Researchers Link Gene To Hereditary Form Of Prostate Cancer

Ever since 1992, when Johns Hopkins researchers first showed that some forms of prostate cancer could be inherited, scientists have intensely searched for specific genes that cause the disease. In 1996, NHGRI scientists, in collaboration with researchers at Johns Hopkins and in Sweden, studied 91 high-risk prostate cancer families and mapped the first hereditary susceptibility to prostate cancer to a region of chromosome 1 that they called the Hereditary Prostate Cancer 1 Region, or HPC1. Since then, these and other research teams have mapped prostate cancer susceptibly genes to two other parts of chromosome 1, as well as to chromosomes 17, 20 and X.

Now, researchers at NHGRI and Johns Hopkins have identified a specific gene -- called ribonuclease L or RNASEL - in the HPC1 region that contains mutations associated with prostate cancer in some families with a history of the disease. The scientists found mutations that inactivate the RNASEL gene. Scientists at the Cleveland Clinic Foundation have been studying RNASEL for years and have shown that it plays a role in defending cells from viruses and assists in normal cell turnover or programmed cell death. Inactivating this cellular self-destruct mechanism through genetic mutation may explain why some prostate cells become cancerous.

Mutations in this one gene, however, do not explain all forms of inherited prostate cancer, cautioned John D. Carpten, Ph.D., an NHGRI cancer genomics researcher and the paper's lead author, adding, "This is not the only gene involved in prostate cancer. We know that mutations in any number of genes can lead to the development of prostate cancer, and this gene possibly represents a new member in the repertoire of prostate cancer genes."

These germline or hereditary mutations often do not explain the so-called sporadic cases that are not inherited. Sporadic prostate cancer is much more common and is caused by genetic mutations that arise spontaneously in the genes of prostate cells in adult males. In the United States, there is an approximately 16 percent likelihood that an adult male will develop prostate cancer sometime in his life. Of the more than 189,000 cases of prostate cancer diagnosed each year, researchers believe only about 9 percent are hereditary.

Despite these limitations, said Jeffrey M. Trent, Ph.D., NHGRI's scientific director, chief of the Cancer Genetics Branch and the paper's senior author, "The new finding presents a tantalizing clue about the workings of the complex genetic machinery that leads to this common cancer."

"It has been clear for some time that hereditary factors play a major role in prostate cancer risk," added Francis S. Collins, M.D., Ph.D., director of the National Human Genome Research Institute. "The discovery of heritable inactivating mutations in a specific gene is an exciting step towards understanding the causes of this common and devastating form of cancer. Ultimately, this should bring us closer to better diagnosis, prevention, and cure."

This discovery will not immediately lead to new diagnostic tests or new treatments. "This is not the breakthrough gene that is going to solve everything," said Patrick C. Walsh, M.D., an author of the study and chairman of the James Buchanan Brady Urological Institute at Johns Hopkins Medical Institutes. But it does create a number of new research opportunities for better understanding prostate cancer. Eventually, an improved understanding will lead to better tests and treatments.

"We expect that there will be multiple genes involved in prostate cancer," Trent said, " and as we identify them, we should be able to put together a picture of the factors that convert a normal prostate into the most common cancer in men."

This research was coordinated by NHGRI's Division of Intramural Research and the Brady Urological Institute at Johns Hopkins. It was supported in part by grants from the U.S. National Institutes of Health, U.S. Public Health Service, U.S. Department of Defense, CaPCURE, The Fund for Research and Progress in Urology, The Johns Hopkins University, The Swedish Cancer Society, SSF Genome Programs, V Foundation for Cancer Research, Finnish Cultural Foundation, Paulo Foundation, Ella & Georg Ehrnrooth Foundation and Maud Kuistila Foundation.