The intramural research program of the NHGRI continues to focus significant effort on the identification of genes important in hereditary susceptibility to prostate cancer as well as genes involved in sporadic cases and disease progression. In the past, genetic contributions to most common diseases were virtually impossible to sort out. NHGRI intramural studies of prostate cancer provide a compelling example of how research tools developed by the Human Genome Project are bringing clarity to such scientifically murky health problems. Because prostate cancer clusters in some families, especially when the onset is early, researchers have suspected the disorder has a strong genetic component. That suspicion was borne out two years ago when an international team of researchers, led by scientists at the NHGRI and Johns Hopkins, located a region on chromosome 1 that appears to contain a gene variation (HPC1) that predisposes men to prostate cancer. This was the first proof that prostate cancer risk is controlled by specific genes.
Less than six months ago, studying over 300 families, each with many affected men, the same team of researchers found a second site, on the X chromosome (HPCX), that also appears to contribute to the development of prostate cancer. These discoveries pinpoint the neighborhood in which two prostate cancer susceptibility genes must lie. In a "house to house" search of those chromosomal regions, NHGRI investigators now are working vigorously to identify the precise genes and the misspellings on both chromosomes that correlate with risk of prostate cancer. In this way, Human Genome Project tools are allowing scientists to develop a comprehensive understanding of the causes of prostate cancer. Improved understanding of the molecular causes of prostate cancer will lead to better abilities to predict which men are at highest risk, which can allow them to be carefully watched for early signs of prostate cancer. In the longer term, better understanding of this disease will expand potential areas for new therapies and provide a fundamentally new paradigm for sorting out the hereditary, environmental, and socio-economic bases of human illness.
Genetic Factors - African American Men
While prostate cancer is common among all U.S. males, it is especially common among African-American men. African American men are 35 percent more likely than their white male counterparts to develop the disease and more than twice as likely to die from it. Researchers based at NHGRI and Howard University, supported by funds provided from the NIH Office of Research on Minority Health, are heading a nationwide study that applies the full force of genome technologies to attempt to explain the causes of this apparent disparity. Are men of African descent inherently more susceptible to prostate cancer, and what role do other community-based factors play? The Howard-NHGRI study is being carried out primarily by black scientists and doctors located in seven study centers around the country. So far, 31 large African-American families with several affected men have volunteered medical histories and blood samples that will be used to zero in on prostate cancer-related gene alterations on chromosomes 1, X, and others. In the next few years, these studies will bring a much broader understanding of this very common disorder, and ideally suggest new ways to intervene, treat, or even prevent it.
Genetic Changes - Prostate Cancer Cells
While hereditary factors are heavy contributors to the development of prostate cancer for some men, most prostate cancer results from changes in the genetic material of individual cells that occur throughout life. Using the techniques of modern genomics, NHGRI investigators are seeking to define the genetic changes in cells that lead to the initiation and progression of prostate cancer.
Several developing technologies now are being used to gain insight into the human cell and to transform the study of human genetics. Much of it is borrowed from the computer chip industry and the devices are often called "DNA chips." In most experiments in the past investigators have looked at one gene at a time. Yet humans are thought to have tens of thousands of genes, and they work in concert or committees (scientists call these pathways) to get things accomplished. Ultimately, to really understand the behavior of the human organism, and what goes wrong when a disease occurs, what we would really like to be able to do is look at the behavior of all the genes in a single experiment. That might finally provide a true picture of what's going on inside the body.
Work emanating in part from the NHGRI's intramural research program has developed robotic tools to touch the surface of a microscope slide and leave behind a microscopic drop of fluid. Each drop contains millions of strands of DNA-copies of a single gene. The current model is capable of creating an array of 15,000 tiny drops on each of the slides. Each spot is a detector or specific assay reagent. The strands of DNA in it are like tiny pieces of Velcro that stick only to the products of one particular gene. When researchers pour the contents of a cell over that slide, the spots that pick up evidence of active genes can be made to glow. The thousands of glowing dots provide a landscape of active genes that could suggest how tumor cells work or how a cell responds to disease.
This approach is now being used to look at the changes in gene expression that occur as prostate tissue progresses from normal epithelium, to a pre-malignant state called "pin," to a low grade malignancy, to a higher grade malignancy, to a malignancy which is no longer hormonally responsive. In each state of progression, certain genes are turned on and off in a particular tumor, representing the pathways of control of cell growth that are contributing to the malignant state. Each of these changes represents a crucial clue to the pathogenesis of prostate cancer, and can suggest new ways of treating or preventing the disease.
Of course not every prostate cancer follows the same set of steps; when a pattern of abnormal gene expression is observed in a particular tumor, it is critical to determine whether this is a common or rare event. To explore this question, NHGRI investigators have developed the "Tissue Chip" -- hundreds of different tissue samples, derived from normal or malignant tissue, are arrayed on to a microscope slide using robotic technology. Using this chip, the over expression of a particular candidate prostate cancer gene can be assessed in one experiment in a very large number of tumors, and an analysis which would have taken many months in the past can be done in one day. In this way one can identify the major culprits in prostate cancer, and focus new interventions on these common themes.
Future Directions - NHGRI Prostate Cancer Research
Over the next five years, NHGRI investigators aim to identify all of the common contributing genes to hereditary susceptibility - besides HPC1 and HPCX, there is strong evidence pointing to another region of another chromosome, and other regions also contain hints of hereditary factors. As the precise genes are identified, clinical studies would be undertaken to offer genetic testing to men from high risk families, to identify those at greatest risk for life-threatening disease and design a program of surveillance to identify their cancers early enough to achieve cure. In addition, using the chip technology, the common changes in gene expression that contribute to various steps in malignant transformation would be cataloged, and used to derive new hypotheses about the molecular steps involved in prostate cancer. These would in turn suggest new and more powerful ways to treat or prevent the disease.
National Center for Research Resources
Through its support of multidisciplinary research infrastructure, the National Center for Research Resources (NCRR) is uniquely positioned to provide complementary research support in partnership with other institutes or Centers to address clinical and basic research needs for prostate cancer research. The NCRR can provide the infrastructure support for clinical trials and other related clinical studies, the development of animal models, development of new technologies and instrumentation, including imaging technologies. This support would facilitate interdisciplinary collaborations across NIH components and would advance efforts to develop more sensitive and specific screening technologies and more effective therapeutic interventions.