Editors' ChoiceCancer

DAMD to Do Better!

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Science Translational Medicine  27 Jan 2010:
Vol. 2, Issue 16, pp. 16ec12
DOI: 10.1126/scitranslmed.3000854

The role of genetic changes in cancer formation is well appreciated. However, it is now clear that epigenetic changes that affect gene expression, including histone modifications and DNA methylation, are also critical, and our ability to characterize these epigenetic changes has been transformed by new technologies, including chromatin immunoprecipitation followed by microarrays or sequencing. Diede et al. now describe a new method to more comprehensively measure DNA methylation changes in medulloblastoma, an aggressive pediatric brain tumor for which little information on the importance of DNA methylation was known.

Their method, denaturation analysis of methylated DNA (DAMD), operates on the fact that higher temperatures are necessary for the denaturation of DNA with methylated (versus unmethylated) CpG dinucleotides. DAMD allows for the enrichment of methylated DNA fragments, which may then be hybridized to DNA microarrays or be sequenced. DAMD was more sensitive than current methods to detect DNA methylation, and DAMD showed that methylation of genes in critical developmental pathways—including Ptch1, which negatively regulates the sonic hedgehog (SHH) pathway, which is important for medulloblastoma formation—is common. Indeed, treatment with a DNA demethylating agent led to restored mRNA expression of Ptch1 in medulloblastoma cell lines.

Given that SHH inhibitors have shown activity in medulloblastoma patients and that DNA methyltransferase inhibitors can penetrate the CNS and prevent medulloblastomas in preclinical models, it is rational to begin testing DNA methyltransferase inhibitors in medulloblastoma patients. DAMD illustrates the power of discovery platforms to globally assess epigenetic changes in cancer, which may then be targeted rationally with epigenetic therapies.

S. J. Diede et al., DNA methylation of developmental genes in pediatric medulloblastomas identified by denaturation analysis of methylation differences. Proc. Natl. Acad. Sci. U.S.A. 107, 234–239 (2010). [Abstract]

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