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Patterns of hypermutation shape gliomagenesis and immunotherapy response in mismatch repair deficient glioma

ABSTRACT: Primary mismatch-repair deficient (priMMRD) gliomas are lethal tumours characterized by hypermutation, resistance to chemoradiation, and variable response to immunotherapy.To investigate the mechanisms governing the emergence of driver mutations and their impact on gliomagenesis and outcome, we analyzed genomic and clinical data of 162 priMMRD gliomas. We identified three subgroups defined by secondary driver mutations in replicative DNA polymerases or IDH1. These subgroups converge on glioma drivers through distinct combinations of genomic instability-generating mechanisms, displaying an inverse correlation between point mutation and copy number alteration. MMRD signaturesdrive the emergence of specific mutations in TP53 and IDH1, notably excluding common pediatric glioma drivers. Global hypomethylation stratifies priMMRD gliomas into a unique methylation cluster. DNA-polymerasemut priMMRD gliomas exhibit ultrahypermutation, an immune-hot microenvironment, and immunotherapy responsiveness, whereas IDH1mut priMMRD gliomas are immune-cold and immunotherapy resistant. MMRD-driven gliomagenesis defines the role of non-random mutagenesis-patterns in cancer development, providing frameworks for targeted and immune-therapeutics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307219 | GEO | 2025/10/09

REPOSITORIES: GEO

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Project description:Isocitrate dehydrogenase 1 (IDH1) mutations are key drivers of glioma biology, influenc-ing tumor aggressiveness and treatment response. To elucidate their molecular impact, we performed proteome analysis on patient-derived (PD) and U87MG glioma cell models with either mutant or wildtype IDH1. We quantified over 6,000 protein groups per model, identifying 1,594 differentially expressed proteins in PD-AS (IDH1MUT) vs. PD-GB (IDH1WT) and 904 in U87MUT vs. U87WT. Both IDH1MUT models exhibited enhanced MHC antigen presentation and interferon signaling, indicative of an altered immune microen-vironment. However, metabolic alterations were model-dependent: PD-AS cells shifted toward glycolysis and purine salvage, while U87MUT cells retained oxidative phosphory-lation, potentially due to D2-hydroxyglutarate (2OHG)-mediated HIF1A stabilization. We also observed a predominance of downregulated DNA repair proteins in IDH1MUT mod-els, particularly those involved in homologous recombination. In contrast, RB1 and AS-MTL were strongly upregulated in both IDH1MUT models, implicating them in DNA repair and cellular stress responses. We also found distinct expression patterns of proteins reg-ulating histone methylation in IDH1MUT cells, favoring increased methylation of H3K4, H3K9, and H3K36. A key driver of this may be the upregulation of SETD2 in PD-AS, an H3K4 and H3K36 trimethyltransferase linked to recruitment of HIF1A as well as DNA mismatch repair proteins. This study uncovers candidate biomarkers and pathways rele-vant to glioma progression and therapeutic targeting but also underscores the complexity of predicting glioma pathogenesis and treatment responses based on IDH1 mutation sta-tus. While proteome profiling provides valuable insights, a comprehensive understand-ing of IDH1MUT gliomas will likely require integrative multi-omics approaches, including DNA/RNA methylation profiling, histone and protein post-translational modification analyses, and targeted DNA damage and repair assays.

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Patterns of hypermutation shape gliomagenesis and immunotherapy response in mismatch repair deficient glioma

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