Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival.
In addition to the previously reported p.R132H and p.R132S alleles, we identified three novel somatic mutations (p.R132C, p.R132G, and p.R132L) affecting residue IDH1(R132) in GBM.
The total NADPH production capacity in glioblastoma was provided for 65% by IDH activity and the occurrence of IDH1 (R132 ) mutation reduced this capacity by 38%.
Another mitochondrial and TCA cycle-related protein, isocitrate dehydrogenase 2 is, together with IDH1, frequently mutated in the brain tumour glioblastoma.
The systematic sequencing of glioblastoma multiforme (GBM) genomes has identified the recurrent mutation of IDH1, a gene encoding NADP(+)-dependent isocitrate dehydrogenase 1 (IDH1) that catalyzes the oxidative decarboxylation of isocitrate yielding alpha-ketoglutarate (alpha-KG).
1p/19q codeletion and IDH1 mutations are also useful to support and extend the histological classification of gliomas since they are strongly linked to oligodendroglial morphology and grade II/III gliomas, as opposed to glioblastoma, respectively.
The discovery of somatic mutations in the isocitrate dehydrogenase (IDH) enzymes through a genome-wide mutational analysis in glioblastoma represents a milestone event in cancer biology.
Therefore, we inhibited glutaminase with siRNA or the small molecule inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) and found slowed growth of glioblastoma cells expressing mutant IDH1 compared with those expressing wild-type IDH1.
The sequence from more favorable to poorer outcome was (1) anaplastic astrocytoma with IDH1 mutation, (2) glioblastoma with IDH1 mutation, (3) anaplastic astrocytoma without IDH1 mutation and (4) glioblastoma without IDH1 mutation (p < 0.0001).
Recent examples of NGS application to cancer genomes include the sequencing of 22 cases of glioblastoma multiforme that identified IDH1, the gene encoding isocitrate dehydrogenase 1, as target for cancer-driving mutations.
Recent advances in clinical medicine have elucidated two significantly different subtypes of glioblastoma which carry very different prognoses, both defined by mutations in isocitrate dehydrogenase-1 (IDH-1).
Furthermore, SMab-1 specifically stained the IDH1-R132S-expressing glioblastoma cells in immunocytochemistry and immunohistochemistry, but did not react with IDH1-WT or IDH1-R132H-containing glioblastoma cells.
No significant difference was observed in the frequency of amplification of these genes in primary and secondary glioblastomas or in glioblastomas with and without IDH1 mutations, suggesting that amplification of PDGFRA, KIT and KDR may be implicated in the pathogenesis of a small fraction of both subtypes of glioblastoma.
Some findings, such as that of IDH mutation in low-grade gliomas and secondary glioblastoma (GBM), fit well into established notions of different routes of gliomagenesis.
In addition, the method identified a known synthetic lethal interaction between TP53 and PLK1, other potential synthetic lethal interactions with TP53, and correlations between IDH1 mutation status and the overexpression of known GBM survival genes.
However, the interest on metabolism has been recently renewed by the discovery of recurrent mutation of IDH1 genes by systematic sequencing of a glioblastoma series.
Following the publication of a landmark genetic sequencing study in 2008, which identified IDH1 as a frequently mutated gene in glioblastoma, much work has been carried out to further characterize the frequency, associations and clinical implications of IDH1/2 mutations.
Although histologically similar, GBMs arising with and without IDH1(R132MUT) appear to represent distinct disease entities that arise from separate cell types of origin as the result of largely nonoverlapping sets of molecular events.