Genetic Mutation Linked to Prostate Cancer

MOST PROSTATE CANCER, says Dr. Timothy Rebbeck, assistant professor of epidemiology, “just sort of appears out of nowhere, without any family history.” It is, he adds, an “extremely complex disease,” and no single gene or environmental exposure is going to explain all of it.
   But recently, Rebbeck and a team of researchers at Penn’s Cancer Center identified a genetic mutation associated with prostate cancer, one that could ultimately lead to better prevention strategies. In a study of 230 Caucasian men with prostate cancer, those who carried a mutation of the CYP3A4 gene, were diagnosed after the age of 63, and had no family history of prostate cancer were nearly 10 times as likely to have a higher-stage (read: worse) tumor than men who did not. The findings were published in the August 19 issue of the Journal of the National Cancer Institute.
   “What the study is essentially saying is that if you carry this variant, you’re much more likely to have a bad tumor, a worse tumor, than if you don’t carry the gene,” says Rebbeck, who served as the study’s principal investigator. “The gene essentially predicts whether you’ll have a bad tumor or not.”
   A lot of men are diagnosed with prostate cancer, he points out, “and most of those prostate cancers don’t go anywhere. So our ability to identify who’s going to have a bad outcome and who isn’t is really important.”
   Rebbeck’s team focused on the CYP3A4 gene because it processes testosterone through the body — and because there is a strong correlation between elevated testosterone levels and the development of prostate cancer.
   “We think this gene may be involved in regulating how much testosterone may be available,” he says. “Since testosterone is the fuel that makes prostates grow, how much testosterone you have hanging around in your system may be very important for whether your prostate tumor grows or not.”
   The next steps, he says, are to study the gene more closely at the molecular level and to conduct a larger study involving African-American men. “African Americans have the highest rate of prostate cancer in the world,” Rebbeck points out, “and the genetic variant we found is carried by about 50 percent of African-American men, compared with only about 10 percent of Caucasian men.”
   Unlike the HPC1 gene, which has a hereditary link to prostate cancer but rarely mutates, the CYP3A4 mutation is not believed to be associated with hereditary prostate cancer. It appears to be associated with the commonly occurring variety of prostate cancer, which occurs in older men without a strong family history of the disease. The American Cancer Society estimates that 184,500 new cases of prostate cancer will be diagnosed this year in the United States, and that some 39,000 men will die from it.

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