TY - JOUR
T1 - The transcriptional regulatory network of proneural glioma determines the genetic alterations selected during tumor progression
AU - Sonabend, Adam M.
AU - Bansal, Mukesh
AU - Guarnieri, Paolo
AU - Lei, Liang
AU - Amendolara, Benjamin
AU - Soderquist, Craig
AU - Leung, Richard
AU - Yun, Jonathan
AU - Kennedy, Benjamin
AU - Sisti, Julia
AU - Bruce, Samuel
AU - Bruce, Rachel
AU - Shakya, Reena
AU - Ludwig, Thomas
AU - Rosenfeld, Steven
AU - Sims, Peter A.
AU - Bruce, Jeffrey N.
AU - Califano, Andrea
AU - Canoll, Peter
PY - 2014/3/1
Y1 - 2014/3/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-13-2150
DO - 10.1158/0008-5472.CAN-13-2150
M3 - Article
C2 - 24390738
AN - SCOPUS:84896510486
VL - 74
SP - 1440
EP - 1451
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 5
ER -