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," Tian-Li Wang, assistant
gynecology/obstetrics and oncology,
The scientists' findings, reported in the Sept. 27
issue of 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 vs. 36
months from date of primary surgery.
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. 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
According to Ie-Ming Shih, associate professor of
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 said.
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
Rsf-1 typically opens and closes the scaffolding
structure of DNA, which acts as the gatekeeper to protein
manufacturing. The Johns 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," Wang said. "But right now, we'll need to test
larger samples to determine if Rsf-1 accurately predicts
Funding for this research was provided by the U.S.
Department of Defense, National Institute of Health,
Alexander and Margaret Stewart Trust and Richard TeLinde
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.