BETHESDA, MD - For the first time, scientists have publicly reported that they found a gene on chromosome 1 that's associated with an inherited form of prostate cancer in some families. The findings, released on the Internet today in the Advance Online Publication of Nature Genetics (http://www.nature.com/ng/), will be published in the February issue of the journal by researchers at the National Human Genome Research Institute, Johns Hopkins Medical Institutes, the Cleveland Clinic and their collaborators.
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.
Citation:
Germline Mutations in the Ribonuclease L (RNASEL) Gene in Hereditary Prostate Cancer 1 (HPC1) Linked Families, Nature Genetics, Volume 30, Pages 1-4, February 2002.
Reporters can get the full text at http://press.nature.com.
The research paper lists the following authors and their affiliations:
John Carpten1, Nina Nupponen1, Sarah Isaacs2, Raman Sood1, Christiane Robbins1, Jianfeng Xu3, Mezbah Faruque1, Tracy Moses1, Charles Ewing2, Elizabeth Gillanders1, Ping Hu1, Piroska Bujnovszky2, Izabela Makalowska4, Agnes Baffoe-Bonnie5,6, Dennis Faith2, Jeffrey Smith7, Dietrich Stephan8, Kathleen Wiley2, Michael Brownstein9, Derek Gildea1, Brian Kelly2, Robert Jenkins10, Galen Hostetter1, Mika Matikainen11, Johanna Schleutker11, Kathy Klinger12, Tim Connors12, Ying Xiang13, Zhengfu Wang13, A. Demarzo2, Nickolas Papadopoulos14, Olli-P. Kallioniemi1, Robert Burk15, Deborah Meyers3, Henrik Grönberg16, Paul Meltzer1, Robert Silverman13, Joan Bailey-Wilson5, Patrick Walsh2, William Isaacs2, Jeffrey Trent1.
1 Cancer Genetics Branch, 4 Genome Technology Branch, and 5 Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD 20892
2 Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD 21287 3 Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157 6 Division of Population Sciences, Fox Chase Cancer Center, Philadelphia, PA 19012 7 Division of Genetic Medicine, Vanderbilt University, Nashville, TN 37235 8 Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC 20010 9 Laboratory of Genetics, National Institute of Mental Health, NIH, Bethesda, MD 20892 10 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905 11 Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland 12 Genzyme Genetics Corporation, Framingham, MA 01701 13 Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, USA. 14 Institute of Cancer Genetics, Department of Pathology, Columbia University, New York, NY 10032 15 Department of Microbiology and Immunology, Albert Einstein School of Medicine, Yeshiva University, Bronx, NY 10461 16 Department of Oncology, Umeå University, Umeå, SwedenJournal
Nature Genetics