Faury Damien, Nantel André, Dunn Sandra E, Guiot Marie-Christine, Haque Takrima, Hauser Péter, Garami Miklós, Bognár László, Hanzély Zoltán, Liberski Pawel P, Lopez-Aguilar Enrique, Valera Elvis T, Tone Luis G, Carret Anne-Sophie, Del Maestro Rolando F, Gleave Martin, Montes Jose-Luis, Pietsch Torsten, Albrecht Stephen, Jabado Nada
Division of Hemato-Oncology, Department of Pediatrics, Montréal Children's Hospital Research Institute, Montréal, Quebec, Canada.
J Clin Oncol. 2007 Apr 1;25(10):1196-208. doi: 10.1200/JCO.2006.07.8626.
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.
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.
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.
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.
儿童胶质母细胞瘤（pGBM）是一种罕见但具有毁灭性的脑肿瘤。与成人胶质母细胞瘤（aGBM）相比，其发展的潜在机制鲜为人知。我们的目的是深入了解pGBM的分子途径。
使用生化和转录谱分析对32个pGBM样本和7个aGBM样本进行研究。通过下游效应器的磷酸化评估Ras和Akt途径的激活，并使用大学健康网络人类19K cDNA阵列生成基因表达谱。使用实时聚合酶链反应和免疫组织化学对结果进行验证，并与aGBM的现有数据集进行比较。
pGBM至少有两个亚组。一个亚组与Ras和Akt途径激活相关，预后很差，并且与增殖和神经干细胞表型相关的基因表达增加，这与侵袭性aGBM中的发现相似。在对表达谱进行无监督和有监督分析后，该亚组在分子水平上仍与aGBM有区别。第二个亚组预后较好，与Akt和Ras途径的激活无关，可能起源于星形胶质细胞祖细胞，并且不表达显示与aGBM长期生存相关的基因特征和标志物。pGBM的两个亚组均显示Y盒蛋白1过表达，这可能有助于推动该肿瘤的肿瘤发生。
我们的工作是对pGBM基因表达谱的首次研究，为这种生存期极短的癌症中的活跃途径和靶点提供了有价值的见解，并表明不能仅通过对aGBM的研究来理解这些肿瘤。
