Johns Hopkins Kimmel Cancer Center scientists have completed a comprehensive map of genetic mutations occurring in the second-most common form of brain cancer, oligodendroglioma. The findings, reported in the Aug. 4 issue of Science, also appear to reveal the biological cause of the tumors, they say.
To create the map, the scientists sequenced protein-coding genes in seven oligodendroglioma tissue samples, and focused attention on recurring mutations in two genes not previously associated with these tumors -- CIC and FUBP1. The investigators say that CIC and FUBP1 are known to regulate cell-signaling processes, and CIC mutations have been rarely linked to sarcoma, breast and prostate cancers.
More mutations in the two genes were found in an additional 27 oligodendroglioma samples. In all, two-thirds of the samples studied had CIC and FUBP1 mutations.
"Whenever we find genes mutated in a majority of tumors, it is likely that the pathway regulated by that gene is critical for the development and biology of the tumor," says Nickolas Papadopoulos, Ph.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.
In brain cancer, the Hopkins investigators say CIC and FUBP1 mutations may be the "missing link" in what scientists describe as a "two-hit" theory of cancer development. The theory is based on the fact that each cell in the human body has two copies of 23 chromosomes containing thousands of protein-producing genes. If a gene on one chromosome is damaged or deleted, the other copy makes up for the loss of protein. But if the second copy fails as well, the cell cannot make the proper protein and may become cancerous.
In oligodendrogliomas, the "first hit" has long been known to occur in regions of chromosome 1 and 19, which fuse together resulting in a loss of many genes on both chromosomes. Up to 70 percent of oligodendroglioma patients have these DNA fusions, and most of them respond better to chemotherapy and radiation than those who lack the deletions in the chromosomes. For more than a decade, researchers have been looking for evidence of a "second hit" in specific mutated genes that allow oligodendrogliomas to develop.
In the current study, the Johns Hopkins investigators found mutations in the remaining copies of the CIC and FUBP1 genes on chromosomes 1 and 19, suggesting that these mutations represent the second hit needed to create cancer.
"Thanks to the Human Genome Project and advances in cancer genome sequencing, a single study can now resolve decade-old questions and reveal the genetics of this brain cancer," says Kenneth Kinzler, Ph.D., professor and co-director of the Ludwig Center at Johns Hopkins. "Knowing the genetic roadmap of a cancer is the key to attacking it."
Oligodendrogliomas account for up to 20 percent of brain cancers and more commonly occur in younger people aged 30 to 45. The cancer forms most often in the frontal lobe of the brain in cells that coat neurons. Median survival of 10 years is considered far better than other brain cancers. Oligodendrogliomas are treated initially with surgery, followed by chemotherapy and radiation.
The research team says its next step will be to test whether patients with CIC and FUBP1 mutations have the same favorable prognosis as those who have the chromosome 1 and 19 fusion, says Chetan Bettegowda, M.D., Ph.D., chief resident in the Department of Neurosurgery at Johns Hopkins.
"We can focus now on when these mutations develop during tumor formation, whether they can guide prognosis, and how they might form targets for therapy," says Bettegowda.
Bettegowda says the gene map uncovered mutations in other genes, such as PIK3CA, which have been well-studied in cancer. It is possible, he says, that oligodendroglioma patients with mutations in PIK3CA or other genes could be enrolled in current clinical trials using experimental therapies that target these mutations.
Funding for the research was provided by the Virginia and D.K. Ludwig Fund for Cancer Research, the Pediatric Brain Tumor Foundation, the Duke Comprehensive Cancer Center Core, the Burroughs Wellcome Fund, the James S. McDonnell Foundation, state funding from Sao Paulo (FAPESP), the National Cancer Institute and National Institutes of Health.
Contributors to the research include Nishant Agrawal, Yuchen Jiao, Mark Sausen, Laura D. Wood, Ralph H. Hruban, Fausto J. Rodriguez, Daniel P. Cahill, Gregory Riggins, Victor Velculescu and Bert Vogelstein of Johns Hopkins; Roger McLendon, Darell Bigner and Hai Yan of Duke University; and Sueli Mieko Oba-Shinjo and Suely Kazue Nagahashi Marie of the University of Sao Paulo, Brazil.
Under agreements between the Johns Hopkins University, Genzyme, Exact Sciences, Inostics, Qiagen, Invitrogen and Personal Genome Diagnostics, Papadopoulos, Vogelstein, Kinzler and Velculescu are entitled to a share of the royalties received by the University on sales of products related to genes and technologies described in this manuscript. Papadopoulos, Vogelstein, Kinzler, and Velculescu are co-founders of Inostics and Personal Genome Diagnostics stock, which is subject to certain restrictions under Johns Hopkins University policy.
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