Dataset Information

Identification of a Prognostic Hypoxia-Associated Gene Set in IDH-Mutant Glioma.

ABSTRACT: Glioma growth is often accompanied by a hypoxic microenvironment favorable for the induction and maintenance of the glioma stem cell (GSC) phenotype. Due to the paucity of cell models of Isocitrate Dehydrogenase 1 mutant (IDH1mut) GSCs, biology under hypoxic conditions has not been sufficiently studied as compared to IDH1 wildtype (IDH1wt) GSCs. We therefore grew well-characterized IDH1mut (n = 4) and IDH1wt (n = 4) GSC lines under normoxic (20%) and hypoxic (1.5%) culture conditions and harvested mRNA after 72 h. Transcriptome analyses were performed and hypoxia regulated genes were further analyzed using the expression and clinical data of the lower grade glioma cohort of The Cancer Genome Atlas (LGG TCGA) in a confirmatory approach and to test for possible survival associations. Results show that global expression changes were more pronounced in IDH1wt than in IDH1mut GSCs. However, when focusing on known hypoxia-regulated gene sets, enrichment analyses showed a comparable regulation in both IDH1mut and IDH1wt GSCs. Of 272 significantly up-regulated genes under hypoxic conditions in IDH1mut GSCs a hypoxia-related survival score (HRS-score) of five genes (LYVE1, FAM162A, WNT6, OTP, PLOD1) was identified by the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm which was able to predict survival independent of age, 1p19q co-deletion status and WHO grade (II vs. III) in the LGG TCGA cohort and in the Rembrandt dataset. Altogether, we were able to identify and validate a novel hypoxia-related survival score in IDH1mut GSCs consisting of five hypoxia-regulated genes which was significantly associated with patient survival independent of known prognostic confounders.

SUBMITTER: Dao Trong P

PROVIDER: S-EPMC6212863 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Identification of a Prognostic Hypoxia-Associated Gene Set in IDH-Mutant Glioma.

Dao Trong Philip P Rösch Saskia S Mairbäurl Heimo H Pusch Stefan S Unterberg Andreas A Herold-Mende Christel C Warta Rolf R

International journal of molecular sciences 20180925 10

Glioma growth is often accompanied by a hypoxic microenvironment favorable for the induction and maintenance of the glioma stem cell (GSC) phenotype. Due to the paucity of cell models of Isocitrate Dehydrogenase 1 mutant (IDH1mut) GSCs, biology under hypoxic conditions has not been sufficiently studied as compared to IDH1 wildtype (IDH1wt) GSCs. We therefore grew well-characterized IDH1mut (n = 4) and IDH1wt (n = 4) GSC lines under normox ...[more]

PMID: 30257451

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Project description:Alterations in the expression of the Duchenne muscular dystrophy (DMD) gene have been associated with the development, progression and survival outcomes of numerous cancers including tumours of the central nervous system. We undertook a detailed bioinformatic analysis of low-grade glioma (LGG) bulk RNAseq data to characterise the association between DMD expression and LGG survival outcomes. High DMD expression was significantly associated with poor survival in LGG with a difference in median overall survival between high and low DMD groups of over 7 years (P = < 0.0001). In a multivariate model, DMD expression remained significant (P = 0.02) and was an independent prognostic marker for LGG. The effect of DMD expression on overall survival was only apparent in isocitrate dehydrogenase (IDH) mutant cases where non-1p/19q co-deleted LGG patients could be further stratified into high/low DMD groups. Patients in the high DMD group had a median overall survival time almost halve that of the low DMD group. The expression of the individual DMD gene products Dp71, Dp71ab and Dp427m were also significantly associated with overall survival in LGG which have differential biological effects relevant to the pathogenesis of LGG. Differential gene expression and pathway analysis identifies dysregulated biological processes relating to ribosome biogenesis, synaptic signalling, neurodevelopment, morphogenesis and immune pathways. Genes spanning almost the entirety of chromosome 1p are upregulated in patients with high overall DMD, Dp71 and Dp427m expression which worsens survival outcomes for these patients. We confirmed dystrophin protein is variably expressed in LGG tumour tissue by immunohistochemistry and, overall, demonstrate that DMD expression has potential utility as an independent prognostic marker which can further stratify IDH mutant LGG to identify those at risk of poor survival. This knowledge may improve risk stratification and management of LGG.

Dataset Information

Identification of a Prognostic Hypoxia-Associated Gene Set in IDH-Mutant Glioma.

Publications

Identification of a Prognostic Hypoxia-Associated Gene Set in IDH-Mutant Glioma.

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