Transcriptional Characterization of Glioma Neural Stem Cells Diva ...

1.3 Primary and Secondary Glioblastomas Introduction
of the most specific ones [154]. GFAP is universally expressed in astrocytic
and ependymal tumours and OLIG2 is an oligodendroglial as well as stem cell
marker expressed at high levels only in diffuse gliomas [281,338,435]. Recently
investigated novel markers are stem and progenitor cell markers. Intensive
research efforts are attempting to uncover agents that may target subpopula-
tions of these cells with high tumourigenic potential and increased resistance
to current therapies [154]. The cell surface marker CD133 and other mark-
ers of stem cells, such as Nestin, Musashi and Sex determining region y-box
2 (SOX2), have been shown to negatively correlate with outcome parame-
ters [304].
In an attempt to optimise the association of different prognoses with differ-
ent therapies, several studies have focused their efforts in building an accurate
classification system [154,383,390]. Elucidating patterns between prognosis
and specific genetic lesions would allow therapies to tailor to the group of
patients who will most likely respond to them, an approach also known as
"stratification of treatment" [383]. Genome-wide profiling studies such as the
ones conducted by Freije et al in 2004 [148] Phillips et al in 2006 [390] and
Verhaak et al in 2010 [511], have tried to categorise glioblastoma in molecular
subclasses that could be predictive of survival outcomes. Thus, microarray
gene expression data for hundreds of high-grade glioma samples was analysed
and has shown that most tumours can be classified into a small number of
subtypes correlated with survival and response to therapy.
The largest such study to date [511] built a dataset from 200 GBM and two
normal brain samples that was used to identify four glioblastoma subtypes
named Proneural, Neural, Classical and Mesenchymal, each characterised by
a distinct gene expression signature encompassing a set of 210 up-regulated
genes. An independent set of 260 GBM expression profiles was compiled from
the public domain, including TCGA and Phillips et al [390], that successfully
assessed subtype reproducibility. The Proneural subtype was associated with
younger age, Platelet-derived growth factor receptor α (PDGFRA) abnormal-
ities, and IDH1 and TP53 mutations, all of which have previously been as-
sociated with secondary GBM and correlate with longer survival times [326].
In confirmation of this pattern, the Proneural subtype previously identified
in the study by Phillips et al also included most grade III gliomas and 75%
of lower grade gliomas [390]. The Classical subtype was strongly associated
with the astrocytic signature and contained all common genomic aberrations
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