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Mismatch repair deficiency drives malignant progression and alters the tumor immune microenvironment of glioblastoma

ABSTRACT: Mutations in DNA mismatch repair (MMR) pathway genes (MSH2, MSH6, MLH1, and PMS2) have been associated with acquired resistance to temozolomide and with a high tumor mutation burden (TMB) in high-grade gliomas (HGG), including glioblastoma (GBM). However, the specific roles of individual MMR genes in the initiation, progression, increased TMB and microsatellite instability (MSI), and resistance to temozolomide (TMZ) in glioma have not been extensively studied. In the present study, we developed de novo mouse models of germline and somatic MMR-deficient (MMRd) HGG. Surprisingly, we found that loss of Msh2 or Msh6 does not lead to a high TMB and MSI nor confer response to anti-PD-1 in GBM. Our data also revealed that germline MMRd leads to the transition from low to high-grade glioma. Additionally, we show that mice with germline MMRd had reduced survival compared to MMR-proficient (MMRp) tumor-bearing mice. This effect was tumor cell intrinsic but was associated with MMRd in the tumor immune microenvironment, which led to increased immunosuppressive pathways in myeloid cells, reduced lymphoid infiltration, and increased exhaustion of CD8+ T cells. We have found that both MMR-reduced (MMRr) and MMRd GBM are resistant to TMZ, unlike MMRp tumors. Our study shows that KL-50, a new imidazotetrazine-based DNA targeting agent designed to induce DNA interstrand cross-links, is effective in treating both germline and somatic MMRr and MMRd GBM-bearing mice. These findings present a new treatment option for HGG patients with inherited or acquired MMRd who are resistant to TMZ.

ORGANISM(S): Mus musculus

PROVIDER: GSE292092 | GEO | 2025/12/15

REPOSITORIES: GEO

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RNA-seq Reveals Differences in Expressed Tumor Mutation Burden in Colorectal and Endometrial Cancer With and Without Defective DNA Mismatch Repair

Project description:Tumor mutation burden (TMB) is an evolving biomarker for predicting response to immune checkpoint inhibitors (ICI’s). The goal of this study was to evaluate the use of RNA-seq for determining TMB in patients with defective DNA MMR (dMMR) due to MMR mutations or MLH1 promoter hypermethylation (HM) and tumors without dMMR. We included tumors and paired normal tissue from 58 patients for TMB analysis using RNA-seq. Forty-six tumors were MSI-H (29 with a DNA MMR germline mutation and 17 with MLH1 promoter HM) and 12 were MSS. TMB was measured using the expressed somatic nucleotide variants (eTMB). We developed a method that leverages mutational signatures to remove FFPE derived artifact from total eTMB and thereby accurately measure the eTMB. There was a significant difference in the eTMB observed between MSI-H and MSS cases; MSI-H cases had a median of 27.3 mutations/Mb compared to 6.7 mutations/Mb for MSS cases (p=3.5e-9). Among tumors with dMMR the tumors with DNA MMR mutations had a significantly higher eTMB (p=0.037) than tumors with MLH1 promoter HM: a median of 28.1 mutations/Mb vs. a median of 17.5 mutations/Mb. Furthermore, through multivariate analysis we found that MSI status, tissue type (endometrial or colorectal) and patient ages are significantly associated with eTMB. These results demonstrate that RNA-seq analysis can be used to measure eTMB in FFPE tumor specimens. Further studies are needed to determine how eTMB as determined by RNA-seq compares to TMB as determined by DNA-based NGS assays

2020-03-13 | GSE146889 | GEO

Divergent immune microenvironments in two tumor nodules from a patient with mismatch repair-deficient prostate cancer.

Project description:Patients with prostate cancer (PC) generally do not respond favorably to immune checkpoint inhibitors, which may be due to a low abundance of tumor-infiltrating lymphocytes even when mutational load is high. Here, we identified a patient who presented with high-grade primary prostate cancer with two adjacent tumor nodules. While both nodules were mismatch repair- deficient (MMRd), exhibited pathogenic MSH2 and MSH6 alterations, had a high tumor mutational burden (TMB), and demonstrated high microsatellite instability (MSI), they had markedly distinct immune phenotypes. The first displayed a dense infiltrate of lymphocytes (“hot nodule”), while the second displayed significantly fewer infiltrating lymphocytes (“cold nodule”). Whole-exome DNA analysis found that both nodules shared many identical mutations, indicating that they were derived from a single clone. However, the cold nodule appeared to be sub-clonal relative to the hot nodule, suggesting divergent evolution of the cold nodule from the hot nodule. Whole-transcriptome RNA analysis found that the cold nodule demonstrated lower expression of genes related to antigen presentation (HLA) and, paradoxically, classical tumor immune tolerance markers such as PD-L1 (CD274) and CTLA-4. Immune cell deconvolution suggested that the hot nodule was enriched not only in CD8+ and CD4+ T lymphocytes, but also in M1 macrophages, activated NK cells, and gamma delta T cells compared to the cold nodule. This case highlights that MMRd/TMB-high PC can evolve to minimize an anti-tumor immune response, and nominates downregulation of antigen presentation machinery (HLA loss) as a potential mechanism of adaptive immune evasion in PC.

