Relevance of DNA methylation in the management of cancer

doi:10.1016/S1470-2045(03)01115-X

The Lancet Oncology

Volume 4, Issue 6, June 2003, Pages 351-358

https://doi.org/10.1016/S1470-2045(03)01115-X Get rights and content

Summary

Many genetic and environmental factors contribute to development of cancer, but DNA methylation may provide a link between these influences. Genome stability and normal gene expression are largely maintained by a fixed and predetermined pattern of DNA methylation. In cancer, this idealistic scenario is disrupted by an interesting phenomenon: the hyper-methylation of regulatory regions called CpG islands in some tumour suppressor genes—eg, BRCA1, hMLH1, p16INK4a, APC, VHL—which causes their inactivation. Development of new techniques that couple bisulphite modification with PCR has enabled these alterations to be studied in all types of biological fluids and archived tissues. Potentially, there are four types of translational studies that can be used to investigate the aberrant pattern of DNA methylation in cancer. First, CpG island hypermethylation can be used as a marker to identify cancer cells from biological samples, eg, serum and urine. This technique is highly sensitive and informative because profiles of tumour-suppressor-gene inactivation are specific to particular cancers. Second, single and combined genes that are inactivated by promoter hypermethylation, such as p16INK4a and DAPK, can be used as prognostic factors. Third, products of genes that are silenced by DNA methylation can be used as biomarkers of response to chemotherapy or hormone therapy—eg, the DNA repair O6-methylguanine-DNA methyltransferase and the oestrogen receptor. Finally, dormant tumour suppressor genes can be reactivated by DNA demethylating drugs, with the aim of reversing the neoplastic phenotype. These are new avenues worth exploring in the fight against cancer.

Section snippets

Silencing tumour suppressor genes

The particular genes that are hypermethylated in tumour cells are strongly specific to the tissue of origin of the tumour.⁹ We have recently described a profile of hypermethylation among various primary human tumours;⁹ however, we do not currently know why some genes become hypermethylated in specific tumours and others, with similar properties—eg, a typical CpG island, a history of loss of expression in other tumour types, and the absence of mutations—remain free from methylation. We can

Cell cycle

Hypermethlation of the cell-cycle inhibitor p16INK4a, a feature common to many tumours, enables cancer cells to escape senescence and begin to proliferate.11, 12, 13 The retinoblastoma gene (RB) and the cell-cycle inhibitor p15INK4b can also occasionally undergo aberrant methylation.14, 15

p53

Although p53 is the most commonly mutated tumour suppressor gene in human cancer cells, half of all primary cancers have a wild-type gene. However, p53 can also become inactivated through methylation-mediated

Global genomic hypomethylation

When CpG islands become hypermethylated, the genome of the cancer cell undergoes marked global hypomethylation. A malignant cell can contain 20–60% less genomic 5-methylcytosine than its normal counterpart.3, 5 This loss of methyl groups is achieved mainly by hypomethylation of the coding region and introns and demethylation of repetitive DNA sequences,⁵ which account for 20–30% of the human genome. Global hypomethylation contributes to carcinogenesis through three possible mechanisms:

The translational application of epigenetics

Two examples that highlight the advances made in cancer detection and treatment based on the knowledge of the molecular biology of tumours are the development of antibodies against tumours that overexpress the c-ERBB2/neu oncogene in breast cancer and the development of compounds targetting the BCR-ABL translocation in chronic myelogenous leukaemia. Knowledge of CpG island hypermethylation of tumour suppressor genes may be a valuable tool in this essential transfer of research from laboratory

Tumour behaviour

Prediction of tumour behaviour through analysis of biopsy samples is an important goal. Identification of prognostic factors that can provide information about the aggressiveness of a tumour has long been the coveted application of genetic markers. In the past few years, numerous attempts have been made to establish a genetic technique for reliably predicting tumour prognosis, but these attempts have been hindered by two main problems. First, only a few genes are somatically mutated in solid

