Dataset Information

Glycolytic expression in lower-grade glioma reveals an epigenetic association between IDH mutation status and PDL1/2 expression.

ABSTRACT:

Background

The interplay between glycolysis and immunosuppression in cancer has recently emerged as an intriguing area of research. The aim of this study was to elucidate a potential epigenetic link between glycolysis, isocitrate hydrogenase (IDH) status, and immune checkpoint expression in human lower-grade glioma (LGG).

Methods

Genomic analysis was conducted on 507 LGG samples from The Cancer Genome Atlas (TCGA). Data types analyzed included RNA-seq (IlluminaHiSeq) and DNA methylation (Methylation450K). Unsupervised clustering grouped samples according to glycolytic expression level and IDH status. Global promoter methylation patterns were examined, as well as methylation levels of LDHA/LDHB and immune checkpoint genes. Methylation data from a knock-in IDH1^R132H/WT allele in HCT116 cells and ChIP-seq data from immortalized human astrocytes using an inducible IDH1^R132H mutation were also assessed.

Results

Glycolytic expression distinguished a tumor cluster enriched for wild-type IDH and poorer overall survival (P < .0001). This cluster showed lower levels of LDHA promoter methylation and a higher LDHA/LDHB expression ratio. These samples also displayed lower PDL1/2 promoter methylation and higher PDL1/2 expression, which was more pronounced for PDL2. IDH1^R132H/WT cell line data showed that induced changes in methylation were enriched for genes involved in immune regulation, and ChIP-seq data showed that promoter H3K4me3 decreased for LDHA, PDL2, and PDL1 upon induction of IDH1^R132H.

Conclusions

These results suggest a previously unrecognized epigenetic link between glycolysis and immune checkpoint expression in LGG. This work advances our understanding of glioma genomics and provides support for further exploration of the metabolic-immune interface in LGG.

SUBMITTER: Givechian KB

PROVIDER: S-EPMC7837356 | biostudies-literature | 2021 Jan-Dec

REPOSITORIES: biostudies-literature

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Publications

Glycolytic expression in lower-grade glioma reveals an epigenetic association between IDH mutation status and PDL1/2 expression.

Givechian Kevin B KB Garner Chad C Benz Steve S Rabizadeh Shahrooz S Soon-Shiong Patrick P

Neuro-oncology advances 20201127 1

<h4>Background</h4>The interplay between glycolysis and immunosuppression in cancer has recently emerged as an intriguing area of research. The aim of this study was to elucidate a potential epigenetic link between glycolysis, isocitrate hydrogenase (IDH) status, and immune checkpoint expression in human lower-grade glioma (LGG).<h4>Methods</h4>Genomic analysis was conducted on 507 LGG samples from The Cancer Genome Atlas (TCGA). Data types analyzed included RNA-seq (IlluminaHiSeq) and DNA methy ...[more]

