Study finds gene combination seems to raise risk of prostate cancer

Scientists have taken a key step toward revealing the causes of prostate cancer, finding that a combination of five gene variants dramatically raises the risk of the disease. Added to family history, they accounted for nearly half of all cases in a study of Swedish men.

The discovery is remarkable not just for the big portion of cases it might explain, but also because this relatively new approach, looking at combos rather than single genes, may help solve the mystery of many complex diseases that are thought to involve multiple genes or interactions between them.

"It gives us a new way of looking at genetic risk factors," said Dr. Teri Manolio of the National Human Genome Research Institute, the federal agency focused on such work.

It also might lead to a blood test to predict who is likely to develop prostate cancer. These men could be closely monitored and perhaps offered hormone-blocking drugs like finasteride to try to prevent the disease.

The results must be verified in other countries and races, where the gene variants, or markers, may not be as common. Researchers already have plans to look for them in U.S. men.

The markers do not help doctors tell which cancers need treatment. They turned out to have nothing to do with a tumor's aggressiveness, only whether a man is likely to develop one.

Nor did they correlate with levels of PSA, a blood substance often used to gauge cancer risk. PSA is a notoriously imprecise measure, so a gene test that independently predicts risk would be very valuable, experts said.

The study was led by doctors at Wake Forest University in Winston-Salem, N.C., and involved Johns Hopkins University in Baltimore and the Karolinska Institute in Stockholm, Sweden.

Results were published online Wednesday by the New England Journal of Medicine.

Prostate cancer is the most common cancer in American men and arguably the most mysterious. Unlike breast cancer, where variants in single genes like BRCA are known to confer greater risk, few have been discovered for prostate cancer. In the past year, other researchers identified five, but none individually seemed to raise risk very much.

Combinations of them did, the new work reveals.

It involved 2,893 men with prostate cancer and 1,781 similar men who did not have the disease. Sweden was chosen because the population is so ethnically similar and well suited to gene studies.

Researchers looked for "hot spots" of differences in genes of the men with cancer compared to the others, then focused on the five most common variants, which were single letter changes in the gene's usual DNA alphabet.

When four or five variants were present, men were more than four times more likely to develop prostate cancer than those with none of the markers.

When family history was added in, men with five of the six factors were more than nine times more likely to develop the disease. These six factors accounted for 46 percent of the prostate cancer cases in the study.

"That is a lot," Manolio said, but added, "you have to take those estimates with a grain of salt" because less than 2 percent of men had all of the variants.

Still, some are very common -- one is estimated to occur in 60 percent of men.

Government and cancer groups in the U.S. and Sweden funded the work. Some of the U.S. researchers are seeking patents to develop a blood test using the results.

However, scientists must prove that any such blood test does not give too many false alarms, Dr. Edward Gelmann of Columbia University Medical Center writes in an editorial. In the Swedish study, 2 percent of the men without prostate cancer had four of the five gene variants purported to raise risk.

Until more is known, men should talk with their families about any history of prostate cancer, Sandler and Manolio suggested.

The U.S. Surgeon General and various federal health agencies recently launched the U.S. Surgeon General's Family History Initiative to encourage people to learn more about their family health history. A Web site for the project gives families an Internet tool and advice on how to track this information.

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On the Net:

New England Journal: http://www.nejm.org

Family health history tool: http://www.hhs.gov/familyhistory/