2023-10-31 | GSE246684 | GEO

Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Hypermutation Status

Project description:In this study, MMRd metastatic colorectal cancer (mCRC) patients who failed standard therapies will undergo treatment with pembrolizumab, while RAS-extended mutated MMR-proficient mCRC patients will be tested for o6-methylguanine-DNA-methyltransferase (MGMT) expression (IHC) and then for MGMT promoter methylation. MGMT IHC-negative, promoter methylation positive patients will be treated with temozolomide (TMZ). Patients progressing under temozolomide will be tested for tumor mutational burden (TMB) and proceed to pembrolizumab if TMB is > 20 mutations/Mb. The primary study hypothesis is that tumors with acquired resistance to temozolomide become hypermutated and are sensitive to pembrolizumab.

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Recurrent frameshift neoantigen vaccine elicits protective immunity with reduced tumor burden and improved overall survival in a Lynch syndrome mouse model

Project description:DNA mismatch repair deficiency (MMRD) drives microsatellite instability (MSI). Cells with MSI accumulate numerous frameshift mutations. Frameshift mutations affecting cancer-related genes may promote tumorigenesis and, therefore, are shared among independently arising MSI tumors. Consequently, such recurrent frameshift mutations can give rise to shared immunogenic frameshift peptides (FSPs) that represent ideal candidates for a vaccine against MSI cancer. Pathogenic germline variants of mismatch repair genes cause Lynch syndrome (LS), a hereditary cancer syndrome affecting approximately 20-25 million individuals worldwide. LS individuals are at high risk of developing MSI cancer. Previously, we demonstrated safety and immunogenicity of an FSP-based vaccine in a Phase I/IIa clinical trial. However, the cancer-preventive effect of FSP vaccination in the scenario of LS has not been demonstrated so far.

2021-08-30 | GSE175744 | GEO

The mismatch-repair proteins MSH2 and MSH6 interact with the imprinting control regions through the ZFP57-KAP1 complex (ChIP-Seq)

Project description:Genomic imprinting is controlled by CpG-rich regions (ICRs) acquiring differential methylation in the female and male germline and maintaining it in a parental origin-specific manner in somatic cells. Despite their expected mutation rate due to spontaneous deamination of methylated cytosines, ICRs maintain their CpG-richness and show conservation of CpG-bearing transcription binding sites in mammals. In order to gain further insights into the mechanisms of maintenance of methyl CpGs, we sought to identify the proteins interacting with the methylated allele of the ICRs, by determining the interactors of ZFP57 that recognizes a specific methylated ICR motif in mouse ESCs. Several proteins including factors involved in mRNA processing/splicing, chromatin organization, transcription and DNA repair were identified through a tagged approach coupled to LC–MS/MS analysis. The demonstration of the components of the post-replicative mismatch-repair (MMR) complex as ZFP57 interactors prompted us to investigate the DNA binding profile of MSH2 and MSH6 by chromatin immunoprecipitation and sequencing. We found that these proteins were enriched at the methylated allele of the ICRs and their binding was mediated by the ZFP57/KAP1 complex, suggesting that the MMR complex is recruited to these loci to preserve their genetic integrity.

2022-08-16 | GSE205041 | GEO

The mismatch-repair proteins MSH2 and MSH6 interact with the imprinting control regions through the ZFP57-KAP1 complex (RRBS)

2022-08-16 | GSE205042 | GEO

Loss of Msh2 and a single-radiation hit induce common, genome-wide, and persistent epigenetic changes in the intestine

Project description:Background: Mismatch repair (MMR)-deficiency increases the risk of colorectal tumorigenesis. To determine whether the tumors develop on a normal or disturbed epigenetic background and how radiation affects this, we determined genome-wide histone H3 methylation profiles in macroscopic normal intestinal tissue of young radiated and untreated MMR-deficient VCMsh2LoxP/LoxP (Msh2−/−) mice months before tumor onset. Results: Histone H3 methylation increases in Msh2−/− compared to control Msh2+/+ mice. Activating H3K4me3 and H3K36me3 histone marks frequently accumulate at genes that are H3K27me3 or H3K4me3 modified in Msh2+/+ mice, respectively. The genes recruiting H3K36me3 enrich in gene sets associated with DNA repair, RNA processing, and ribosome biogenesis that become transcriptionally upregulated in the developing tumors. A similar epigenetic effect is present in Msh2+/+ mice 4 weeks after a single-radiation hit, whereas radiation of Msh2−/− mice left their histone methylation profiles almost unchanged. Conclusions: MMR deficiency results in genome-wide changes in histone H3 methylation profiles preceding tumor development. Similar changes constitute a persistent epigenetic signature of radiation-induced DNA damage.

