Transcriptional Characterization of Glioma Neural Stem Cells Diva ...

1.3 Primary and Secondary Glioblastomas Introduction
were found mostly in all non-CpG dinucleotides. This pattern is consistent
with the failure to repair alkylated guanine residues that is caused by treat-
ment if MGMT methylation is also shifting the mutation spectrum of treated
samples to a preponderance of GC to AT transitions at non-CpG sites [326].
The molecular mechanisms lying behind such pattern could find an expla-
nation in the interesting observation that the mutation spectra of mismatch
repair genes reflected MGMT promoter methylation as well. In fact, in treated
hypermutated samples with methylated MGMT, mismatch repair genes accu-
mulated GC to AT transitions in non-CpG islands, which was not observed
in any of the hypermutated tumours with unmethylated MGMT. Thus, mis-
match repair deficiency and MGMT methylation status together could have
powerful clinical implications in the context of treatment, raising the possibil-
ity that patients who initially respond to the frontline therapy in use today may
evolve not only treatment resistance, but also an MMR-defective hypermuta-
tor phenotype. The fact that newly diagnosed glioblastomas with methylated
MGMT respond well to treatment with alkylating agents, is in part due to
the initiation of many mismatch repair cycles that attempt to repair the alky-
lated guanines and in doing so lead to cell death, which is consistent with
the observation that the mismatch repair genes themselves are mutated with
CG to AT transitions at non-CpG sites [326]. Therefore, initial methylation
of MGMT in this scenario would have an effect on two fronts: shifting the
mutation spectrum that will affect mutations at mismatch repair genes, and
increasing the selective pressure to lose mismatch repair function, resulting
in aggressive recurrent tumours with a hypermutator phenotype [363]. These
findings highlight the importance of designing selective strategies that target
mismatch-repair-deficient cells in combination with alkylating agents, in order
to prevent or minimise the emergence of treatment resistance [326].
Genetically Engineered Mouse Models Murine gliomas that appear to
develop in the absence of lower grade precursors are very important disease
models because they reproduce de novo conditions for the onset of glioblas-
toma. GEMMs are useful research tools towards that end because they can
accurately reproduce the initiation and progression stages in the human pathol-
ogy upon introduction of few mutations, although it is still debated whether
they can accurately recreate the genomic and expression heterogeneity of the
original human disease [308]. In some cases these mouse models helped pre-
dict the importance in human gliomas of events such as TP53 and NF1 in-
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