DNA methylation: an alternative pathway to cancer

Abstract

Objective: To provide an introduction to the concept of DNA methylation and its function in normal cells, and to explain the possible mechanisms as to how abnormalities in this phenomenon can relate to carcinogenesis. The clinical implications with reference to common malignancies encountered in surgical practice are discussed.

Summary background data: Methylation of DNA is a heritable, enzyme-induced modification to DNA structure without alteration of the specific sequence of the base pairs responsible for encoding the genome. DNA methylation can both directly inhibit the expression of genes and also increase the probability that affected genes undergo a mutational event. Although DNA methylation plays an essential role in normal biologic processes, distinct and abnormal patterns of methylation are observed in cancers. In particular, there has been increased documentation that methylation of the promoter regions of several genes, including known tumor suppressor genes, results in the subsequent failure to express their functional proteins. Consequently, DNA methylation may represent an early and fundamental step in the pathway by which normal tissue undergoes neoplastic transformation. Further, an assessment of the methylation profiles within neoplastic tissues may provide key information in enhancing the diagnosis, predicting the clinical behavior, and designing specific treatment plans for individual patients.

Methods: Published literature from 1925 to 2000 contributing to an understanding of the purpose of DNA methylation and how pathology of this phenomenon could contribute to cancer are reviewed. Theories on these issues and the evidence that led to them are described. The present status of the subject in a clinical context is discussed.

Results: Gene expression can be significantly modulated by alterations in DNA methylation patterns. Methylation within the promoter regions of tumor suppressor genes causes their silencing, and methylation within the gene itself can induce mutational events. These mechanisms may play a fundamental role in precipitating the development of a large and diverse number of human cancers.

Conclusions: DNA methylation is an important factor in the development of cancer. A greater understanding of the relationship between DNA methylation events at the molecular level and its interaction in the clinical context may provide the basis for future advances in the surgical and pharmacologic management of malignant diseases.

Figure 1. DNA double helix and CpG dinucleotide pairs. DNA structure with opposing base pairs arranged on a double helix sugar–phosphate backbone. CpG dinucleotide pair units that are the sites for possible methylation are outlined.

Figure 2. The methylation cycle. Methylation of the 5-carbon on the cytosine residue is executed by the DNA methyltransferase enzyme, which uses a methyl group from S-adenyl methionine (SAM). This is converted to S-adenyl homocysteine (SAH), which is then broken down to homocysteine (HCY) and adenosine. SAM is reconstituted from HCY by methionine. Folate and cobalamin are required for and provide the methyl groups for this reaction.

Figure 3. Transcriptional repression resulting from alteration of chromatin structure. Methylated DNA binds to a protein complex consisting of a methyl binding protein (MBP), which has a methyl-binding domain and a transcriptional repression domain, a corepressor molecule (CR), and a histone deacetylase (HDAC). After binding of this complex to the methylated DNA, the histones around which the DNA is wrapped become deacetylated, resulting in a compression and compaction of the chromatin structure. This makes the DNA inaccessible, and thus functional transcription is no longer possible.

Figure 4. Mechanisms of carcinogenesis induced by methylation events. (A) Activation of previously silent protooncogenes after hypomethylation. (B) Silencing of tumor suppressor genes after methylation of gene promoter region.

Figure 5. Methylation precipitating a point mutation. Cytosine-to-thymine point mutation after deamination of methylated cytosine.

Figure 6. Alternative pathways to cancer. Combination of independent genetic (mutation, deletion, insertion) and epigenetic (methylation) events leading to complete gene inactivation through different routes and molecular heterogeneity within cancers. Genetic events may also be precipitated by an initial methylation event.