2019-03-26 | GSE128842 | GEO

Dual role of PCNA-monoubiquitination in facilitating Fanconi Anemia-mediated interstrand crosslink repair

Project description:The Fanconi Anemia (FA) repair pathway governs the repair of highly genotoxic DNA interstrand crosslinks (ICLs) with the assistance of translesion synthesis (TLS), that is facilitated by site-specific monoubiquitination of PCNA (PCNA-Ub) at lysine 164 (K164). Mutation at this residue (K164R) renders mammals hypersensitive to ICLs. Besides the FA pathway, alternative pathways have been associated with ICL repair However, the decision-making between the different pathways remains elusive. To study the dependence and relevance of PCNA-Ub in FA repair and pathway preference, we generated a germline Fancg-/- mouse and intercrossed PcnaK164R/+;Fancg-/+ mice. A compound mutation (KR;FGko) was embryonic lethal with the noted exception of very infrequent escapers. RNAseq of primary double mutant mouse embryonic fibroblasts (MEFs) revealed elevated levels of replication stress-induced checkpoints, which were rescued by Trp53 knockdown. Upon crosslink induction, KR and FGko MEFs displayed a similar phenotype regarding sensitivity, cell cycle arrest, fork progression and accumulation of single stranded DNA.Remarkably, PCNA-Ub excludes the mismatch recognition complex MSH2/MSH6 from being recruited. Our results implicate a dual function of PCNA-Ub in ICL repair: 1. Facilitate TLS opposite the unhooked ICL and 2. simultaneously exclude MSH2/MSH6 recruitment to channel the ICL towards canonical FA repair.

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The MLH1 c.-27C>A and c.85G>T variants are borne on a European ancestral haplotype which underlies an autosomal dominant form of MLH1 epimutation.

Project description:Lynch syndrome, caused by germline heterozygous mutations of the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2, or deletions affecting the EPCAM gene upstream of MSH2, is characterized by a predisposition to early-onset colorectal and additional extracolonic cancers. An alternative but rare cause of Lynch syndrome is a constitutional epimutation of MLH1, which is characterized by promoter methylation and transcriptional silencing of a single allele in normal tissues. Worldwide, five families with autosomal dominant transmission of a constitutional MLH1 epimutation linked to an MLH1 haplotype with two single nucleotide variants (c.-27C>A and c.85G>T) have been identified. Array-based genotyping using Affymetrix SNP 6.0 data in four of these families revealed a shared haplotype extending across a ≤2.6 Mb region of chromosome 3p22 encompassing MLH1 and additional flanking genes, indicating common ancestry. Genomic DNA from 5 carriers of the c.-27C>A and c.85G>T variants was hybridized on Affymetrix SNP6.0 array according to manufacturer's procedures

2013-04-01 | E-GEOD-45149 | biostudies-arrayexpress

The clinicopathological characteristics, prognosis and immune microenvironment mapping in MSI-H/MMR-D endometrial carcinomas

Project description:Endometrial cancer had a relatively high prevalence of MMR deficiency. MMR-D/MSI-H endometrial cancer patients are suggested to be potential beneficiaries of PD-1/PD-L1 inhibitor therapy. Here, we explored the prognostic value of MSI subtype in endometrial cancer and its correlation with immune environment. Based on expression and clinical data of 78 POLE, 123 MSI and 299 Other EC samples from the TCGA-UCEC project, we found that the MSI tumors were identified more often in early stage, had a lower age, better patient survival, enriched CD8+ T cells, and regulatory T cells and less M2 macrophages and activated dendritic cells than the Other group, and shared a relatively similar expression profile with POLE group by differential analysis. In addition, we established the immune landscape of an MMR-D endometrial cancer tissue using unbiased single-cell RNA-seq analysis of 3371 cells. By immunohistochemistry analysis, we found that the MMR-D tumors showed a higher trend of CD20+ B cells infiltration. Our study might expand our understanding of the role of immune subsets in MSI endometrial carcinomas and provide guidance of immunotherapy for endometrial cancer.

2022-03-09 | GSE193430 | GEO

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