The James Buchanan Brady Urological Institute

   Methylation Changes:
   "Extra Baggage" on DNA Seems to be Permanent

       Volume 10, Winter 2014

We all carry extra baggage that we don't want. It turns out that DNA is no different; it accumulates some barnacles, too – tiny changes that don't look like much, but which make a gene unable to function properly. Scientists used to think that these methylation changes were "plastic" – that they weren't necessarily permanent. But a recent study by William Nelson, M.D., Ph.D., the Marion I. Knott Director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and Vasan Yegnasubramanian, M.D., Ph.D., is changing that viewpoint.

The study, published in Science Translational Medicine, revealed for the first time that DNA methylation changes in cancers were like other, more serious alterations – events like mutations, deletions, insertions, translocations, and amplifications. And when they happen as cancer is progressing, they can threaten life. "Of course, essentially all human cancers harbor epigenetic defects," changes to genes that come from an external source, such as diet, "including DNA methylation abnormalities," says Nelson. "And these can be passed on to succeeding generations when cells divide. Nonetheless, we thought that they were reversible in any cell at any time."


DNA accumulates some barnacles
– tiny changes that don't look like
much, but which make a gene
unable to function properly

To test whether these epigenetic defects in cancer cells go away as the disease progresses, Nelson and Yegnasubramanian invented a new platform for genome analysis that can simultaneously assess DNA methylation defects and the alterations in next-generation cells in different samples of metastatic cells from men who had died of prostate cancer. "Our logic was that if DNA methylation changes were stable, then similar, if not identical, alterations should be present in each metastatic deposit recovered from any man who had died of prostate cancer." This proved to be the case, leading Nelson and Yegnasubramanian to conclude that DNA methylation changes are equivalent to mutations, and "thus could formally be considered drivers of cancer."

What they have learned, Nelson says, "gives further weight to the ongoing attempts to exploit cancer-specific DNA methylation changes as molecular biomarkers." Knowing what to look for could help scientists develop new tests for prostate cancer screening, early detection, and helping to predict a man's risk of having aggressive cancer. "It also adds promise to the growing arsenal of epigenetic drugs that are slowly working into early-phase clinical trials for cancer."

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