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Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
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Aberrant DNA methylation as a cancer-inducing mechanism

Manel Esteller1

  • 1Cancer Epigenetics Laboratory, Spanish National Cancer Center (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain. mesteller@cnio.es

Annual Review of Pharmacology and Toxicology
|April 12, 2005
PubMed

Insights

Aberrant DNA methylation is a common cancer lesion, often silencing tumor suppressor genes. Research is exploring its mechanisms, potential as biomarkers, and therapeutic demethylating agents.

Area of Science:

  • * Epigenetics and Molecular Oncology
  • * Cancer Genomics and Biomarkers

Background:

  • * Aberrant DNA methylation is the most frequent molecular alteration in cancer cells, surpassing gene mutations and cytogenetic abnormalities.
  • * CpG island promoter hypermethylation commonly silences critical tumor suppressor genes (e.g., p16INK4a, BRCA1, hMLH1) across various malignancies.
  • * A distinct CpG island hypermethylation profile exists for different tumor types, affecting all cellular pathways.

Purpose of the Study:

  • * To review the landscape of aberrant DNA methylation in cancer, focusing on CpG island hypermethylation.
  • * To discuss the current understanding and remaining questions regarding the mechanisms of aberrant DNA methylation.
  • * To highlight the translational potential of DNA methylation alterations as cancer biomarkers and therapeutic targets.

Main Methods:

  • * Review of existing literature on DNA methylation in cancer.
  • * Integration of bisulfite-PCR methodologies and genomic approaches to identify methylated genes.
  • * Analysis of studies on DNA methyltransferases and methyl CpG binding proteins.

Main Results:

  • * CpG island hypermethylation is a prevalent epigenetic event in cancer, targeting numerous genes across all cellular functions.
  • * Specific hypermethylation profiles are associated with distinct tumor types.
  • * Genes like MGMT and GSTP1 show potential as biomarkers in brain and prostate tumors, respectively.

Conclusions:

  • * Aberrant DNA methylation is a hallmark of cancer, with significant implications for tumor suppressor gene silencing.
  • * Further research is needed to elucidate the mechanisms of aberrant DNA methylation and its maintenance.
  • * Validated hypermethylated genes hold promise as diagnostic biomarkers, and novel demethylating agents offer therapeutic potential.

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