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

Adam M. Sonabend, Mukesh Bansal, Paolo Guarnieri, Liang Lei, Benjamin Amendolara, Craig Soderquist, Richard Leung, Jonathan Yun, Benjamin Kennedy, Julia Sisti, Samuel Bruce, Rachel Bruce, Reena Shakya, Thomas Ludwig, Steven Rosenfeld, Peter A. Sims, Jeffrey N. Bruce, Andrea Califano, Peter Canoll

Research output: Contribution to journalArticle

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1440-1451
Number of pages12
JournalCancer research
Volume74
Issue number5
DOIs
StatePublished - Mar 1 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Sonabend, A. M., Bansal, M., Guarnieri, P., Lei, L., Amendolara, B., Soderquist, C., Leung, R., Yun, J., Kennedy, B., Sisti, J., Bruce, S., Bruce, R., Shakya, R., Ludwig, T., Rosenfeld, S., Sims, P. A., Bruce, J. N., Califano, A., & Canoll, P. (2014). The transcriptional regulatory network of proneural glioma determines the genetic alterations selected during tumor progression. Cancer research, 74(5), 1440-1451. https://doi.org/10.1158/0008-5472.CAN-13-2150