Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment
- 28 February 2015
- journal article
- research article
- Published by Springer Science and Business Media LLC in Acta Neuropathologica
- Vol. 129 (4), 597-607
- https://doi.org/10.1007/s00401-015-1403-6
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 positive selection during TMZ treatment in the context of MMR deficiency.This publication has 58 references indexed in Scilit:
- MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-statusActa Neuropathologica, 2012
- First-line temozolomide chemotherapy in progressive low-grade astrocytomas after radiotherapy: molecular characteristics in relation to responseNeuro-Oncology, 2010
- MGMT promoter hypermethylation is a frequent, early, and consistent event in astrocytoma progression, and not correlated with TP53 mutationJournal of Neuro-Oncology, 2010
- Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short readsBioinformatics, 2009
- Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapyBritish Journal of Cancer, 2009
- Fast and accurate short read alignment with Burrows–Wheeler transformBioinformatics, 2009
- Comprehensive genomic characterization defines human glioblastoma genes and core pathwaysNature, 2008
- Assessing the significance of chromosomal aberrations in cancer: Methodology and application to gliomaProceedings of the National Academy of Sciences of the United States of America, 2007
- The 2007 WHO Classification of Tumours of the Central Nervous SystemActa Neuropathologica, 2007
- The multifaceted mismatch-repair systemNature Reviews Molecular Cell Biology, 2006