January 30, 2015

   A Publication of the James Buchanan Brady
   Urological Institute Johns Hopkins Medical Institutions

Volume II, Autum 2005


New Tests Look for“Silenced” Genes

What is it with methylation, anyway? Why does this word keep popping up in some of the Brady’s most exciting research? Chemically speaking, methylation is like taking a zipper and adding an extra tooth, so it doesn’t work properly — or changing the tumblers on a lock ever so slightly, so the key doesn’t fit it anymore. What does this have to do with prostate cancer?

Quite a lot, says William G. Nelson, M.D.,Ph.D., professor of oncology, medicine,pathology, pharmacology and molecular sciences, and urology. When a gene is methylated, it’s silenced, rendered useless. In more than 90 percent of men with prostate cancer, Nelson has discovered, themajor gene that’s supposed to defend the

Methylation is like taking a zipper and adding an extra tooth,so it doesn’t work properly.What does this have to do withprostate cancer?

prostate against oxidative damage to DNA— incremental harm that occurs over years or even decades, as carcinogens repeatedly attack our genes — is silenced, or methylated, early on. This gene is called GSTPI (pronounced “GST pie”), and what happens here — this targeted “hit,” an assassination on the genetic level — allows cancer to develop much more easily.

Exploring the role of methylation as a cause of prostate cancer has helped Nelson and colleagues look for new genetic markers to help detect it. Nelson is working to develop tests that can detect abnormal GSTPI methylation changes in DNA from cancer cells; specifically, the tests look for altered clumps of DNA, called “hypermethylated CpG islands,” that aren’t supposed to be there. “Exactly how such tests might be used has not been established yet,” says Nelson. But, he speculates, “they could be used in prostate biopsies or even urine specimens, to help identify men who harbor prostate cancers that have been missed by prostate biopsy.”Also, such tests targeting CpG islands of other genes, such as the endothelin B receptor or cyclooxygenase-2 (COX-2), in DNA in prostate cancer cells and tissues, might one day help doctors predict outcomes from radical prostatectomy or radiation therapy.

Methylation and inflammation: Methylation helps cause cancer. Now, can we somehow backtrack — retrace the steps of cancer— and catch methylation in the act? Pathologist Angelo De Marzo, M.D., Ph.D., has been named the Dr. and Mrs. Peter S. Bing scholar from The Patrick C. Walsh Prostate Cancer Research Fund. He believes that prostate cancer is driven by a bad combination of forces from within and without. From inside the prostate comes inflammation; from without come attacks by cancer-causing elements in the diet. Together, they causedamage that results in regions of “proliferative inflammatory atrophy,” or PIA.

De Marzo believes these PIA spots, or lesions, represent evidence of a “field effect” change, “indicating that a very large region of the prostate has been exposed to something that causes cancer,” and that these PIA lesions somehow pave the way for cancer. It may be that the next step a pathologist could detect in the tissue is high-grade PIN(prostatic intraepithelial neoplasia), and from there, the next step is cancer.

To prove that PIA lesions are early precursors on the way towards cancer, De Marzo is looking for intermediate changes in the DNA between normal cells and cancer cells. The most common of these changes, which he expects to find in abundance, is our old friend — the hypermethylated “CpG island”in GSTPI. “We suspect that PIA will contain intermediate levels of CpG island methylation, greater than normal, but less than high grade PIN and carcinoma,” he says. He will also look for some of the other genes with DNA methylation changes that Bill Nelson and colleagues have discovered. If his work is able to connect the dots from PIA to PIN to cancer, he hopes to use these results as pilot data for a larger, externally funded grant to investigate the order of events in early prostate cancer.

Better biomarkers to predict recurrence: Oncologist Joshi Alumkal has been named the Irene and Bernard L. Schwartz scholar from The Patrick C. Walsh Prostate Cancer Research Fund. He is studying methylationin a different gene, with the alphabet-soup name of NKX3.1. Although the genetic players are different, the basic script is the same: Whatever causes the DNA to methylate in this gene — or, as Alumkal believes, several genes — knocks out the body’s ability to prevent cancer’s development, growth, and spread. In this case, the kind of cancer that results is particularly unpleasant, and most likely to defy treatment.

The gene NKX3.1 is important in normal prostate development, and its loss can mean not only that prostate cancer develops, but that it’s an aggressive form. “Loss of this gene in animal models leads to precancerous and cancerous prostates — many of which appear very primitive, much like high Gleason score tumors,” Alumkal explains. In this case, figuring out a way to screen for these DNA methylation changes “may help us identify those at highest risk of recurrent and potentially lethal prostate cancer.”



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