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Single-nucleotide-resolution genomic maps of O6-methylguanine from the glioblastoma drug temozolomide

ABSTRACT: Temozolomide kills cancer cells by forming O6-methylguanine (O6-MeG), which leads to apoptosis due to mismatch-repair overload. However, O6-MeG repair by O6-methylguanine-DNA methyltransferase (MGMT) contributes to drug resistance. Genomic profiles of O6-MeG could elucidate how O6-MeG accumulation is influenced by repair mechanisms, but there are no methods to map genomic locations of O6-MeG. Here, we developed an immunoprecipitation- and polymerase-stalling-based method, termed O6-MeG-seq, to locate O6-MeG across the whole genome at single-nucleotide resolution. We analyzed O6-MeG formation and repair with regards to sequence contexts and functional genomic regions in glioblastoma-derived cell lines and evaluated the impact of MGMT transfection. O6-MeG signatures were highly similar to mutational signatures of patients previously treated with temozolomide. Furthermore, MGMT did not preferentially repair O6-MeG with respect to sequence context, chromatin state or gene expression level, however, may protect oncogenes from mutations. Finally, we found an MGMT-independent strand bias in O6-MeG accumulation in highly expressed genes, suggesting an additional transcription-associated contribution to its repair. These data provide high resolution insight on how O6-MeG formation and repair is impacted by genome structure and regulation. Further, O6-MeG-seq is expected to enable future studies of DNA modification signatures as diagnostic markers for addressing drug resistance and preventing secondary cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE249155 | GEO | 2023/12/12

REPOSITORIES: GEO

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Single-nucleotide-resolution genomic maps of O6-methylguanine from the glioblastoma drug temozolomide

Project description:Temozolomide kills cancer cells by forming O6-methylguanine (O6-MeG), which leads to cell cycle arrest and apoptosis. However, O6-MeG repair by O6-methylguanine-DNA methyltransferase (MGMT) contributes to drug resistance. Characterizing genomic profiles of O6-MeG could elucidate how O6-MeG accumulation is influenced by repair, but there are no methods to map genomic locations of O6-MeG. Here, we developed an immunoprecipitation- and polymerase-stalling-based method, termed O6-MeG-seq, to locate O6-MeG across the whole genome at single-nucleotide resolution. We analyzed O6-MeG formation and repair with regards to sequence contexts and functional genomic regions in glioblastoma-derived cell lines and evaluated the impact of MGMT. O6-MeG signatures were highly similar to mutational signatures from patients previously treated with temozolomide. Furthermore, MGMT did not preferentially repair O6-MeG with respect to sequence context, chromatin state or gene expression level, however, may protect oncogenes from mutations. Finally, we found an MGMT-independent strand bias in O6-MeG accumulation in highly expressed genes in TMZ-exposed cells and naked DNA proposing an indirect influence of transcription to O6-MeG formation. These data provide high resolution insight on how O6-MeG formation and repair is impacted by genome structure and nucleotide sequence. Further, O6-MeG-seq is expected to enable future studies of DNA modification signatures as diagnostic markers for addressing drug resistance and preventing secondary cancers.

2024-10-30 | GSE279423 | GEO

Extent and Patterns of MGMT Promoter Methylation in Glioblastoma- and Respective Glioblastoma-Derived Spheres

Project description:Quantitative methylation-specific tests suggest that not all cells in a glioblastoma with detectable promoter methylation of the O6-methylguanine DNA methyltransferase (MGMT) gene carry a methylated MGMT allele. This observation may indicate cell subpopulations with distinct MGMT status, raising the question of the clinically relevant cutoff of MGMT methylation therapy. Epigenetic silencing of the MGMT gene by promoter methylation blunts repair of O6-methyl guanine and has been shown to be a predictive factor for benefit from alkylating agent therapy in glioblastoma. Samples of glioblastoma and respective glioblastoma-derived spheres (GS), cultured under stem cell conditions, were analyzed for the degree and pattern of MGMT promoter methylation by methylation-specific clone sequencing, MGMT gene dosage, chromatin status, and respective effects on MGMT expression and MGMT activity.

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Plasma Mouse LC-MSMS - Bortezomib administered prior to temozolomide depletes MGMT, chemosensitizes glioblastoma with unmethylated MGMT promoter and prolongs animal survival

Project description:Patients diagnosed with glioblastoma (GBM) with sustained synthesis of the DNA repair enzyme, O6-methyl guanine DNA methytransferase (MGMT), are rendered resistant to Temozolomide (TMZ) chemotherapy. Here, we hypothesized that pretreatment with the proteasome inhibitor Bortezomib (BTZ, Velcade) might sensitize these GBM to TMZ by depleting MGMT.

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Class I HDAC overexpression promotes temozolomide resistance in glioma cells by regulating RAD18 expression

Project description:Overexpression of histone deacetylases (HDACs) in cancer commonly causes resistance to genotoxic based therapies. Here we report on the novel mechanism whereby overexpressed class I HDACs increase the resistance of glioblastoma cells to the SN1 methylating agent temozolomide (TMZ). The chemotherapeutic TMZ triggers the activation of the DNA damage response (DDR) in resistant glioma cells, leading to DNA lesion bypass and cellular survival. Mass spectrometry analysis revealed that the catalytic activity of class I HDACs stimulates the expression of the E3 ubiquitin ligase RAD18. Furthermore, the data show that RAD18 is part of the O6-methylguanine-induced DDR as TMZ induces the formation of RAD18 foci at sites of DNA damage. Downregulation of RAD18 by HDAC inhibition prevents glioma cells from activating the DDR upon TMZ exposure. Lastly, RAD18 or O6-methylguanine-DNA methyltransferase (MGMT) overexpression abolishes the sensitization effect of HDAC inhibition on TMZ-exposed glioma cells. Our study describes the mechanism whereby class I HDAC overexpression in glioma cells causes resistance to TMZ treatment. HDACs accomplish this by promoting the bypass of O6-methylguanine DNA lesions via enhancing RAD18 expression. It also provides a treatment option with HDAC inhibition to undermine this mechanism.

