title: The transcriptional regulatory network of proneural glioma determines the genetic alterations selected during tumor progression.
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.
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, NY.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Sonabend
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY.|Center for Computational Biology and Bioinformatics, Columbia University, New York, NY.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Bansal
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY.|Center for Computational Biology and Bioinformatics, Columbia University, New York, NY.
authors.forename: Paolo
authors.initials: P
authors.lastname: Guarnieri
authors.affiliation: Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, NY.
authors.forename: Liang
authors.initials: L
authors.lastname: Lei
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, NY.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Amendolara
authors.affiliation: Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, NY.
authors.forename: Craig
authors.initials: C
authors.lastname: Soderquist
authors.affiliation: Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, NY.
authors.forename: Richard
authors.initials: R
authors.lastname: Leung
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, NY.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Yun
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, NY.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kennedy
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, NY.
authors.forename: Julia
authors.initials: J
authors.lastname: Sisti
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, NY.
authors.forename: Samuel
authors.initials: S
authors.lastname: Bruce
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, NY.
authors.forename: Rachel
authors.initials: R
authors.lastname: Bruce
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University Medical Center, Columbus, OH.
authors.forename: Reena
authors.initials: R
authors.lastname: Shakya
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University Medical Center, Columbus, OH.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.affiliation: Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH.
authors.forename: Steven
authors.initials: S
authors.lastname: Rosenfeld
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY.|Department of Biochemistry & Molecular Biophysics, Columbia University Medical Center, New York, NY.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Sims
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, NY.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY.|Center for Computational Biology and Bioinformatics, Columbia University, New York, NY.|Department of Biochemistry & Molecular Biophysics, Columbia University Medical Center, New York, NY.|Department of Biomedical Informatics, Columbia University, New York, NY.|Institute for Cancer Genetics, Columbia University, Columbia University, New York, NY.|Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY.
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, NY.|Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, NY.
authors.forename: Peter
authors.initials: P
authors.lastname: Canoll
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics*; D005910:Glioma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D051379:Mice; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D016159:Tumor Suppressor Protein p53