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Tumor Mutation Burden, Expressed Neoantigens and the Immune Microenvironment in Diffuse Gliomas.

ABSTRACT: A consistent correlation between tumor mutation burden (TMB) and tumor immune microenvironment has not been observed in gliomas as in other cancers. Driver germline and somatic mutations, TMB, neoantigen, and immune cell signatures were analyzed using whole exome sequencing (WES) and transcriptome sequencing of tumor and WES of matched germline DNA in a cohort of 66 glioma samples (44 IDH-mutant and 22 IDH-wildtype). Fourteen samples revealed a hypermutator phenotype (HMP). Eight pathogenic (P) or likely pathogenic (LP) germline variants were detected in 9 (19%) patients. Six of these 8 genes were DNA damage repair genes. P/LP germline variants were found in 22% of IDH-mutant gliomas and 12.5% of IDH-wildtype gliomas (p = 0.7). TMB was correlated with expressed neoantigen but showed an inverse correlation with immune score (R = -0.46, p = 0.03) in IDH-wildtype tumors and no correlation in IDH-mutant tumors. The Antigen Processing and Presentation (APP) score correlated with immune score and was surprisingly higher in NHMP versus HMP samples in IDH-wildtype gliomas, but higher in HMP versus NHMP in IDH-mutant gliomas. TMB was inversely correlated with immune score in IDH-wildtype gliomas and showed no correlation in IDH-mutant tumors. APP was correlated with immune score and may be further investigated as a biomarker for response to immunotherapy in gliomas. Studies of germline variants in a larger glioma cohort are warranted.

SUBMITTER: Yu G

PROVIDER: S-EPMC8657099 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Tumor Mutation Burden, Expressed Neoantigens and the Immune Microenvironment in Diffuse Gliomas.

Yu Guangyang G Pang Ying Y Merchant Mythili M Kesserwan Chimene C Gangalapudi Vineela V Abdelmaksoud Abdalla A Ranjan Alice A Kim Olga O Wei Jun S JS Chou Hsien-Chao HC Wen Xinyu X Sindiri Sivasish S Song Young K YK Xi Liqiang L Kaplan Rosandra N RN Armstrong Terri S TS Gilbert Mark R MR Aldape Kenneth K Khan Javed J Wu Jing J

Cancers 20211203 23

<h4>Background</h4>A consistent correlation between tumor mutation burden (TMB) and tumor immune microenvironment has not been observed in gliomas as in other cancers.<h4>Methods</h4>Driver germline and somatic mutations, TMB, neoantigen, and immune cell signatures were analyzed using whole exome sequencing (WES) and transcriptome sequencing of tumor and WES of matched germline DNA in a cohort of 66 glioma samples (44 IDH-mutant and 22 IDH-wildtype).<h4>Results</h4>Fourteen samples revealed a hy ...[more]

PMID: 34885201

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Project description:BackgroundDiffuse gliomas possess a kind of malignant brain tumor with high mortality. Glutamine represents the most abundant and versatile amino acid in the body. Glutamine not only plays an important role in cell metabolism but also involves in cell survival and malignancies progression. Recent studies indicate that glutamine could also affect the metabolism of immune cells in the tumor microenvironment (TME).Materials and methodsThe transcriptome data and clinicopathological information of patients with glioma were acquired from TCGA, CGGA, and West China Hospital (WCH). The glutamine metabolism-related genes (GMRGs) were retrieved from the Molecular Signature Database. Consensus clustering analysis was used to discover expression patterns of GMRGs, and glutamine metabolism risk scores (GMRSs) were established to model tumor aggressiveness-related GMRG expression signature. ESTIMATE and CIBERSORTx were applied to depict the TME immune landscape. The tumor immunological phenotype analysis and TIDE were utilized for predicting the therapeutic response of immunotherapy.ResultsA total of 106 GMRGs were retrieved. Two distinct clusters were established by consensus clustering analysis, which showed a close association with the IDH mutational status of gliomas. In both IDH-mutant and IDH-wildtype gliomas, cluster 2 had significantly shorter overall survival compared with cluster 1, and the differentially expressed genes between the two clusters enriched in pathways related to malignant transformation as well as immunity. In silico TME analysis of the two IDH subtypes revealed not only significantly different immune cell infiltrations and immune phenotypes between the GMRG expression clusters but also different predicted responses to immunotherapy. After the screening, a total of 10 GMRGs were selected to build the GMRS. Survival analysis demonstrated the independent prognostic role of GMRS. Prognostic nomograms were established to predict 1-, 2-, and 3-year survival rates in the four cohorts.ConclusionDifferent subtypes of glutamine metabolism could affect the aggressiveness and TME immune features of diffuse glioma, despite their IDH mutational status. The expression signature of GMRGs could not only predict the outcome of patients with glioma but also be combined into an accurate prognostic nomogram.

Dataset Information

Tumor Mutation Burden, Expressed Neoantigens and the Immune Microenvironment in Diffuse Gliomas.

Publications

Tumor Mutation Burden, Expressed Neoantigens and the Immune Microenvironment in Diffuse Gliomas.

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