Transcriptional Characterization of Glioma Neural Stem Cells Diva ...

1.3 Primary and Secondary Glioblastomas Introduction
attempt focusing on this problem. In the Parsons et al study from 2008 [383],
mutational data obtained from the exome sequencing of 22 human glioblas-
tomas was analysed for copy number aberrations (CNAs), and integrated to
identify glioblastoma candidate driver genes, i.e. genes that carry mutations
providing a selective advantage to the tumour cell. Interestingly, in 12% of the
glioblastoma patients mutations were found in the active site of the Isocitrate
dehydrogenase 1 (IDH1) gene on the long arm of chromosome 22, a gene never
previously associated with glioblastoma. IDH1 encodes an isocitrate dehydro-
genase, which catalyses the carboxylation of isocitrate to α-ketoglutarate and
nicotinamide adenine dinucleotide phosphate (NADPH), a coenzyme used as a
reducing agent in anabolic 14 biosynthetic reactions [225]. Five isocitrate dehy-
drogenase genes exist in humans and three are localised in the mitochondria,
while IDH1 is localised within the cytoplasm and peroxisomes. The func-
tion of IDH1 is to help release cellular stress from oxidative damage through
the generation of NADPH. Mutations in IDH1 were observed preferentially
in younger glioblastoma patients, on average 33 years of age, as opposed to
wild type carriers, on average 53 years of age, and most of them were found
in patients with secondary glioblastomas. These patients had a longer median
survival time of 3.8 years as compared to 1.1 years for patients with wild-type
IDH1. A similar pattern was also observed in the subgroup of young patients
with Tumour protein 53 (TP53) mutations. All mutations of IDH1 resulted
in an amino acid activating substitution at an evolutionary conserved residue
located within the enzyme’s binding site, reminiscent of known activating al-
terations in oncogenes such as BRAF, KRAS and PIK3CA [383].
The study by Watanabe et al [522] carried these results further by finding a
total of 130 IDH1 mutations involving amino acid 132 in 321 gliomas that
specifically affected 88% of the low-grade diffuse astrocytomas, 82% of the
secondary glioblastomas that developed through progression from low-grade
diffuse or anaplastic astrocytoma, 79% of the oligodendrogliomas and 94% of
the oligoastrocytomas. Interestingly, analyses of multiple biopsies from the
same patient showed that an IDH1 mutation never occurred after the acquisi-
tion of a TP53 mutation, suggesting that IDH1 mutation is a very early event
in gliomagenesis that may affect a common glial precursor cell population.
IDH1 mutations were co-present with TP53 mutations in 63% of low-grade
14 An anabolic reaction, as opposed to a catabolic one, is a metabolic pathway that constructs
molecules from smaller units and requires energy.
11