1. Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment
- Author
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Koki Aihara, Hiroyuki Aburatani, Peter Söderkvist, Joseph F. Costello, Jaap C. Reijneveld, Mitchell S. Berger, Martine L.M. Lamfers, Pieter Wesseling, Shaun D. Fouse, Tali Mazor, Marie Stenmark-Askmalm, Annette M. Molinaro, Barry S. Taylor, Annika Malmström, Martin Hallbeck, Nobuhito Saito, Brett E. Johnson, Jan J. Heimans, Hinke F. van Thuijl, Akitake Mukasa, Chibo Hong, Bauke Ylstra, Susan M. Chang, Jenneke Kloezeman, Neurosurgery, Pathology, Neurology, and CCA - Innovative therapy
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Male ,Methyltransferase ,medicine.disease_cause ,Cohort Studies ,Immunologic ,Receptors ,Hypermutator ,Receptors, Immunologic ,DNA Modification Methylases ,Cancer ,Mutation ,Brain Neoplasms ,Statistics ,Glioma ,Alkylating ,Dacarbazine ,DNA methylation ,Disease Progression ,DNA mismatch repair ,Female ,MGMT ,medicine.drug ,DNA repair ,Clinical Sciences ,Low-grade glioma ,Clinical Neurology ,Antineoplastic Agents ,Context (language use) ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,Biology ,Statistics, Nonparametric ,Article ,Mismatch repair ,Pathology and Forensic Medicine ,Cellular and Molecular Neuroscience ,Rare Diseases ,Genetics ,medicine ,Temozolomide ,Humans ,Nonparametric ,neoplasms ,Antineoplastic Agents, Alkylating ,Neurology & Neurosurgery ,Tumor Suppressor Proteins ,Neurosciences ,DNA Methylation ,medicine.disease ,DNA Repair-Deficiency Disorders ,digestive system diseases ,Brain Disorders ,Brain Cancer ,DNA Repair Enzymes ,Immunology ,Cancer research ,Neurology (clinical) - Abstract
Contains fulltext : 155226.pdf (Publisher’s version ) (Closed access) 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-naive 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 positive selection during TMZ treatment in the context of MMR deficiency.
- Published
- 2015
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