News Release

Genetic mutation tied to increased prostate cancer risk in African-American and Latino men

Peer-Reviewed Publication

University of Southern California

African-American and Latino men who carry a simple genetic mutation have a five times greater risk of developing prostate cancer than do men without the mutation, University of Southern California researchers say in the Sept. 18 issue of The Lancet.

"This is the first mutation directly associated with prostate cancer," says Juergen Reichardt, Ph.D., assistant professor in the department of biochemistry and molecular biology and the Institute for Genetic Medicine (IGM) at the Keck School of Medicine of USC. "There have been hints and suggestions before, but this study really spells it out."

Nearly 40,000 men died from prostate cancer in the United States in 1998 alone; more than 179,000 will be diagnosed with the disease this year. In addition, the incidence of prostate cancer is substantially higher in African-American men than in Caucasian men, and their death rate is twice that of Caucasians with the same diagnosis.

Pinning down this genetic mutation, says Reichardt, may help reverse that trend. "If we can identify men at risk presymptomatically, we might be able to better treat them and get a better outcome," he notes.

The finding also sheds some light on a medical mystery that plagues physicians treating prostate cancer: the most promising drug being investigated as a treatment for the disease -- finasteride, or Proscar -- fails in a certain percentage of men. "We found out that the drug does not work particularly well in men who have the mutation we discovered," says Reichardt. "This may help us screen out those who are likely to respond poorly to the drug." In addition, he says, it may allow them to develop drugs with a broader spectrum of use, "ones that don't care whether you have a normal or mutant enzyme."

How does this mutation increase a man's risk of prostate cancer? For some time now, researchers have known that prostate cancer is androgen-dependent -- in other words, that it can feed off of male hormones like testosterone in much the same way that some breast cancers rely on the female hormone estrogen. Indeed, Reichardt and his USC colleagues had previously theorized that changes in the way the body processes androgens may play a role in determining a man's risk of the disease.

The gene in question codes for an enzyme found in the prostate called steroid 5a-reductase, which controls the "activation" of testosterone -- i.e., its metabolism into dihydrotestosterone (DHT). DHT is an androgen that is some 10 to 50 times more powerful than testosterone; indeed, it's the most potent androgen in the human body.

A single nucleotide substitution in the genetic code for this protein results in the amino acid alanine being replaced with threonine, subtly altering the protein's structure. The consequence of this restructuring is that the enzyme actually becomes more efficient at what it does, says Reichardt. "All of a sudden, men with this mutation begin making buckets of DHT, and their prostate grows faster."

Just how the extra DHT results in prostate cancer is still unknown; Reichardt believes the gene may interact with other mutations caused by environmental factors -- so-called somatic mutations -- to turn a predisposition to the disease into the disease itself.

In order to pin down this so-called missense genetic mutation, Reichardt and IGM colleague Nick Makridakis, Ph.D., entered into a unique collaboration with Keck School preventive medicine and prostate cancer specialists Ronald Ross, M.D., Malcolm Pike, Ph.D., Laura Crocitta, M.D., C. Leigh Pearce, M.P.H., and Brian Henderson, M.D., as well as with University of Hawaii researcher Laurence Kolonel, M.D.

Using data collected as part of the prospective Hawaii-Los Angeles Multiethnic Cohort Study of Diet and Cancer, the researchers screened the genomes of 218 African-American and 172 Latino men with prostate cancer, and 261 African-American and 200 Latino controls, who were healthy. (They also looked at Asian and Caucasian men, but the link between the mutation and prostate cancer was not as clear.)

Less than 1 percent of normal, healthy men carry this mutation, they found; however, in African-American and Latino men with prostate cancer, the rate of mutation can rise to as high as 10 percent.

"The genetics of prostate cancer is somewhat controversial," says Reichardt. "But we need to figure out the interplay of the different genetic changes that occur in the predisposition or progression of the disease. The one thing I know is that this won't be the only gene discovered: it's sure to be the first of many."

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