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Cancer Res. 2014 Mar 1;74(5):1440-1451. doi: 10.1158/0008-5472.CAN-13-2150. Epub 2014 Jan 3.

The transcriptional regulatory network of proneural glioma determines the genetic alterations selected during tumor progression.

Author information

1
Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, NY.
2
Department of Systems Biology, Columbia University, New York, NY.
3
Center for Computational Biology and Bioinformatics, Columbia University, New York, NY.
4
Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, NY.
5
Department of Molecular and Cellular Biochemistry, The Ohio State University Medical Center, Columbus, OH.
6
Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH.
7
Department of Biochemistry & Molecular Biophysics, Columbia University Medical Center, New York, NY.
8
Department of Biomedical Informatics, Columbia University, New York, NY.
9
Institute for Cancer Genetics, Columbia University, Columbia University, New York, NY.
10
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY.
#
Contributed equally

Abstract

Proneural glioblastoma is defined by an expression pattern resembling that of oligodendrocyte progenitor cells and carries a distinctive set of genetic alterations. Whether there is a functional relationship between the proneural phenotype and the associated genetic alterations is unknown. To evaluate this possible relationship, we performed a longitudinal molecular characterization of tumor progression in a mouse model of proneural glioma. In this setting, the tumors acquired remarkably consistent genetic deletions at late stages of progression, similar to those deleted in human proneural glioblastoma. Further investigations revealed that p53 is a master regulator of the transcriptional network underlying the proneural phenotype. This p53-centric transcriptional network and its associated phenotype were observed at both the early and late stages of progression, and preceded the proneural-specific deletions. Remarkably, deletion of p53 at the time of tumor initiation obviated the acquisition of later deletions, establishing a link between the proneural transcriptional network and the subtype-specific deletions selected during glioma progression.

PMID:
24390738
PMCID:
PMC3981545
DOI:
10.1158/0008-5472.CAN-13-2150
[Indexed for MEDLINE]
Free PMC Article

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