Genetic determinants of malignancy in a mouse model for oligodendroglioma.
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 S100 beta 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.
Weiss
William A
WA
Department of Neurology, University of California, San Francisco, California 94143-0663, USA. weiss@cglucsf.edu
Burns
Michael J
MJ
Hackett
Christopher
C
Aldape
Ken
K
Hill
John R
JR
Kuriyama
Hiroko
H
Kuriyama
Nagato
N
Milshteyn
Nadezhda
N
Roberts
Tim
T
Wendland
Michael F
MF
DePinho
Ron
R
Israel
Mark A
MA
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002869:Chromosome Aberrations; D033481:Chromosomes, Mammalian; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D018773:Genes, erbB-1 / Q000235:genetics*; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009154:Mutation; D009414:Nerve Growth Factors / Q000235:genetics; D009837:Oligodendroglioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018739:Oncogene Proteins v-erbB / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000235:genetics; D014407:Tumor Cells, Cultured
D019941:Cyclin-Dependent Kinase Inhibitor p16; D009414:Nerve Growth Factors; D018739:Oncogene Proteins v-erbB; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; D066246:ErbB Receptors