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Researchers Home in on a Gene
that Could Play a
Major Role in Prostate Cancer
St. Louis, March 6, 2000 – Researchers who have spent 10 years studying
brothers with prostate cancer are hot on the trail of a gene that may be
significant for the cancer's development in many men. They have identified
the genetic 'neighborhoods' of five genes statistically linked to prostate
cancer in about 500 men. The strongest candidate has the hallmarks
of a gene that thwarts cell division.
"It is very likely that a gene on chromosome 16 plays a major role in
causing prostate cancer when it fails to function," says William J. Catalona,
M.D., a professor of Urologic surgery at Washington University School of
Medicine in St. Louis.
Catalona led the research group, which also determined the neighborhood
for an additional gene with a strong link to chromosome 1. This finding
resulted from a second analysis of those prostate cancer patients whose
families also had a history of breast cancer.
The study results will be published in the March issue of The American
Journal of Human Genetics. The article is posted on the journal's
Web site, http://www.ajhg.org.
The lead author is Brain K. Suarez, Ph.D, and a professor of psychiatry
at the medical school.
The findings will guide efforts to pinpoint prostate cancer-related
genes to chromosome 16 and other chromosomes. Once found, the genes
might lead to molecular tests that improve the accuracy of prostate-cancer
screening. Such tests also would benefit relatives of susceptible men who
might share the same mutations and therefore be at greater risk for other
cancers.
In 1991, Catalona's group began gathering blood samples from brothers
with prostate cancer belonging to 230 families that had two or more such
brothers. Samples from 504 men were analyzed in the study. DNA was
isolated from the samples at Washington University and sent to the Center
for Medical Genetics at the Marshfield Medical Research and Education Foundation
in Marshfield, Wis.
The center's director, James L. Weber, Ph.D., and James K. Burmester,
Ph.D., analyzed the purified DNA samples from each brother using markers
that function like flags along the DNA's length. The flags help indicate
the position of genes along human chromosomes in the way street names help
locate someone's house.
The genotype information obtained at the center was sent on compact
discs to Brian K. Suarez, Ph.D., at Washington University and Karl W. Broman,
Ph.D., formerly at Marshfield and now at Johns Hopkins University, who
performed independent statistical analysis. An independent analysis
also was performed in Cleveland by Robert C. Elston, Ph.D., and John S.
Witte, Ph.D. at Case Western Reserve University, in collaboration with
Graham Casey, Ph.D., at the Cleveland Clinic Foundation.
All three research groups identified two regions on chromosome 16 and
one region on each of chromosomes 2, 12 and 15 that were linked to prostate
cancer susceptibility. All the regions may contain tumor suppressor genes
that normally prevent potentially cancerous cells from dividing.
When growth suppressors are faulty, tumors form.
The difficulty of obtaining information about male relatives of study
participants has complicated the search for general-susceptibility genes
for prostate cancer. Men usually are diagnosed with the disease after
age 50, when their fathers and grandfathers may no longer be living and
their sons may be too young to have prostate cancer.
Despite these difficulties, Catalona's group was able to recruit enough
pairs of brothers with prostate cancer to identify the linkage on chromosome
16. Using the sibling-pair approach, they found that one region on
the long arm of chromosome 16 (subband 23.2) had a strong link to prostate
cancer susceptibility in most of the men studied. Other researchers
previously had demonstrated that this region of chromosome 16 often is
deleted in men with prostate cancer, but the region's linkage to prostate-cancer
susceptibility was unclear.
The new finding, if verified, strengthens researchers' suspicions that
the region contains a tumor suppressor gene – a gene that inhibits tumor
development. The absence of the gene would reveal the division of
prostate gland cells, setting the stage for cancer. "When you lose
a tumor suppressor and its braking ability, cell growth can run wild,"
Suarez says.
The researchers found a strong candidate region on the short arm of
chromosome 1 by analyzing pairs of brothers in the study who shared a family
history of breast cancer. "This finding suggests that this gene,
when mutated in a woman, helps cause breast cancer; if it is mutated in
a man, it helps cause prostate cancer," Catalona says.
The same region on the short arm of chromosome 1 stood out in a recent
study the researchers performed on an additional 58 pairs of brothers with
prostate cancer. Recent studies of breast cancer tumors by other
researchers indicate that this region of chromosome 16. They also
are evaluating tumor tissue from these men to determine genetic errors
in this region of interest. They plan to use the same approaches
for further analysis of chromosome 1 and the other chromosomal regions
identified. "When the whole story is told, we'll probably find a
series of genes that can give arise to prostate cancer," Catalona says.
Editor's Note: Previous studies of large families with many members
that have prostate cancer have revealed several regions on chromosome 1
that might contain a gene that is important in some rare cases of hereditary
prostate cancer. These regions differ from that on chromosome 1 identified
by Catalona's team during their hunt for genes that promote a general susceptibility
to the disease.
(Suarez BK, LinJ, Burmester,JK, Broman KW,Weber JL, Benergee TK, Goddard
KAB, Witte JS, Elston RC, Catalona JW.)A Genome Screen of Multiplex Prostate
Cancer Sibships. The American Journal of Human Genetics, March 2000.
This research was supported by awards from the Urological Research Foundation,
and the CaP CURE Foundation and grants
from the United States Public Health Service and the U.S. Army.
Web Link: http://www.ajhg.org.
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