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
"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
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.nchgr.nih.gov/
1 "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.