Bethesda, MD-- Researchers at the National Center for Human Genome Research (NCHGR), Johns Hopkins University (JHU) and Umea University, Umea, Sweden, have identified the location of the first major gene that predisposes men to prostate cancer. The gene, named HPC-1 (hereditary prostate cancer 1) by the researchers, is situated on the long arm of chromosome 1. The finding, to be published in the November 22 issue of the journal Science*, is the first proof that genes conferring hereditary predisposition to prostate cancer exist.
Scientists discovered the gene location through an international study involving 91 families in which at least three members suffered from prostate cancer. The region implicated represents about 0.3 percent of the human genome and will now be the subject of intense scrutiny to identify the gene responsible. Once the HPC-1 gene itself is identified, it is expected to shed light on how and why prostate cancer develops and also suggest strategies for preventing and treating it.
"The application of genetic tools to the understanding of common disorders is becoming a state-of-the-art strategy in biomedical research, " said Donna Shalala, Secretary of the U.S. Department of Health and Human Services. "Discoveries such as this one continue to bear out the wisdom of our national investment in genetics technology for understanding human illness."
Although the disease has been known to run in families, genetic analyses of prostate cancer have been difficult. In the United States, men stand a one-in-five chance of developing prostate cancer; the most common malignancy among men and the cause of more than 40,000 deaths annually. That indicates many different factors, genetic and environmental, may contribute to the disease. A high-fat diet, cigarette smoking, and multiple sexual partners are among the environmental suspects, but none has definitely been established as a risk factor. In addition, nearly all prostate cancer is diagnosed late in life, so an affected man's ancestors are rarely available for studies that might explain the part genes play in the disease.
Approximately 1 in every 500 men is believed to possess an altered version of the gene. The researchers estimate that alterations in the HPC-1 gene are responsible for at least a third of familial prostate cancer. Familial prostate cancer accounts for about 1 in 10 cases of the disease, while the numbers for the early onset form of the disease are somewhat higher.
"We know this gene seems to contribute to prostate cancer risk in a number of ethnic backgrounds," says Dr. Jeffrey Trent, scientific director of NCHGR's division of intramural research and head of the laboratory where the genotyping was conducted. "There's linkage in Swedish families as well as American families, including African-American families," adds Trent.
Development of a susceptibility test is still several steps away, requiring at a minimum the identification of the HPC-1 gene itself, according to NCHGR Director Dr. Francis Collins. "In the future," says Collins, "combining genetic susceptibility testing with testing for prostate-specific antigen and other early detection measures will be potentially of value in preventing deaths from this common disorder."
The study focused first on analyzing data and tissue samples from 66 high-risk American families collected by Johns Hopkins researchers. Most of the families were recruited through letters from urologists, and some were identified through media advertisements. At NCHGR, a genome-wide scan of DNA from these families indicated a gene on chromosome 1. The site was confirmed by analyzing DNA from an additional 13 high-risk American families and 12 high-risk families studied by scientists at Umea University.
"This is a monumental advance that could not have been achieved without the dedicated assistance of the families with hereditary prostate cancer, their referring physicians and the scientists working on this project," says Dr. Patrick Walsh, urologist-in-chief and director of John's Hopkins Brady Institute.
NCHGR's Jeff Smith, first author of the paper, agrees. "The power of this study came from the recognition by clinicians that this disease had a familial component. It's challenging to collaborate on this scale. I hope it will stimulate clinicians to think about how to organize other studies like this. We can use this project as a model for future approaches to disease."
"There have been arguments up to the present day that this type of study would be a total failure, that prostate cancer was so common and so complex that finding genes that predispose to the disease was going to be impossible," says Trent.
NCHGR's recent report of a major gene for Parkinson's disease is another example of such a discovery, notes Trent. "The same thing has been said about multiple sclerosis, diabetes, schizophrenia, hypertension, and other complex diseases. These diseases are so common that in the past geneticists have said we can't address them. But a study like this shows that they really are approachable. And the information we get from them will ultimately be of tremendous benefit to patients."
The number of prostate cancer cases varies widely among different ethnic groups. African-American men suffer the highest incidence rate in the world, more than 180 cases annually per 100,000 population, and their death rate is also the highest, about 54 per 100,000. Both of the African-American families included in the study showed linkage to the site of HPC-1, suggesting that the gene may eventually help explain why African-American men are exceptionally vulnerable to the disease. In the U.S., incidence is quite high also (almost 135 cases per 100,000) among white men, lower (around 89 cases per 100,000) among Hispanic and Japanese men, and lowest of all in other groups whose ancestors came from Asia. It is estimated that 317,000 American men will be diagnosed with prostate cancer this year.
"The study provides the first strong evidence that specific genes for prostate cancer do exist," says Dr. William Isaacs, associate professor of urology and oncology at Hopkins. "And it's a major step toward finding those genes."
Hopkins researchers are asking individuals from families in which three or more close relatives have had prostate cancer and who wish to participate in a research study on the genetics of that disease to contact the study team at (410) 614-5434, or write to Dr. Patrick C. Walsh, Hereditary Prostate Cancer Study, Dept. W., Brady Urological Institute, Johns Hopkins University Hospital, Baltimore, MD 21287.
For more information about prostate cancer, call the Cancer Information Service at 1-800-4-CANCER.
Part of this study was funded by the NIH's National Cancer Institute.
The National Center for Human Genome Research, a component of the
National Institutes of Health, is a major partner in the Human Genome Project,
the international research effort to map the estimated 50,000-100,000 genes and
read the complete set of genetic instructions encoded in human DNA. NCHGR also
supports research on the application of genome technologies to the study of
inherited disease, as well as the ethical, legal, and social implications of
this research. For more information about NCHGR or the Human Genome Project,
visit our World Wide Web site: http://www.
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*"Major Susceptibility Locus for Prostate Cancer on Chromosome 1 Revealed by a Genome-Wide Search," by J.R. Smith, J. Carpten, O. Kallioniemi, J. Walker-Daniels, J. Bailey-Wilson, F. Collins, and J. Trent, National Center for Human Genome Research, NIH in Bethesda, MD; D. Freije, H. Gronberg, S. Isaacs, G.S. Bova, H. Guo, P. Bujnovsky, D. Nusskern, P. Walsh, W. Isaacs, J. Xu, and D. Meyers, Johns Hopkins School of Medicine in Baltimore, MD; M. Brownstein, National Institute of Mental Health, NIH; T. Beaty, JHU School of Hygiene and Public Health, Baltimore; J. Smith, University of Michigan, Ann Arbor; H. Gronber, M. Emanuelsson, J.-E. Damber, and A. Bergh at Umea University, Sweden, Vol. 274, pp. 1371-1374, November, 22, 1996.
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