AJOG ReviewThe epigenetics of ovarian cancer drug resistance and resensitization
Section snippets
DNA methylation
The term epigenetics refers to heritable DNA modifications that occur outside of primary base-coding sequences. The most common of these modifications is methylation of cytosines, usually located within the dinucleotide CpG.19., 20. This modification is catalyzed by enzymes known as DNA methyltransferases (DNMTs), of which three are known in humans: DNMT1, DNMT3a, and DNMT3b.21 DNMT1 is primarily involved in maintenance of methylation patterns, whereas DNMTs 3a and 3b effect de novo DNA
Epigenetic markers as prognostic indicators
DNA methylation profiling. As several aberrantly methylated loci have been identified in ovarian cancer, an emerging diagnostic strategy is to use such loci as prognostic and/or predictive markers. Prognostic markers refer to those associated with overall clinical outcome, whereas predictive markers are those used to monitor therapeutic response.78 Distinguishing these two types of biomarkers is clinically quite difficult; however, examination of methylation alterations of specific genes during
Conclusions
Epigenetic alterations have been firmly demonstrated to play a role in tumor initiation, development, and progression. Aberrations in DNA methylation and histone deacetylation almost certainly also contribute to progression to a drug-resistant state. As these aberrations occur in several genes involved in apoptotic and differentiation pathways, their correction might allow for resensitization of tumor cells to drugs that affect such pathways. Figure 3 shows three hypothetical ovarian cancer
Acknowledgment
We thank Phil Abbosh and John Montgomery for constructive review of this manuscript.
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Supported by NCI grant CA05289 and Cancer Research UK grant C536.