Gene fusion discovery may lead to improved prostate cancer test

NEW YORK (April 9, 2009) -- A newly discovered gene fusion is highly expressed in a subset of prostate cancers, according to a study by researchers at Weill Cornell Medical College. The findings, reported in the April 1 issue of Cancer Research, may lead to more accurate tests for prostate cancer. The gene fusion biomarker is also a different type of fusion than researchers have found in cancer previously and may represent an entirely new mechanism that cancer cells use to outgrow their healthy neighbors.

The SLC45A3-ELK4 gene fusion is detectable at high levels in the urine of some men at risk for prostate cancer. If these data are validated, it may be that in the future men could be tested for prostate cancer through a simple urine test. If the fusion gene is present at a high level, they likely have the disease, and if not, they likely don't have it.

"We think this is going to be a potentially important diagnostic marker in prostate cancer," says senior author Dr. Mark A. Rubin, the Homer T. Hirst Professor of Oncology in Pathology, professor of pathology and laboratory medicine, and vice chair for experimental pathology at Weill Cornell Medical College. "PSA testing is inadequate. PSA detects men with cancer but also many men with benign conditions. As we have seen recently from two major studies on PSA screening, for every 50 men with a positive PSA screening, only one man's life is saved. We urgently need biomarkers to detect clinically significant prostate cancer."

"Our work has a long-term goal of achieving a test that distinguishes clinically significant prostate cancer from indolent disease that does not require additional treatment. With better diagnosis, we will be able to treat cancer patients with individualized therapies -- one of the main goals of the Cancer Center at NewYork-Presbyterian Hospital/Weill Cornell Medical Center," continues Dr. Rubin, who is the Center's associate director of translational research and a pathologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

Dr. Rubin's team is already working with a company to develop a urine test for prostate cancer using a chromosome-based gene fusion called TMPRSS2-ERG that the team discovered previously while working with members of Dr. Arul Chinnaiyan's research group at the University of Michigan. Dr. Rubin anticipates that the newly discovered SLC45A3-ELK4 gene fusion may be added to that urine test in the future to increase its accuracy and also to potentially help determine the level of response to certain non-surgical systemic treatments. The TMPRSS2-ERG urine test is being evaluated in multiple early clinical trials in the United States and Europe.

Novel Gene Fusion Sheds Light on How Cancer Works

Unlike the gene fusions previously found in cancers, which arise when two chromosomes join together in an abnormal way, the new fusion occurs when the genes are being copied into RNA. The two genes, SLC45A3 and ELK4, reside next to one another on the chromosome in normal and prostate cancer cells. However, when the genes are copied into RNA in the prostate cancer cells, they frequently generate a single RNA message that fuses information from both genes. Ongoing work is exploring the potential biologic implications of this discovery. However, the diagnostic implications are more immediate because these types of genetic chimera occur at significantly higher levels in abnormal tumor cells.

"We think this type of gene fusion might be a common mechanism in cancer," Dr. Rubin says. "This expands our understanding of how tumor cells may hijack androgen-regulated genes with neighboring genes and effectively alter its regulation. This may be a way tumors gain a competitive advantage."

Additional co-authors include Dr. David S. Rickman, Ms. Dorothee Pflueger, Mr. Benjamin Moss, Ms. Vanessa E. VanDoren, Mr. Chen X. Chen, Dr. Ashutosh K. Tewari and Dr. Francesca Demichelis from Weill Cornell Medical College; Dr. Alexandre de la Taille from the CHU Mondor (Créteil, France); Dr. Rainer Kuefer from Ulm University Hospital (Ulm, Germany); and Dr. Sunita R. Setlur from the Brigham and Women's Hospital, Boston.

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Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Weill Cornell, which is a principal academic affiliate of NewYork-Presbyterian Hospital, offers an innovative curriculum that integrates the teaching of basic and clinical sciences, problem-based learning, office-based preceptorships, and primary care and doctoring courses. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research in areas such as stem cells, genetics and gene therapy, geriatrics, neuroscience, structural biology, cardiovascular medicine, transplantation medicine, infectious disease, obesity, cancer, psychiatry and public health -- and continue to delve ever deeper into the molecular basis of disease in an effort to unlock the mysteries of the human body in health and sickness. In its commitment to global health and education, the Medical College has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, the first indication of bone marrow's critical role in tumor growth, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. For more information, visit www.med.cornell.edu.

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