The discovery sheds new light on how cells in the cerebellum called granule neuronal precursor cells (GNPs) give rise to medulloblastoma when certain genes are absent or not functioning normally. A report on this work appears in the November 15 issue of Genes & Development and is currently available online.
Based on these findings, the Pediatric Brain Tumor Program at St. Jude will try to determine if the absence or presence of the Ink4c gene or its protein in medulloblastoma cells can help doctors predict patient outcomes, according to Martine Roussel, Ph.D., a member of the Department of Genetics and Tumor Biology at St. Jude and senior author of the paper.
Medulloblastoma arises in the cerebellum, located in the lower, back part of the brain. The cerebellum processes information coming into the brain from the environment to help maintain balance and fine-muscle control. Ptch1 acts like a brake on the activity of a pathway of signals that drives the multiplication of cells; p53 activates a self-destruct mechanism in cells whose DNA is so severely damaged that they might become cancerous.
Previously, St. Jude investigators found evidence that Ink4c halts the cycle in which cells repeatedly make new DNA and divide into two daughter cells. By inhibiting this cell division cycle, Ink4c apparently forces GNPs to stop dividing and become specialized and migrate to their final, assigned location deep within the cerebellum. By halting cell division, Ink4c also reduces the chance that mutations arise in the cell's DNA, which is duplicated in each cycle. In a previous study, St. Jude researchers found evidence that inactivation of Ink4c, in combination with other genetic defects, increases the risk of GNPs becoming cancerous and causing medulloblastoma (Cancer Research; 2003 Sept 1; 63 (17):5428-37).
Based on this finding, the current team of investigators studied the specific roles played by Ink4c, Ptch1 and p53 in preventing medulloblastoma.
Part of their work was done using a laboratory model that the St. Jude team developed to study the genetic control of medulloblastoma. Reflecting years of laboratory model development by St. Jude researchers, the newest model proved to be more genetically similar to most human tumors in a key way. Previous models of medulloblastoma required eliminating the p53 gene, thereby permitting uncontrolled growth of certain nerve cells in the developing cerebellum. However, most human medulloblastoma cases have functional p53 genes. The team found that models lacking Ptch1 and either one or both Ink4c genes developed medulloblastoma even when p53 function was not subverted. Moreover, the incidence of medulloblastoma was the same regardless of whether one or both copies of Ink4c were missing.
"Interestingly, when p53 is inactivated, both copies of Ink4c must be disrupted, whereas when Ptch is lost, loss of one copy of Ink4c is enough to drive tumorigenesis," Roussel said. "The fact that the loss of just one copy of the Ink4c gene permits medulloblastoma to develop in certain settings shows that gene dosage is important in mediating the protective effect."
In the team's study of 23 human medulloblastoma samples, the Ink4c gene was not expressed in four cases; the section of DNA next to it, called the promoter, had been inactivated. Normally, promoters trigger their target genes to produce RNA, the decoded form of the gene that the cell uses to make a specific protein. In another study of medulloblastomas from 73 children, the investigators found that the Ink4c protein was absent in samples from 14 patients (19 percent) even though Ink4c was present and active.
"This suggests that something must happen to destroy the protein after it is made," said postdoctoral fellow Tamar Uziel, Ph.D. "And the absence of detectable p18INK4C protein in 19 percent of tumors strongly suggests that the loss of Ink4c contributes to the development of medulloblastoma," added Frederique Zindy (staff scientist). Uziel and Zindy did much of the work on this project.
Other authors of this study include Suqing Xie, Youngsoo Lee, Antoine Forget, Susan Magdaleno, Jerold E. Rehg, Christopher Calabrese, Sarah E. Sherr, Peter J. McKinnon, Richard J. Gilbertson, Tom Curran and Charles J. Sherr (St. Jude); David Solecki and Mary E. Hatten (Rockefeller University, New York); Charles G. Eberhart (Johns Hopkins University, Baltimore, Md.); and Sarah Plimmer and Steven C. Clifford (University of Newcastle, UK).
This work was supported in part by the Children's Brain Tumor Foundation, the V Foundation, a Cancer Center Core Grant from the National Cancer Institute and ALSAC. Sherr is a Howard Hughes Medical Institute investigator.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization. For more information, please visit www.stjude.org.
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Genes & Development