Transcriptional Characterization of Glioma Neural Stem Cells Diva ...

1.3 Primary and Secondary Glioblastomas Introduction
diffuse astrocytomas, but only 10% of pilocytic astrocytomas, 5% of primary
glioblastomas and none of the ependymomas. The frequent presence of IDH1
mutations in secondary glioblastomas and their near complete absence in pri-
mary glioblastomas reinforces the concept that, despite their histological sim-
ilarities, these subtypes are genetically and clinically distinct entities [522].
In an even larger study by Yan et al [535], the sequences of the IDH1 and
closely related IDH2 genes were determined in 445 tumours of the CNS and
494 tumours that did not affect the CNS. In corroboration of the Parsons et
al [383] and Watanabe et al [522] studies, mutations in the IDH1 gene were
found in more than 70% of WHO grade II and III astrocytomas and oligoden-
drogliomas, as well as in the glioblastomas that developed from these lower-
grade lesions. Each of these mutations affected amino acid 132 and reduced
the enzymatic activity of the encoded protein [535]. Interestingly, tumours
that did not carry mutations in the IDH1 gene often had mutations affect-
ing the analogous amino acid (R172) on the closely related IDH2 gene that
also reduced the enzymatic activity of the encoded protein, suggesting a form
of functional redundancy between the two genes. Similarly to the results by
Parsons et al [383], the tumours carrying IDH1 or IDH2 mutations showed dis-
tinctive genetic and clinical characteristics that resulted in better outcomes for
those patients with respect to the patients carrying wild-type IDH genes [535].
In a study by Zhao et al [548] the functional impact of the IDH1 mutation
was assessed in cultured glioma cells. By using the human cytosolic IDH1
crystal structure reported by Xu et al in 2004 [532], this study showed that
the tumour-derived IDH1 mutation impaired the affinity of the enzyme for its
substrate by forming catalytically inactive heterodimers. Interestingly, when
the expression of a mutant IDH1 was forced in cultured glioma cells, the for-
mation of α-ketoglutarate was greatly reduced but levels of the subunit α of
hypoxia-inducible factor 1 (HIF1A) were greatly increased. In fact, the tran-
scription factor HIF1A is regulated by the product of the reaction catalysed by
IDH1, α-ketoglutarate, and as a result, the IDH1 mutated human glioma cul-
tures displayed higher levels of HIF1A unlike wild-type IDH1 glioma cultures.
This was indicative that IDH1 may function as a tumour suppressor and, when
inactivated by mutation, may contribute to tumourigenesis through induction
of the HIF1 pathway [548]. In summary, the possibility of detecting an IDH1
mutation in a patient has the clinical potential, for a subpopulation of mostly
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