Predicting treatment response

The most compelling evidence for predicting treatment response is provided by the methylation-associated silencing of O6-methylguanine-DNA methyltransferase. This protein is responsible for the removal of alkyl groups from guanine, which is the preferred point of DNA attack of several alkylating agents used in cancer treatment, such as carmustine, nimustine, procarbazine, streptozotocin, and temozolamide. Thus, tumours which lack function of O6-methylguanine-DNA methyltransferase due to

DNA methylation as a therapeutic target

Since the mid-1980s we have been able to reactivate hypermethylated genes in vitro; however, translating this capability to humans has proved difficult. One obstacle is that the drugs used to demethylate DNA are non-specific, so cannot be used to target particular genes.⁶⁶ Demethylating agents such as 5-aza-cytidine or 5-aza-2 -deoxycytidine inhibit DNA methyltransferases and cause global hypomethylation.⁶⁷ Furthermore, the demethylating effect of 5-aza-2 -deoxycytidine seems to be universal,

Conclusions

Findings from experiments with demethylating drugs have proved attractive to several pharmaceutical and biotechnology companies, who are now using novel approaches, such as antisense constructs, ribozymes, and RNA interference, to target DNA methyltransferases, methyl-binding proteins, or other elements of the methylation machinery. However, the issue of non-specificity still remains. Some companies are tackling the problem by use of gene-therapy-like strategies to reactivate specific

Search strategy and selection criteria

Data for this review were identified by searches of PubMed with the terms “methylation”, “CpG island”, “epigenetic”, and “cancer”. Only papers published in English between 1986 and 2003 were selected.

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View all citing articles on Scopus

View full text

ReviewRelevance of DNA methylation in the management of cancer

Summary

Section snippets

Silencing tumour suppressor genes

Cell cycle

p53

Global genomic hypomethylation

The translational application of epigenetics

Tumour behaviour

Predicting treatment response

DNA methylation as a therapeutic target

Conclusions

Search strategy and selection criteria

Trends Genet

Am J Pathol

Lancet

Drug Resist Updat

Blood

DNA methylation in health and disease

Nat Rev Genet

Germ-line variants in methyl-group metabolism genes and susceptibility to DNA methylation in normal tissues and human primary tumours

Cancer Res

DNA hypomethylation and cancer

High performance capillary electrophoretic method for the quantification of 5-methyl 2′-deoxycytidine in genomic DNA: application to plant, animal and human cancer tissues

Electrophoresis

DNA methylation patterns in hereditary human cancer mimics sporadic tumorigenesis

Hum Mol Genet

CpG-rich islands and the function of DNA methylation

Nature

Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer

Hum Mol Genet

A gene hypermethylation profile of human cancer

Cancer Res

CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future

Oncogene

Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers

Cancer Res

5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers

Nat Med

Methylation of the 5′ CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing

Cancer Res

Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma

Hum Genet

Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B

Cancer Res

The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53

Mol Cell Biol

Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status

Cancer Res

P14ARF silencing by promoter hypermethylation mediates abnormal intracellular localization of MDM2

Cancer Res

Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt's lymphoma is associated with 5′ CpG island methylation

Cancer Res

Analysis of APC promoter hypermethylation in human cancer

Cancer Res

E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas

Cancer Res

Loss of expression and aberrant methylation of the CDH13 (H-cadherin) gene in breast and lung carcinomas

Cancer Res

Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines

Cancer Res

Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma

Proc Natl Acad Sci USA

MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinoma

Oncogene

Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability

Cancer Res

Inactivation of the DNA repair gene O-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia

Cancer Res

Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis

Cancer Res

Promoter hypermethylation of the DNA repair gene O-Methylguanine-DNA methyltransferase is associated with the presence of G:C to A:T transition mutations in p53 in human colorectal tumorigenesis

Cancer Res

Aberrant hypermethylation of the CHFR prophase checkpoint gene in human lung cancers

Oncogene

Promoter hypermethylation is a cause of BRCA1 inactivation in sporadic breast and ovarian tumors

J Natl Cancer Inst

Gene-expression profiles in hereditary breast cancer

New Engl J Med

Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells

Review
Relevance of DNA methylation in the management of cancer