A multigene predictor of outcome in glioblastoma

Abstract

Only a subset of patients with newly diagnosed glioblastoma (GBM) exhibit a response to standard therapy. To date, a biomarker panel with predictive power to distinguish treatment sensitive from treatment refractory GBM tumors does not exist. An analysis was performed using GBM microarray data from 4 independent data sets. An examination of the genes consistently associated with patient outcome, revealed a consensus 38-gene survival set. Worse outcome was associated with increased expression of genes associated with mesenchymal differentiation and angiogenesis. Application to formalin fixed-paraffin embedded (FFPE) samples using real-time reverse-transcriptase polymerase chain reaction assays resulted in a 9-gene subset which appeared robust in these samples. This 9-gene set was then validated in an additional independent sample set. Multivariate analysis confirmed that the 9-gene set was an independent predictor of outcome after adjusting for clinical factors and methylation of the methyl-guanine methyltransferase promoter. The 9-gene profile was also positively associated with markers of glioma stem-like cells, including CD133 and nestin. In sum, a multigene predictor of outcome in glioblastoma was identified which appears applicable to routinely processed FFPE samples. The profile has potential clinical application both for optimization of therapy in GBM and for the identification of novel therapies targeting tumors refractory to standard therapy.

Analysis of Olig2 and YKL-40 expression: a clinicopathological/immunohistochemical study for the distinction between subventricular zone II and III glioblastomas

“…Under the stem cell hypothesis, Olig2 fulfills criteria of a lineagerestricted compe tence factor for gliogenesis [8,15] that is necessary for the development of neural progenitors and prog eny cells in the CNS [12]. Like others, [22] we have suggested that Olig2 expression may be downregu lated in mature astrocyte.…”

“…However, the literature on Olig2 and its asso ciation with glioblastoma prognosis is ambivalent [1,11,12,22]. Recent reports have found associations between glioblastoma and neural stem cells express ing Olig2 [8,12,20,35]. Therefore, a significant amount of the ongoing GB research is focused on better under standing how cells expressing Olig2 contribute to the gliomagenesis and therapeutic targets.…”

Glioma Big Potassium Channel Expression in Human Cancers and Possible T Cell Epitopes for Their Immunotherapy

“…Both chloride channel-1 and aquaporins are also overexpressed in glioma (41)(42)(43). BK channel activation leads to cell swelling, whereas CLIC1 activation leads to cell shrinkage (7,8,44). Both of these functions, swelling and shrinking, are needed for cell volume regulation and motility.…”

The intrinsic fusogenicity of glioma cells as a factor of transformation and progression in the tumor microenvironment

“…Such path to progression of glioma, recognized by appearance of traits and markers specific of mesenchyme in the tumor cells, implies enhanced capacity of invasion and proangiogenesis, correlating with recurrence and worse outcome of the disease. 15,18 In relation to this, genetic reprogramming by hybridization might explain the emergence of endogeneous resistance to drugs, as some types of mesenchymal cells, e.g., fibroblasts, 32 express aldehyde dehydrogenase, an enzyme that detoxifies reactive products of chemotherapeutic agents.…”

“…13 In gliomas, the high vascular density found in advanced stages of malignancy implies the inclusion of endothelial cells, pericytes, fibroblasts and inflammatory cells, 14 into the growing tumor mass; neoplastic progression brings about, in some cases, a mesenchymal phenotype, associated with increased invasiveness, angiogenesis and resistance to treatment. [15][16][17][18] The relevance of cell fusion as mechanism of genetic reprogramming is being increasingly considered in tumor progression. [19][20][21][22] A prerequisite for tumor cell heterotypic fusion is that the necessary colocalization with nontumor cells is enabled by the tumor stroma.…”