Contributions to Progress and Promise of Epigenetics for Diagnosis and Therapy in Cancer5-hydroxymethylcytosine in cancer: significance in diagnosis and therapy
Section snippets
Detection of 5-hmC
Commonly used techniques for the detection of methylated cytosines, such as bisulfite sequencing and methods that employ methyl-sensitive restriction enzymes, cannot distinguish between 5-mC and 5-hmC (21). However, these modified cytosines can be discriminated using several techniques, including 1) thin layer chromatography, 2) mass spectrometry, 3) antibodies, and 4) chemical conjugation.
Thin layer chromatography (TLC) and liquid chromatography-electron spray ionization tandem mass
Potential molecular mechanisms of modified cytosine bases
First identified in T-even bacteriophages approximately 60 years ago, 5-hmC was hypothesized to play a role in nucleic acid metabolism during viral replication. This base was found in mammalian cells in the 1970s (36), but its functional importance was not appreciated fully. In 2009, the catalytic function of the TETs was identified as the conversion of 5-mC to 5-hmC, which is found at reasonably high levels in Purkinje cells in the murine brain (19) and in undifferentiated embryonic stem (ES)
Disruption of 5-hmC levels in hematological malignancies
Perturbation of global 5-mC levels is one of the hallmarks of human cancers, and hypomethylation, and in some cases hypermethylation, has been observed in various hematological malignancies. More recently, several whole genome sequencing studies from myeloid malignancies have identified mutations in genes that encode DNA cytosine modifiers, including the DNMT3A, TET2, and IDH1/2 genes (3). Specifically, the disruption of TET2 and IDH1/2 gene function by mutations perturbs 5-hmC levels in
Solid tumors are associated with low 5-hmC levels
A broad spectrum of solid tumors, including gliomas, colorectal, breast, and prostate cancers, reportedly have low levels of 5-hmC associated with down-regulation of TET1, TET2, or TET3 mRNA transcription 12, 110, 111, 112, 113, suggesting that the loss of TET-mediated regulation of DNA demethylation contributes to cellular transformation. The significant loss of 5-hmC that is found in several types of solid tumors indicates a general epigenetic event in malignant transformation, correlating
Clinical implications of low 5-hmC in cancer prognosis and therapy
Many studies have sought to evaluate the impact of mutations in epigenetic modifiers on patient response to therapy. Mutations in TET2 and a favorable cytogenetic risk were both independent predictors of a higher response rate to therapy (133). A recent study correlated the levels of 5-hmC with clinical and molecular parameters in adult AML patients and found that whereas TET2 and IDH1/2-mutated cases had low levels of 5-hmC, higher levels of 5-hmC associated positively with high blast count at
Conclusions
The role of 5-hmC in cancer has been widely studied ever since its rediscovery in 2009, and these studies have revealed a loss of 5-hmC in hematological as well as solid tumors. However, the mechanisms by which 5-hmC levels are reduced are unclear. The down-regulation of 5-hmC in different malignancies appears to depend on the specific tumor type. For example, TET2 and IDH1/2 mutations in hematological malignancies lead to low hydroxymethylation, whereas down-regulation of TET transcription and
Acknowledgments
This work was supported by F32-DK092030 (A.V.) and National Institutes of Health CA129831 (L.A.G.).
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