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Quantitative DNA methylation analysis: the promise of high-throughput epigenomic diagnostic testing in human neoplastic disease.

The term “epigenetics” was first introduced by Conrad Waddington in 1942 to describe “the interactions of genes with their environment, which bring the phenotype into being.”1 Later that same decade came the identification and characterization of DNA methylation,2 the first epigenetic mark to be discovered. The major target for DNA methylation in the mammalian genome is cytosine, where enzymatic attachment of a methyl group to the 5 position of the pyrimidine ring produces 5-methyl-cytosine,3 which has been referred to as the fifth base of genomic DNA. Although 5-methylcytosine is indistinguishable from cytosine within the structure of the DNA molecule where it base-pairs with guanine, the presence of the methyl group has considerable biological implications for DNA function.3 Alterations in DNA methylation affecting target sequences within the transcriptional control regions of genes produce changes in gene expression, with hypomethylation leading to increased ex-pression and hypermethylation leading to decreased expression. In contemporary terms, epigenetics refers to modifications of the genome that are heritable during cell division but do not involve a change in the DNA sequence.4 Thus, epigenetics describes heritable changes in gene expression that are not simply attributable to nucleotide sequence variation.5 It is now recognized that epigenetic regulation of gene expression reflects contributions from both DNA methylation and complex modifications of histone proteins and chromatin structure.6 Nonetheless, DNA methylation plays a central role in nongenomic inheritance and in the preservation of epigenetic states and remains the most accessible epi-genomic feature because of its inherent stability.4 Thus, DNA methylation represents a target of fundamental importance in the characterization of the epigenome, in defining the role of epigenetics in disease pathogenesis, and in the development of useful molecular tools for diagnostic testing and prediction of prognosis (clinical responses and patient outcomes) in neoplastic and non-neoplastic diseases.7,8,9 In this issue of The Journal of Molecular Diagnostics, Ogino et al10 investigate one such molecular tool, sodium bisulfite conversion of DNA followed by MethyLight real-time polymerase chain reaction (PCR), and describe the factors that influence the variability of quantitative analysis. However, to fully understand these results, it is important to comprehend the importance of DNA methylation in cancer and the significance of such information to cancer diagnosis and prognosis.