in gastroenterologic neoplasia: A maturing field

https://doi.org/10.1053/j.gastro.2004.09.007Get rights and content

Fifteen years after the first demonstration of epigenetic tumor-suppressor gene inactivation associated with promoter methylation, the field has reached a level of understanding that threatens a rewriting of established biologic concepts. In gastrointestinal malignancies, epigenetic analysis has led to novel hypotheses regarding the etiology of age-associated cancer susceptibility and the interactions between environmental exposures and neoplasia. Methylation profiling has uncovered a distinct pathway to colorectal neoplasia that may arise from a hitherto underestimated precursor lesion, the proximal hyperplastic polyp-serrated adenoma pathway. Epigenetic information has shown promise in clarifying susceptibility to cancer and defining poor prognosis groups in gastrointestinal cancers. Finally, the field has engendered renewed interest in therapeutic targeting of epigenetic regulatory molecules, and several such drugs are currently in clinical trials. It is likely that epigenetic pathways will be integrated in the routine management of gastrointestinal malignancies over the next decade.

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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      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.

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    Research in the author’s laboratory was supported by NIH grants CA41108 and CA89245 (to J.P.J.I.).

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