Molecular signatures classify astrocytic gliomas by IDH1 mutation status

Abstract

To identify novel glioma‐associated pathomechanisms and molecular markers, we performed an array‐based comparative genomic hybridization analysis of 131 diffuse astrocytic gliomas, including 87 primary glioblastomas (pGBIV), 13 secondary glioblastomas (sGBIV), 19 anaplastic astrocytomas (AAIII) and 12 diffuse astrocytomas (AII). All tumors were additionally screened for IDH1 and IDH2 mutations. Expression profiling was performed for 74 tumors (42 pGBIV, 11 sGBIV, 13 AAIII, 8 AII). Unsupervised and supervised bioinformatic analyses revealed distinct genomic and expression profiles separating pGBIV from the other entities. Classifier expression signatures were strongly associated with the IDH1 gene mutation status. Within pGBIV, the rare subtype of IDH1 mutant tumors shared expression profiles with IDH1 mutant sGBIV and was associated with longer overall survival compared with IDH1 wild‐type tumors. In patients with IDH1 wild‐type pGBIV, PDGFRA gain or amplification as well as 19q gain were associated with patient outcome. Array‐CGH analysis additionally revealed homozygous deletions of the FGFR2 gene at 10q26.13 in 2 pGBIV, with reduced FGFR2 mRNA levels being frequent in pGBIV and linked to poor outcome. In conclusion, we report that diffuse astrocytic gliomas can be separated into 2 major molecular groups with distinct genomic and mRNA profiles as well as IDH1 gene mutation status. In addition, our results suggest FGFR2 as a novel glioma‐associated candidate tumor suppressor gene on the long arm of chromosome 10.

Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1

“…This led to the identification of 12 phosphatases potentially involved in the stem-like phenotype of GSCs (Figures 1c and d). Six of the twelve candidate genes (PPEF1, ENPP1, PTPN9, PPP4C, PPP2R2A and DUSP5) were found to be highly expressed in astrocytic gliomas compared with adult normal brain and/or to be essential for stem cell maintenance (Supplementary Figure S2A) [17][18][19][20][21][22] and hence selected for validation studies. Decreased CD133 level 6 days posttransduction was confirmed in NCH421k (GSCs used in the primary screen) and in additional GSCs (NCH441, NCH644) in two independent experiments using the two shRNAs that showed the strongest CD133 reduction in the primary screen (Figure 1e; Supplementary Figure S2B).…”

“…To compare gene expression of the selected candidate phosphatases (PPEF1, ENPP1, PTPN9, PPP4C, PPP2R2A and DUSP5) in primary glioblastoma samples and adult normal brain samples, a publicly available glioma expression data set (GSE18166, Toedt et al 22 ) was used. Preprocessed mRNA expression data of a subset of 40 IDH1 wild-type primary glioblastoma samples were normalised to the mean expression values of four adult normal brain samples.…”

Diagnostic implications of IDH1-R132H and OLIG2 expression patterns in rare and challenging glioblastoma variants

“…In glioblastomas, immunoreactivity for IDH1 mutant protein suggests that the tumor is secondary, even without the appropriate history of a preceding lower grade glial neoplasm. 6,8 In support of this notion, such patients tend to be younger and enjoy similarly prolonged survival times as those of more classically defined secondary glioblastomas. IDH1 mutant protein expression has also proven to be diagnostically useful in the distinction of entrapped dysmorphic cortical neurons in low-grade infiltrative gliomas from gangliogliomas, the majority of which do not show IDH1 mutations.…”

“…1 This discovery was subsequently validated and expanded in larger series of human gliomas, establishing that roughly 80% of all WHO grade II-III infiltrating/diffuse gliomas (astrocytomas, oligodendrogliomas, and oligoastrocytomas) and secondary glioblastomas show mutations in IDH1 and to a lesser extent, IDH2; 2-4 these mutations correlate with enhanced patient survival, and by far the most common alteration is the R132H mutation in IDH1. 5,6 Immunohistochemistry (IHC) for expression of R132H IDH1 mutant protein 7 is increasingly performed in the routine pathologic evaluation of glioblastoma and lower grade diffuse gliomas because of its prognostic significance. In glioblastomas, immunoreactivity for IDH1 mutant protein suggests that the tumor is secondary, even without the appropriate history of a preceding lower grade glial neoplasm.…”

RNAi screening in glioma stem-like cells identifies PFKFB4 as a key molecule important for cancer cell survival

“…Gene expression of PFKFB4 is associated with glioblastoma prognosis To assess the clinical relevance of the validated candidates, we compared their mRNA expression among a series of astrocytic gliomas of different grades (WHO (World Health Organization) grades II, III and IV, including primary and secondary glioblastomas) using previously published microarray data (GSE15698510) (Toedt et al, 2011). Remarkably, the mRNA expression of PFKFB4, whose gene product plays a key role in energy metabolism, significantly differentiated IDH1 wild-type primary glioblastomas from the secondary glioblastomas as well as diffuse and anaplastic astrocytomas, which mostly carried IDH1 gene mutations ( Figure 3a).…”