Johns Hopkins Kimmel Cancer Center researchers have linked alterationsin a gene, called Rsf-1, to the most deadly ovarian cancers. Thescientists say the discovery is the first to establish a role for thegene in ovarian cancer and may lead to a test that can predict, earlyon, which patients will develop aggressive disease.
"We hope new therapies can be tailored to target Rsf-1, in the same waythat Herceptin for breast cancer attacks the Her2/neu gene pathway,"says Tian-Li Wang, Ph.D., assistant professor of gynecology/obstetricsand oncology at Johns Hopkins.
The scientists' findings, reported in the September 27 issue ofthe Proceedings of the National Academy of Sciences, described a surgein the number of Rsf-1 gene copies in 13.2 percent (16 of 121) of highgrade ovarian cancers, but not in low grade or benign ovarian tumors.Normally, cells contain two copies of every gene. In cancer cells, thecopying mechanism goes haywire creating dozens of gene copies in aprocess called amplification.
Survival data showed that the 16 patients with Rsf-1 amplificationfared worse than patients without the ramped-up genes, living anaverage of 29 months versus 36 months.
Hopkins scientists discovered their first clues to Rsf-1 after siftingthrough the entire genome of seven ovarian cancer cell lines using amethod developed three years ago with their Johns Hopkins colleague,Victor Velculescu, M.D., Ph.D. The search tool digitizes genetic codeand pinpoints abnormalities within precise regions of the DNA, much theway global mapping tools zoom in on specific addresses.
According to Ie-Ming Shih, M.D., Ph.D., associate professor ofpathology and oncology, who co-directs the laboratory with Wang, othergene typing methods can identify abnormalities within wide areas of thegenome, but the tool used for this study, called digital karyotyping,is far more precise. "It's like narrowing down our search from theentire State of Maryland to a certain building in Baltimore City," hesays.
In three of the seven cell lines, the scientists homed in onchromosome 11 after finding high levels of amplification in a regionknown for cancer-related genes. Further analysis of this regionrevealed that the Rsf-1 gene was overexpressed far more than 12 othergenes in the same area.
Rsf-1 typically opens and closes the scaffolding structure of DNA,which acts as the gatekeeper to protein manufacturing. The Hopkinsscientists say that when Rsf-1 is amplified, it may disturb thisprocess and create more space for protein production of certain genesthat may promote tumor growth.
"It's important for us to learn more about how Rsf-1 creates aggressivecancers in order to develop drugs that target it," says Wang. "Butright now, we'll need to test larger samples to determine if Rsf-1accurately predicts clinical outcome."
Funding for this research was provided by the U.S. Department ofDefense, the National Institute of Health, the Alexander and MargaretStewart 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, GiovanniParmigiani, Robert J. Kurman, Clas G. Trope, and Ben Davidson.
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