Tumor cells show abnormal patterns of DNA methylation—a key epigenetic mechanism by which methyl groups attached to DNA reduce gene expression. A broad and deep look at DNA methylation across the genome in multiple tumor types has produced two startling results.
“People expected that cancers would have some unique DNA methylation signatures that distinguish them from normal cells,” says Andrew Feinberg of Johns Hopkins University. “What we found instead, starting with colon cancers, is that at certain places in the genome, the pattern is chaotically different from normal. At places that we call cancer-specific differentially DNA-methylated regions (cDMR), there's a very clear pattern with a random loss of the methylation signature.
“At the very same places where you get the loss of the normal pattern in colon cancer, you also see it in breast, lung, thyroid, and Wilms' tumors,” adds Feinberg, senior author on a paper published in June (Nat Genet 2011;43:768–75). “It looks like a single disruption in methylation that may be a kind of commonality in multiple cancers.” The genomic regions where this occurs are important in controlling normal cell differentiation.
In the paper, the researchers followed up this work on 290 tumor samples, done with a custom high-throughput array-based relative methylation analysis, with whole-genome bisulfite testing of normal, precancerous, and cancer colon tissue samples.
This created the second surprise: Very large blocks of the genome—in fact, making up more than one third of it—are substantially hypomethylated in these tumors. These regions are associated with the regulation of genes involved both in normal development and in cancer.
Overall, the results sound a cautionary note about some current methylation-based diagnostic and therapeutic approaches, which may assume a specific methylation profile in cases where the data instead show “anti-profiles,” Feinberg suggests.