PMID: 33532725

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Project description:PurposeThis prospective clinical trial investigated sodium (23Na) MRI at 7 Tesla (T) field strength as biomarker for tumor extent, isocitrate dehydrogenase (IDH) mutation and O6-methylguanine DNA methyltransferase (MGMT) promotor methylation in glioma patients.Methods28 glioma patients underwent 23Na MRI on a 7T scanner (Siemens Healthcare, Erlangen, Germany) parallel to standard 3T MRI before chemoradiation. Areas of Gadolinium-contrast enhancement (gdce), non-enhancing T2-hyperintensity (regarded as edema), necrosis, and normal-appearing white matter (nawm) were segmented on 3T MRI imaging and were co-registered with the 23Na images. The median total 23Na concentrations of all areas were compared by pairwise t-tests. Furthermore, areas of gdce and edema were merged to yield the whole tumor area without necrosis. Subsequently, the difference in median of the 23Na concentration of this whole tumor area was compared between IDH-mutated and IDH wild-type gliomas as well as MGMT methylated and MGMT not-methylated glioblastomas using Whitney-Mann U-tests. All p-values were corrected after the Bonferroni-Holm procedure.ResultsThe 23Na concentration increased successively from nawm to necrotic areas (mean ± sd: nawm = 37.84 ± 5.87 mM, edema = 54.69 ± 10.64 mM, gdce = 61.72 ± 12.95 mM, necrosis = 81.88 ± 17.53 mM) and the concentrations differed statistically significantly between all regarded areas (adjusted p-values for all pairwise comparisons < 0.05). Furthermore, IDH-mutated gliomas showed significantly higher 23Na concentrations than IDH wild-type gliomas (median [interquartile range]: IDH wild-type = 52.37 mM [45.98 - 58.56 mM], IDH mutated = 65.02 mM [58.87-67.05 mM], p = 0.039). Among the glioblastomas, there was a trend towards increased 23Na concentration in MGMT methylated tumors that did not reach statistical significance (median [interquartile range]: MGMT methylated = 57.59 mM [50.70 - 59.17 mM], MGMT not methylated = 48.78 mM [45.88 - 53.91 mM], p = 1.0).Conclusions23Na MRI correlates with the IDH mutation status and could therefore enhance image guidance towards biopsy sites as wells as image-guided surgery and radiotherapy. Furthermore, the successive decrease of 23Na concentration from central necrosis to normal-appearing white matter suggests a correlation with tumor infiltration.

Project description:BackgroundAbnormal expression of the eukaryotic initiation factor 3 (eIF3) subunits plays critical roles in tumorigenesis and progression, and also has potential prognostic value in cancers. However, the expression and clinical implications of eIF3 subunits in glioma remain unknown.MethodsExpression data of eIF3 for patients with gliomas were obtained from the Chinese Glioma Genome Atlas (CGGA) (n = 272) and The Cancer Genome Atlas (TCGA) (n = 595). Cox regression, the receiver operating characteristic (ROC) curves and Kaplan-Meier analysis were used to study the prognostic value. Gene oncology (GO) and gene set enrichment analysis (GSEA) were utilized for functional prediction.ResultsIn both the CGGA and TCGA datasets, the expression levels of eIF3d, eIF3e, eIF3f, eIF3h and eIF3l highly were associated with the IDH mutant status of gliomas. The expression of eIF3b, eIF3i, eIF3k and eIF3m was increased with the tumor grade, and was associated with poorer overall survival [All Hazard ratio (HR) > 1 and P < 0.05]. By contrast, the expression of eIF3a and eIF3l was decreased in higher grade gliomas and was associated with better overall survival (Both HR < 1 and P < 0.05). Importantly, the expression of eIF3i (located on chromosome 1p) and eIF3k (Located on chromosome 19q) were the two highest risk factors in both the CGGA [eIF3i HR = 2.068 (1.425-3.000); eIF3k HR = 1.737 (1.166-2.588)] and TCGA [eIF3i HR = 1.841 (1.642-2.064); eIF3k HR = 1.521 (1.340-1.726)] databases. Among eIF3i, eIF3k alone or in combination, the expression of eIF3i was the more robust in stratifying the survival of glioma in various pathological subgroups. The expression of eIF3i was an independent prognostic factor in IDH-mutant lower grade glioma (LGG) and could also predict the 1p/19q codeletion status of IDH-mutant LGG. Finally, GO and GSEA analysis showed that the elevated expression of eIF3i was significantly correlated with the biological processes of cell proliferation, mRNA processing, translation, T cell receptor signaling, NF-κB signaling and others.ConclusionsOur study reveals the expression alterations during glioma progression, and highlights the prognostic value of eIF3i in IDH-mutant LGG.

Dataset Information

Glycolytic expression in lower-grade glioma reveals an epigenetic association between IDH mutation status and PDL1/2 expression.

Background

Methods

Results

Conclusions

Publications

Glycolytic expression in lower-grade glioma reveals an epigenetic association between IDH mutation status and PDL1/2 expression.

Similar Datasets

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