Johns Hopkins Kimmel Cancer Center researchers have linked alterations in a gene, called Rsf-1, to the most deadly ovarian cancers. The scientists say the discovery is the first to establish a role for the gene in ovarian cancer and may lead to a test that can predict, early on, which patients will develop aggressive disease.
"We hope new therapies can be tailored to target Rsf-1, in the same way that Herceptin for breast cancer attacks the Her2/neu gene pathway," says Tian-Li Wang, Ph.D., assistant professor of gynecology/obstetrics and oncology at Johns Hopkins.
The scientists’ findings, reported in the September 27 issue of the Proceedings of the National Academy of Sciences, described a surge in the number of Rsf-1 gene copies in 13.2 percent (16 of 121) of high grade ovarian cancers, but not in low grade or benign ovarian tumors. Normally, cells contain two copies of every gene. In cancer cells, the copying mechanism goes haywire creating dozens of gene copies in a process called amplification.
Survival data showed that the 16 patients with Rsf-1 amplification fared worse than patients without the ramped-up genes, living an average of 29 months versus 36 months.
Hopkins scientists discovered their first clues to Rsf-1 after sifting through the entire genome of seven ovarian cancer cell lines using a method developed three years ago with their Johns Hopkins colleague, Victor Velculescu, M.D., Ph.D. The search tool digitizes genetic code and pinpoints abnormalities within precise regions of the DNA, much the way global mapping tools zoom in on specific addresses.
According to Ie-Ming Shih, M.D., Ph.D., associate professor of pathology and oncology, who co-directs the laboratory with Wang, other gene typing methods can identify abnormalities within wide areas of the genome, but the tool used for this study, called digital karyotyping, is far more precise. "It’s like narrowing down our search from the entire State of Maryland to a certain building in Baltimore City," he says.
In three of the seven cell lines, the scientists homed in on chromosome 11 after finding high levels of amplification in a region known for cancer-related genes. Further analysis of this region revealed that the Rsf-1 gene was overexpressed far more than 12 other genes in the same area.
Rsf-1 typically opens and closes the scaffolding structure of DNA, which acts as the gatekeeper to protein manufacturing. The Hopkins scientists say that when Rsf-1 is amplified, it may disturb this process and create more space for protein production of certain genes that may promote tumor growth.
"It’s important for us to learn more about how Rsf-1 creates aggressive cancers in order to develop drugs that target it," says Wang. "But right now, we’ll need to test larger samples to determine if Rsf-1 accurately predicts clinical outcome."
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Funding for this research was provided by the U.S. Department of Defense, the National Institute of Health, the Alexander and Margaret Stewart Trust fund and the Richard TeLinde Endowed Fund.
Other study authors include Jim Jinn-Chyuan Sheu, Antonio Santillan, Kentaro Nakayama, M. Jim Yen, Robert E. Bristow, Russell Vang, Giovanni Parmigiani, Robert J. Kurman, Clas G. Trope, and Ben Davidson.
