Transcriptional Characterization of Glioma Neural Stem Cells Diva ...

1.3 Primary and Secondary Glioblastomas Introduction
observed in GBM, such as chromosome 7 amplifications, chromosome 10 dele-
tions, EGFR amplification, and deletion of the TP53-stabilising isoform of the
cyclin-dependent inhibitor CDKN2A:ARF [326]. As already observed in the
study by Phillips et al, the Mesenchymal subtype was characterised by high
expression of Chitinase 3-like 1 (CHI3L1) and Met proto-oncogene (MET) and
also a lack of association with a specific signature, but rather an equal cor-
relation with the neural, astrocytic, and oligodendrocytic gene signatures. A
striking characteristic of this class was the strong association with NF1 dele-
tion, already known to induce GBM in Nf1;p53 double knockout mice [426] and
shown to occur in a variety of tumours such as neurofibromas [550], but only
recently observed in human GBMs [69,320]. Since the Proneural subtype was
associated with a trend toward longer survival and the samples did not show a
survival advantage from aggressive treatment protocols, but a clear treatment
effect was observed in the Classical and Mesenchymal samples, the results of
this profiling-based classification study may find important roles in suggesting
different therapeutic strategies of high clinical impact. For example, extend-
ing the current biomarker assays for GBM to include subtyping tests for key
genetic events, including NF1 and PTEN loss, IDH1 and Phosphoinositide-3-
kinase (PI3K) mutation, PDGFRA and EGFR amplification [511].
Other studies attempting to define distinct subgroups of glioma identified CpG
island methylator phenotypes [363] and microRNA profiles [231] as part of
the same goal towards a new therapeutic approach. In the former study by
Noushmehr et al, promoter DNA methylation was assessed in 272 glioblas-
tomas from the TCGA dataset and validated in a different set of non-TCGA
glioblastomas and low-grade gliomas. Three DNA methylation clusters were
identified on array-based methylation assay platforms and one of these formed
a particularly tight cluster with a highly characteristic DNA methylation pro-
file designated as the "glioma CpG island methylator phenotype" or G-CIMP.
The G-CIMP sample cluster was highly enriched for the Proneural expression
profile defined by Verhaak et al [511] and the 24 G-CIMP-positive patients
were all significantly associated with IDH1 somatic mutations and a longer
survival time, making G-CIMP status a potential predictor of improved pa-
tient survival. The authors claim that if a transacting factor were involved in
the protection from methylation of the CpG island promoters in the G-CIMP
cluster, then the loss of its function could provide a favourable context for the
acquisition of specific genetic lesions such as IDH1 mutation. The two GBM
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