Gene used in brain development can cause childhood brain cancers

Feb 3 2005

A gene that's normally silenced after contributing to brain development was found to be expressed in cells from medulloblastoma, the most common form of pediatric brain malignancy in children, scientists report in an article published in the February 1 issue of the journal Cancer Research.

In their study, the scientists discovered that multiple extra copies of the gene, called OTX2, had been switched back on among tumor cells removed from patients with medulloblastoma brain tumors. In the United States, medulloblastoma accounts for approximately 30 percent of all pediatric brain tumors.

Further, the scientists discovered that a potent derivative of Vitamin A, known as all trans-retinoic acid or ATRA, suppressed growth and induced cell death among the OTX2-laden tumor cells. More than half of medulloblastomas grown in the laboratory responded to ATRA treatment.

"The response that ATRA imposes upon these medulloblastoma brain tumor cell lines suggests that this type of tumor may respond favorably to ATRA-based therapy," said Hai Yan, M.D., Ph.D., the principle investigator of the study at the Brain Tumor Center at the Duke University Medical Center.

"ATRA is already clinically approved for the treatment of acute promyelocytic leukemia. These studies lay the conceptual and practical framework for clinical trials using ATRA in the treatment of a commonly lethal pediatric disease."

Yan said that the OTX2 gene normally contributes to development and growth of certain areas of the brain, such as the cerebellum, but the gene is generally turned off and no longer used after birth.

Using a novel technique that involves snipping apart the entire DNA content in the chromosomes of medulloblastoma cells and then analyzing the quantity of each, Yan and his colleagues detected an abnormally amplified segment among the tumor cells on chromosome 14.

"There was a striking amplification of genetic coding representing a 28-fold increase in base pairs of DNA in that specific region of chromosome 14," Yan said. The researchers identified OTX2 as the only gene contained within the amplified region of the chromosome.

The scientists also determined that 60-70 percent of the medulloblastoma cells were churning out large numbers of messenger RNA specific for OTX2, compared to normal cells which generally show no activity for this gene.

This latter finding suggested another approach, RNA interference, to blocking OTX2 activity. Discovered in the late 90's, RNA interference or RNAi refers to the introduction of double-stranded RNA (dsRNA) into a cell, where it induces the degradation of complementary messenger RNA, thereby suppressing the gene expression.

"In our studies, we applied several specifically designed RNAi to the tumor cells that expressed OTX2," Yan said. "We then observed that the RNAi knocked down OTX2 expression and killed the tumors cells which expressed OTX2. In contrast, the RNAi did not do any damage to the cells which did not express OTX2."

Among the researchers working with Yan to investigate the OTX2 gene in medulloblastomas were, Chunhui Di, Shaoxi Liao M.D, Ph.D, David C. Adamson, M.D., Ph.D., Timothy J. Parrett, M.D., Daniel K. Broderick, Qun Shi, Roger E. McLendon, M.D., and Darell D. Bigner, M.D., Ph.D. from the Brain Tumor Center, Department of Pathology, Duke University Medical Center, Durham, N.C.; Christoph Lengauer, Ph.D., Jordan M. Cummins, and Victor E.Velculescu, M.D., Ph.D. from The Johns Hopkins University Medical Institutions, Baltimore, Md.; and Daniel W. Fults, M.D. from the University of Utah School of Medicine, Salt Lake City, Utah.

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