Cancer Research Infection and Cancer: Biology, Therapeutics, and Prevention AACR Conference on Molecular Diagnostics - 2008
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[Cancer Research 63, 1589-1595, April 1, 2003]
© 2003 American Association for Cancer Research

Molecular Biology and Genetics

Genetic Determinants of Malignancy in a Mouse Model for Oligodendroglioma1

William A. Weiss2, Michael J. Burns, Christopher Hackett, Ken Aldape, John R. Hill, Hiroko Kuriyama, Nagato Kuriyama, Nadezhda Milshteyn, Tim Roberts, Michael F. Wendland, Ron DePinho and Mark A. Israel

Departments of Neurology [W. A. W., M. B., C. H., N. M.], Pediatrics [W. A. W., M. B., C. H., N. M.], Neurological Surgery [W. A. W., M. B., C. H., J. R. H., H. K., N. K., N. M., M. A. I.], and Radiology [M.F.W.], University of California, San Francisco, California 94143-0663; M. D. Anderson Cancer Center, Houston, Texas 77030 [K. A.], University of Toronto, Toronto Ontario M5S 1A1 Canada [T. R.]; Dana Farber Cancer Institute, Boston, Massachusetts 02115 [R. D.]; and the Norris Cotton Cancer Center, Lebanon, New Hampshire 03756 [J. R. H., M. A. I.]

Oligodendrogliomas of all grades overexpress epidermal growth factor receptor (EGFR), whereas deletion of ink4a/arf is found only in high-grade tumors. We used the S100ß promoter to generate transgenic mice expressing v-erbB, a transforming allele of EGFR. These mice developed low-grade oligodendroglioma. Transgenic animals heterozygous for ink4a/arf or p53 developed high-grade tumors. Comparative genomic hybridization revealed loss of distal mouse chromosome 4, a region orthologous with human chromosome 1p, which is commonly lost in oligodendroglioma. Our results demonstrate that overexpression of EGFR, an epigenetic observation of uncertain significance in human oligodendroglioma, can initiate oligodendroglioma in the mouse. Furthermore, p53 pathway mutations can mediate the transition from low to high grade. These models hold promise for studying tumor lineage, identifying contributing genetic alterations and evaluating preclinical therapies in this important neoplasm.




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