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Finding the epigenetic keys to prostate cancer

The prostate gland can be a real troublemaker. It has already begun developing cancer in nearly half of American men by the time they reach their 40s, and things frequently get worse from there. As William Nelson, a Johns Hopkins oncologist and director of the Sidney Kimmel Comprehensive Cancer Center, puts it: "If you look hard enough, you'll find cancers in most guys." In the United States, that is. Men in Asia are only 10 percent as likely to get prostate cancer as Americans, setting up an epidemiological mystery. A genetic predisposition could be at work, Nelson says—except that when Asians move to the States, their prostate cancer rates skyrocket.

To Nelson, this puzzle has long suggested that the cancer has an epigenetic rather than genetic origin. Epigenetics involves not the genes that code for proteins but molecules that attach to DNA and determine how often genes' instructions get read and acted upon—genetic metadata. These molecules affect what structures a cell builds and, among other things, whether a cell becomes cancerous. And—crucially for oncologists like Nelson—epigenetic patterns are not hard-wired. They can be turned on and off by environmental factors like diet, exposure to pollutants, and drugs.

Nelson's early work on cancer epigenetics in the 1990s discovered a silenced gene that codes for an enzyme called GSTP1. GSTP1 protects a cell's DNA from damage and almost always shuts off as prostate cancer develops. That means nearly all men who have the disease carry an abnormal epigenetic pattern associated with the silenced gene. A test that spots that pattern now exists; Nelson shares the patent with the university and a pharmaceutical company. But it requires men to undergo expensive and possibly dangerous biopsies, which Nelson would like to spare them. So he and his colleagues are seeking a way to detect the same signature in blood or urine. "Our sort of abstract goal is like a home pregnancy test," Nelson says. "It doesn't cost much, it's easy to use, [it can be] used repeatedly and drive informed medical decisions."

Along with seeking better ways to diagnose prostate cancer, Nelson has spent much of his career using epigenetics to try to prevent the disease. The trick here is to figure out which among hundreds of possible risk factors pulls the cancer trigger in so many men living in the United States. Nelson and colleagues hit upon one of these factors by showing they could induce prostate cancer in laboratory animals with compounds produced when meat is grilled or charbroiled. Nelson believes this could help explain why living in Asia, where eating charred meat is rare, seems to have a protective effect. (A supporting piece of evidence, Nelson notes, is that Asian men's prostate cancer rates are now rising in Asian cities, where Western diets are becoming more common.)

When Nelson started his career, most treatment of the disease was done by urologists, who specialized in surgery but not in thinking about cancer systemically. So Patrick Walsh, a Johns Hopkins urologist who pioneered nerve-saving prostate surgery, challenged Nelson and his oncologist colleagues: "'Look, if you guys think as hard about prostate cancer and put as much of a commitment into systemic treatment as I do into localized treatment, you can make a big difference.'" Walsh was right. Thanks in part to the GSTP1 test and other screening advances, prostate cancer is now one of oncology's rare success stories, with mortality in the United States reduced by about half since 1990. While there is much more to be done in both prevention and treatment, Nelson says, "it's kind of gratifying to be in a field where death rates are going down."

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