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

Hinke F. van Thuijl, Tali Mazor, Brett E. Johnson, Shaun D. Fouse, Koki Aihara, Chibo Hong, Annika Malmström, Martin Hallbeck, Jan J. Heimans, Jenneke J. Kloezeman, Marie Stenmark-Askmalm, Martine L.M. Lamfers, Nobuhito Saito, Hiroyuki Aburatani, Akitake Mukasa, Mitchell S. Berger, Peter Söderkvist, Barry S. Taylor, Annette M. Molinaro, Pieter WesselingJaap C. Reijneveld, Susan M. Chang, Bauke Ylstra, Joseph F. Costello

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

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 O6-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.

Original languageEnglish (US)
Pages (from-to)597-607
Number of pages11
JournalActa Neuropathologica
Volume129
Issue number4
DOIs
StatePublished - Apr 1 2015
Externally publishedYes

Keywords

  • Hypermutator
  • Low-grade glioma
  • MGMT
  • Mismatch repair
  • Temozolomide

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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