Gene Combo Seems to Raise Prostate Cancer Risk, Swedish Study Finds
Wednesday, January 16, 2008     14:22 EST

Scientists have taken a key step toward revealing the causes of
prostate cancer, finding that a combination of 5 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 like cancer and diabetes 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 Swedish 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.

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Unfortunately, the markers do not help doctors tell which cancers need
treatment and which do not - they turned out to have nothing to do with
the aggressiveness of a tumor, 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.

This "eyebrow-raising study" should quickly spur more research,
particularly in blacks, who have a higher incidence of prostate cancer,
said Dr. Howard Sandler, a cancer specialist at the University of
Michigan and spokesman for the American Society of Clinical Oncology.

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. 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 5, 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 5 most common
variants, which were single letter changes in the gene's usual DNA alphabet.

When 4 or 5 variants were present, men were more than 4 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 6 factors were
more than 9 times more likely to develop the disease. These 6
factors accounted for 46% 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% of men had
all of the variants.

Still, some are very common - one is estimated to occur in 60% 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% of the men
without prostate cancer had 4 of the 5 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/

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