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Cycad Genotoxin Methylazoxymethanol (MAM) Modulates Cellular Pathways Involved in Cancer and Neurodegenerative Disease

Project description:Methylazoxymethanol (MAM), the genotoxic metabolite of the cycad azoxyglucoside cycasin, induces genetic alterations in bacteria, yeast, plants, insects and mammalian cells, but adult nerve cells are thought to be unaffected. We show that the brains of young adult mice treated with a single systemic dose of MAM display DNA damage (O6-methylguanine lesions) that peaks at 48 hours and decline to near-normal levels at 7 days post-treatment. By contrast, at this time, MAM-treated mice lacking the gene encoding the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT), showed persistent O6-methylguanine DNA damage. The DNA damage was linked to cell-signaling pathways that are perturbed in cancer and neurodegenerative disease. These data are consistent with the established carcinogenic and developmental neurotoxic properties of MAM in rodents, and they support the proposal that cancer and neurodegeneration share common signal transduction pathways. They also strengthen the hypothesis that early life exposure to the MAM glucoside cycasin has an etiological association with a declining, prototypical neurodegenerative disease seen in Guam, Japan, and New Guinea populations that formerly used the neurotoxic cycad plant for medicine and/or food. Exposure to environmental genotoxins may have relevance to the etiology of related tauopathies, notably, Alzheimer’s disease, as well as cancer. Mouse brains from eleven-week-old male C57BL6 wild-type and Mgmt-/- mice were exposed to either MAM or Vehicle for 6 hr, 24 hr, 48 hr, 168 hr. Five or six mice per group for a total of 94 mice.

2013-01-10 | E-GEOD-26600 | biostudies-arrayexpress

A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma

Project description:Temozolomide (TMZ) has been used for the treatment of glioblastoma (GBM) since last decade, but its treatment benefits are limited by acquired resistance, a process that remains incompletely understood. Here we report that a novel enhancer, located between the promoters of Ki67 and O6-methylguanine-DNA-methyltransferase (MGMT) genes, is activated in TMZ-resistant patient-derived xenograft (PDX) lines as well as in recurrent tumor samples. Activation of the enhancer correlates with increased MGMT expression, a major known mechanism for TMZ resistance. We show that forced activation of the enhancer in cell lines with low MGMT expression results in elevated MGMT expression. Deletion of this enhancer in cell lines with high MGMT expression leads to reduced levels of MGMT and Ki67, increased TMZ sensitivity and impaired proliferation. Together, these studies uncover a novel mechanism that regulates MGMT expression, confers TMZ resistance and potentially regulates tumor proliferation.

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Single-nucleotide-resolution genomic maps of O6-methylguanine from the glioblastoma drug temozolomide

Project description:Single-nucleotide-resolution genomic maps of O6-methylguanine from the glioblastoma drug temozolomide

| PRJNA1047565 | ENA

Single-nucleotide-resolution genomic maps of O6-methylguanine from the glioblastoma drug temozolomide

Project description:Single-nucleotide-resolution genomic maps of O6-methylguanine from the glioblastoma drug temozolomide

| PRJNA1172681 | ENA

Combined bioinformatic and clinical assay uncovers resistance and susceptibility mechanisms of human glioblastomas to temozolomide and identifies new survival biomarkers outperforming MGMT promoter methylation

Project description:Glioblastoma (GBM) is the most aggressive and lethal CNS tumor with only 14 months median overall survival after diagnosis and ∼5% 5-years survival rate. The treatment strategy is mainly surgery and/or radiation therapy, both combined with adjuvant temozolomide (TMZ) chemotherapy. TMZ treatment results in methylation of DNA purine bases, where the primary cytotoxic lesion is O6-methylguanine that can be removed by DNA repair enzyme methylguanine methyltransferase (MGMT) when tumors express this protein. Historically, methylation of MGMT gene promoter is used as the major biomarker predicting individual tumor response to TMZ, but there are also additional biomarkers. However, most of them were developed using TCGA project collection of molecular profiles which were unproperly diagnosed as GBM and now need to be reclassified according to the most recent WHO CNS5 tumor classification. Here we for the first time compared biomarker potentials of MGMT methylation, expression levels of 361 DNA repair genes, and activation levels of 38 DNA repair pathways on updated TCGA and other samplings and validated the results on our experimental multicenter GBM patient cohort (n=50). We found that expression/activation levels of 7 and 6 emerging gene/pathway biomarkers served as high-quality positive (HR<0.61) and negative (HR>1.63), respectively, patient survival biomarkers, all performed significantly better than MGMT methylation. Positive survival biomarkers were enriched in the processes of ATM-dependent checkpoint activation and cell cycle arrest whereas negative – in excision DNA repair. We also built and characterized gene signature which was informative for GBM patient survival following TMZ administration (HR 0.27-0.44, p<0,0004; AUC 0.69-0.9).

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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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