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Exploring cellular subpopulations in glioblastoma and matched organoids using single-cell RNA-seq

Published online by Cambridge University Press:  27 July 2018

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Abstract

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Background: Gliomas are the most common and fatal adult brain tumor with distinct genomic subgroups defined by isocitrate dehydrogenase (IDH) mutation status. Mutations in IDH result in overproduction of the oncometabolite 2-hydroxyglutarate (2HG). The landscape of metabolic changes that define gliomas has not previously been explored. Methods: We performed liquid chromotography-mass spectrometry (LC-MS) to examine over 700 metabolites on 90 fresh-frozen glioma samples (30 IDH-wildtype, 30 IDH-mutant 1p/19q codeleted, 30 IDH-mutant 1p/19q non-codeleted) from our institutional biobank. R and S enantiomers of 2HG were quantified using high pressure liquid chromatography tandem mass spectrometry coupled with a CHIROBIOTIC R column. Genome wide DNA methylation was performed on all tumors using Illumina 850k EPIC array. Unsupervised consensus clustering of differentially expressed metabolites and methylated post-processed probes was performed. Copy number variations were determined based on intensity values of the methylation array. Survival of unsupervised cluster groups was determined using the Kaplan-Meier Estimate. Results: Unsupervised clustering of 689 metabolites revealed 2 distinct subgroups of gliomas associated with recurrence-free survival (RFS, P = 0.021). IDH mutant tumours were found in both cluster groups where as IDH-wildtype tumors were found only in Group 2. Group 2 IDH-mutant tumors had unfavourable PFS, higher R/S-2HG levels, and higher proportion of copy number alterations (4q, 9p, 13q, 17q) compared to group 1 IDH-mutant tumors (P=0.048, P=0.0194, P<0.0001 respectively) compared to group 1 IDH-mutant tumors. (P= p=0.048). . Conclusions: Metabolic profiling of gliomas reveals 2 distinct subtypes of IDH-mutant independent of 1p/19q codeletion status with differing survival patterns and large scale chromosomal alterations that may be driven by varying levels of R/S-2HG.

Type
1450-1545 Young Investigator Awards & Presentations
Copyright
© The Canadian Journal of Neurological Sciences Inc. 2018