Geneticists hopes of unraveling the mysteries of prostate cancer have been buoyed by the recent announcement of evidence of a familial prostate cancer susceptibility gene, but that optimism is tempered by the fact that prostate cancer is difficult to genetically characterize and study.
Finding a single gene responsible for the lions share of hereditary prostate cancer cases is unlikely to happen, said Alice Whittemore, Ph.D., professor of biostatistics and epidemiology and chief of the Division of Epidemiology at Stanford University School of Medicine. "So far no one gene such as a BRCA1 is clearly emerging accounting for most of the familial cases of prostate cancer," she said.
In October, research teams from Myriad Genetics Inc. in Salt Lake City and the University of Pennsylvania in Philadelphia reported evidence showing mutations to a gene, HPC2, on chromosome 17 may be key to the development of hereditary prostate cancer. Whats more, they said, another mutated form of the genewhich apparently plays a role in DNA repair in both fruit flies and fungimay somehow be involved in the development of more common garden varieties of prostate cancer.
Myriad scientists uncovered HPC2 by analyzing DNA of large Mormon families in Utah that maintained detailed genealogic records. Men in the families seemed unusually likely to develop prostate cancer. The gene, they discovered, is altered only in men with prostate cancer. They determined that two relatively rare mutations of the gene were associated with a high prostate cancer risk and a third, more common mutation appeared to confer a moderate risk. Both groups studies showed that the rarer gene mutations raised the risk as much as 200 to 300 times normal.
Myriad researchers also found common polymorphisms in HPC2gene variations that were not necessarily associated with high risk of prostate cancer. One of those turned up more frequently in a sample of men with prostate cancer than in those without.
The Penn team subsequently examined a larger group of men with and without prostate cancer and confirmed the Utah findings, showing that the suspect forms of the gene were present more often in men with the disease. The findings suggested that the gene mutation might account for only 4% to 5% of prostate cancer cases.
As more susceptibility genes are uncovered, Myriad hopes to turn these results into a potential genetic test for the rare hereditary version of prostate cancer, and perhaps eventually, a test for general prostate cancer susceptibility. Myriad researchers and others detailed the work in February in the journal Nature Genetics.
But developing a susceptibility test will be particularly difficult. "Its very difficult to identify prostate cancer susceptibility genes," said Stephen Thibodeau, Ph.D., co-director of the DNA diagnostic laboratory and chair of the Division of Experimental Pathology at the Mayo Clinic in Rochester, Minn.
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"Were dealing with an extraordinary level of heterogeneity in prostate cancer," said Kenneth Offit, M.D., chief of the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center in New York. "Finding these susceptibility alleles will be a huge boon to chemoprevention," he noted. "It will lead to better understanding of the prostate cancer disease process and more rational pharmacology. But translating that clinically to families will be a difficult challenge."
Sporadic vs. Hereditary
Some consider HPC2 unusual because it appears to be involved in both hereditary, high-risk prostate cancer and the more common random, non-hereditary version.
But according to Elaine Ostrander, Ph.D., an associate member in the Divisions of Human Biology and Clinical Research at the Fred Hutchinson Cancer Research Center in Seattle, "Genes that contribute to both hereditary and sporadic forms of disease are difficult to find, but I think scientists suspect that the same may be true for many diseases, especially those that are complex like prostate cancer. So few hereditary cancer genes have been cloned, were just starting to find out the roles they may play in sporadic cancer."
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"While the initial work is certainly encouraging, large groups of men with prostate cancer, drawn from the general population, as well as high-risk families that have unusually high levels of prostate cancer, need to be carefully examined," Ostrander said. "We want to learn more about the geneits function in the cell and the roles of its forms in contributing to variability of risk."
In addition to conducting large family studies to identify potential prostate cancer genes, researchers use a "candidate gene" approach, looking at known biochemical pathways thought to be involved in prostate cancer. These would include genes for androgen receptors and genes involved in testosterone metabolism, DNA repair, and carcinogen metabolism, for example.
Researchers believe there are two major types of genes that raise the risk for diseases such as prostate cancer. Damage to high-penetrance genes such as BRCA1 and MLH1, MSH2, and APC greatly increase the likelihood of hereditary breast and colon cancer, respectively. Such genes account for only a small percentage of those cancers and are passed on through generations in families. A much larger number of cancers are caused by different types of gene mutations that dont necessarily inactivate a gene but may slightly change its function. Low-penetrance genes may be present in many individuals but activated in few, playing a lesser role in the cancerous process.
Potential Abounds
"The implications of HPC2 are potentially great," said William Isaacs, Ph.D., professor of urology at Johns Hopkins University in Baltimore, who led the team that reported in 1996 the existence of the first prostate cancer gene, HPC1, on chromosome 1. "The key issue is the ability to examine the gene in other study populations and repeat the result and see how it looks," Isaacs said. "What one group sees in its population may be very different than what another groups sees in its population."
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