Molecular profiling identifies prognostic subgroups of pediatric glioblastoma and shows increased YB-1 expression in tumors.
OBJECTIVE
Pediatric glioblastoma (pGBM) is a rare, but devastating brain tumor. In contrast to GBM in adults (aGBM), little is known about the mechanisms underlying its development. Our aim is to gain insight into the molecular pathways of pGBM.


METHODS
Thirty-two pGBM and seven aGBM samples were investigated using biochemical and transcriptional profiling. Ras and Akt pathway activation was assessed through the phosphorylation of downstream effectors, and gene expression profiles were generated using the University Health Network Human 19K cDNA arrays. Results were validated using real-time polymerase chain reaction and immunohistochemistry and compared with existing data sets on aGBM.


RESULTS
There are at least two subsets of pGBM. One subset, associated with Ras and Akt pathway activation, has very poor prognosis and exhibits increased expression of genes related to proliferation and to a neural stem-cell phenotype, similar to findings in aggressive aGBM. This subset was still molecularly distinguishable from aGBM after unsupervised and supervised analysis of expression profiles. A second subset, with better prognosis, is not associated with activation of Akt and Ras pathways, may originate from astroglial progenitors, and does not express gene signatures and markers shown to be associated with long-term survival in aGBM. Both subsets of pGBM show overexpression of Y-box-protein-1 that may help drive oncogenesis in this tumor.


CONCLUSIONS
Our work, the first study of gene expression profiles in pGBM, provides valuable insight into active pathways and targets in a cancer with minimal survival, and suggests that these tumors cannot be understood exclusively through studies of aGBM.
Faury
Damien
D
Division of Hemato-Oncology, Department of Pediatrics, Montréal Children's Hospital Research Institute, Montréal, Quebec, Canada.
Nantel
André
A
Dunn
Sandra E
SE
Guiot
Marie-Christine
MC
Haque
Takrima
T
Hauser
Péter
P
Garami
Miklós
M
Bognár
László
L
Hanzély
Zoltán
Z
Liberski
Pawel P
PP
Lopez-Aguilar
Enrique
E
Valera
Elvis T
ET
Tone
Luis G
LG
Carret
Anne-Sophie
AS
Del Maestro
Rolando F
RF
Gleave
Martin
M
Montes
Jose-Luis
JL
Pietsch
Torsten
T
Albrecht
Stephen
S
Jabado
Nada
N
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001932:Brain Neoplasms / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D015398:Signal Transduction; D051840:Y-Box-Binding Protein 1
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras)