Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment

Abstract Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O 6 -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT–mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naïve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo...
Source: Acta Neuropathologica - Category: Neurology Source Type: research

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Glioblastoma, the most common primary central nervous system tumor, is characterized by extensive vascular neoformation and an area of necrosis generated by rapid proliferation. The standard treatment for this type of tumor is surgery followed by chemotherapy based on temozolomide and radiotherapy, resulting in poor patient survival. Glioblastoma is known for strong resistance to treatment, frequent recurrence and rapid progression. The aim of this study was to evaluate whether mifepristone, an antihormonal agent, can enhance the effect of temozolomide on C6 glioma cells orthotopically implanted in Wistar rats. The levels ...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
erlik Malignant gliomas (MG) are among the most prevalent and lethal primary intrinsic brain tumors. Although radiotherapy (RT) is the most effective nonsurgical therapy, recurrence is universal. Dysregulated DNA damage response pathway (DDR) signaling, rampant genomic instability, and radio-resistance are among the hallmarks of MGs, with current therapies only offering palliation. A subgroup of pediatric high-grade gliomas (pHGG) is characterized by H3K27M mutation, which drives global loss of di- and trimethylation of histone H3K27. Here, we review the most recent literature and discuss the key studies dissecting the...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
Abstract Ongoing research using cell transplantation and viral-mediated gene therapy has been making progress to restore vision by retinal repair, but targeted delivery and complete cellular integration remain challenging. An alternative approach is to induce endogenous Müller glia (MG) to regenerate lost neurons and photoreceptors, as occurs spontaneously in teleost fish and amphibians. Extracellular vesicles (EVs) can transfer protein and RNA cargo between cells serving as a novel means of cell-cell communication. We conducted an in vivo screen in zebrafish to identify sources of EVs that could induce MG to...
Source: Experimental Eye Research - Category: Opthalmology Authors: Tags: Exp Eye Res Source Type: research
AbstractCentral nervous system tumors in adolescents and young adults (AYA) are rarely reported in the literature. The association with cancer predisposition syndrome is not established. Programmed death ligand 1 (PD-L1) can predict the potential response of patients to immunotherapy. A link between mismatch repair protein deficiency (MMRP-D) and response to immunotherapy is established. P53 is reported to be positive in MMRD-D cases. We aim to investigate the frequency of MMRP-D in AYA with high-grade glioma and any potential association with PD-L1. A total of 96 cases were tested including 49 (51.0%) cases of glioblastom...
Source: Brain Tumor Pathology - Category: Neurology Source Type: research
AbstractReplication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high-grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG presents specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair-deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450  k or 850 k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in gli...
Source: Acta Neuropathologica - Category: Neurology Source Type: research
Abstract Isocitrate dehydrogenase active-site mutations cause a neomorphic enzyme activity that results in the formation of supraphysiological concentrations of D-2-hydroxyglutarate (D-2HG). D-2HG is thought to be an oncometabolite that drives the formation of cancers in a variety of tissue types by altering the epigenetic state of progenitor cells by inhibiting enzymes involved in histone and DNA demethylation. This model has led to the development of pharmacological inhibitors of mutant IDH activity for anti-cancer therapy, which are now being tested in several clinical trials. Emerging evidence in preclinical g...
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
Conclusions: pembrolizumab showed no apparent benefit in these patients. No molecular biomarker was found to be associated with pembrolizumab activity.
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
(Centro Nacional de Investigaciones Oncol ó gicas (CNIO)) * Patients with glioma - a very common type of tumour originating in the brain - see improvement in survival rates with combined treatment of radiotherapy plus temozolomide* Researchers found a novel mechanism on how tumours evade chemotherapy through genomic rearrangements of the MGMT DNA repair gene* This finding is potentially relevant for updating the methods used to monitor temozolomide efficacy. Genomic rearrangement could be a marker to be detected in blood samples and help make therapeutic decisions
Source: EurekAlert! - Cancer - Category: Cancer & Oncology Source Type: news
(Centro Nacional de Investigaciones Oncol ó gicas (CNIO)) * Patients with glioma - a very common type of tumour originating in the brain - see improvement in survival rates with combined treatment of radiotherapy plus temozolomide* Researchers found a novel mechanism on how tumours evade chemotherapy through genomic rearrangements of the MGMT DNA repair gene* This finding is potentially relevant for updating the methods used to monitor temozolomide efficacy. Genomic rearrangement could be a marker to be detected in blood samples and help make therapeutic decisions
Source: EurekAlert! - Cancer - Category: Cancer & Oncology Source Type: news
Opinion statementMalignant gliomas remain a challenging cancer to treat due to limitations in both therapeutic and efficacious options. Tumor treating fields (TTFields) have emerged as a novel, locoregional, antineoplastic treatment modality with favorable efficacy and safety being demonstrated in the most aggressive type of malignant gliomas, glioblastoma (GBM). In 2 large randomized, controlled phase 3 trials, the addition of TTFields was associated with increased overall survival when combined with adjuvant temozolomide (TMZ) chemotherapy in patients with newly diagnosed GBM (ndGBM) and comparable overall survival compa...
Source: Current Treatment Options in Oncology - Category: Cancer & Oncology Source Type: research
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