Abstract
BackgroundClassification of primary central nervous system tumors according to the World Health Organization guidelines follows the integration of histologic interpretation with molecular information and aims at providing the most precise prognosis and optimal patient management. According to the cIMPACT-NOW update 3, diffuse isocitrate dehydrogenase-wild type (IDH-WT) gliomas should be graded as grade IV glioblastomas (GBM) if they possess one or more of the following molecular markers that predict aggressive clinical course: EGFR amplification, TERT promoter mutation, and whole-chromosome 7 gain combined with chromosome 10 loss.MethodsThe Cancer Genome Atlas (TCGA) glioma expression datasets were reanalyzed in order to identify novel tumor subcategories which would be considered as GBM-equivalents with the current diagnostic algorithm. Unsupervised clustering allowed the identification of previously unrecognized transcriptomic subcategories. A supervised machine learning algorithm (k-nearest neighbor model) was also used to identify gene signatures specific to some of these subcategories.ResultsWe identified 14 IDH-WT infiltrating gliomas displaying a “normal-like” (NL) transcriptomic profile associated with a longer survival. Genes such as C5AR1 (complement receptor), SLC32A1 (vesicular gamma-aminobutyric acid transporter), MSR1 (or CD204, scavenger receptor A), and SYT5 (synaptotagmin 5) were differentially expressed and comprised in gene signatures specific to NL IDH-WT gliomas which were validated further using the Chinese Glioma Genome Atlas datasets. These gene signatures showed high discriminative power and correlation with survival.ConclusionNL IDH-WT gliomas represent an infiltrating glioma subcategory with a superior prognosis which can only be detected using genome-wide analysis. Differential expression of genes potentially involved in immune checkpoint and amino acid signaling pathways is providing insight into mechanisms of gliomagenesis and could pave the way to novel treatment targets for infiltrating gliomas.
Highlights
Classification of primary central nervous system tumors according to the World Health Organization guidelines follows the integration of histologic interpretation with molecular information and aims at providing the most precise prognosis and optimal patient management
Separate categories have been created based on the presence of alterations such as isocitrate dehydrogenase-wild type 1/2 (IDH1/2) [8] and histone 3 mutations, which are frequently found in adult low-grade and pediatric high-grade gliomas, respectively [9, 10]
We identified two gene signatures composed of SLC32A1/MSR1 and SYT5/C5AR1 gene combinations whose expression alone strongly correlated with this subgroup of isocitrate dehydrogenase-wild type (IDH-WT) gliomas
Summary
Classification of primary central nervous system tumors according to the World Health Organization guidelines follows the integration of histologic interpretation with molecular information and aims at providing the most precise prognosis and optimal patient management. According to the cIMPACT- update 3, diffuse isocitrate dehydrogenase-wild type (IDH-WT) gliomas should be graded as grade IV glioblastomas (GBM) if they possess one or more of the following molecular markers that predict aggressive clinical course: EGFR amplification, TERT promoter mutation, and whole-chromosome 7 gain combined with chromosome 10 loss. Infiltrating gliomas are the most frequent malignant primary neoplasms of the central nervous system (CNS) in adults [1] They are relentlessly recurring and lethal tumors despite aggressive multimodal treatment (chemotherapy and/or radiotherapy) [2, 3]. For IDH-WT glioma grading, the cIMPACT update 3 recommends the assessment of EGFR amplification, combined chromosomes 7p gain/10q loss, and TERT promoter mutation, which are established predictors of poor outcome, regardless of histology [12]
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