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 Brian K. Suarez, Ph.D., a professor of psychiatry at the medical school.
The findings will guide efforts to pinpoint prostate cancer-related genes on 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 analyses. 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 rev up the division of prostate gland cells, setting the stage for cancer. "When you lose a tumor supressor 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 1 often is deleted in tumors. The combined results support the theory that, as in chromosome 16, a gene in this region of chromosome 1 normally suppresses tumor development when it is intact.
Catalona's group has begun re-analyzing DNA from the 504 men in the original study to identify the gene on the long arm 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 analyses 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 rise 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, Lin J, 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.
Journal
American Journal of Human Genetics