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May 2005 Issue

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Gene Mutation Linked to Higher Prostate Cancer Death Rates

Published May 2005

A gene mutation developed generations ago in West Africa to protect against malaria may explain why African-American men are more susceptible to prostate cancer and die at higher rates than white men, according to UC researchers.

This gene mutation is found in about 70 percent of African-Americans today, says Alex Lentsch, PhD, of the Department of Surgery. Dr. Lentsch led the research, presented April 5 at the American Society of Investigative Pathology's Experimental Biology 2005 conference in San Diego.

The mutation halts the action of a red blood cell receptor known as the Duffy antigen/receptor for chemokines (DARC). Chemokines are small proteins that promote angiogenesis (blood vessel growth)--a function essential for tumor growth.

Originally identified by scientists as the red blood cell receptor involved in infection by the malarial parasite, the DARC is now thought to play a role in preventing or slowing tumor growth.

The DARC receptor--when able to function properly--is believed to bind to and remove chemokines from a site of overproduction, such as a tumor.

When the DARC is "knocked out," however, which is exactly what happened as a result of the anti-malarial genetic mutation in West African men, chemokines remain active and new blood vessels are formed, allowing tumors to grow much quicker.

Dr. Lentsch and his research staff bred mice engineered to develop prostate cancer to those with the DARC gene knocked out. They were then able to compare the growth and size of prostate cancer tumors in mice with and without the gene for the DARC.

The mice developed tumors at the same time, but the researchers say this is not surprising.

"Chemokines have not been linked to the formation of tumors," says Dr. Lentsch. "Once the tumors are formed and they begin to grow is when the story changes."

In mice bred to have the mutation--those with the DARC knocked out--tumors grew much faster and were nearly four times the size of tumors in mice without the mutation. In addition, researchers noticed higher levels of chemokines in tumors without the gene for DARC.

These findings, says Dr. Lentsch, could one day be applied to prostate cancer patients.

"Our research shows that prostate cancer could grow more aggressively in men who have the mutated DARC gene," says Dr. Lentsch. "We think this is an important first step to understanding why African-American men have a 60 percent higher prevalence of prostate cancer and double the mortality compared with white men."

These preclinical studies will need to be validated in prostate cancer patients, the researchers add. But once that is done, a simple blood test measuring the presence or absence of DARC could be used to identify prostate cancer patients at higher risk for aggressive tumor growth.

It is also possible that anti-chemokine therapies could be tested and applied to these patients.

This research was funded by the United States Army Medical and Material Command.

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