Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment
2015 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 129, no 4, 597-607 p.Article in journal (Refereed) Published
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-na less than ve 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.
Place, publisher, year, edition, pages
Springer Verlag (Germany) , 2015. Vol. 129, no 4, 597-607 p.
Low-grade glioma; Temozolomide; Hypermutator; Mismatch repair; MGMT
IdentifiersURN: urn:nbn:se:liu:diva-117202DOI: 10.1007/s00401-015-1403-6ISI: 000351517200008PubMedID: 25724300OAI: oai:DiVA.org:liu-117202DiVA: diva2:807120
Funding Agencies|Accelerate Brain Cancer Cure; Grove Foundation; TDC Foundation; Anne and Jason Farber Foundation; UCSF Brain Tumor SPORE grant [NIH P50CA097257]; Dutch Cancer Society (KWF) [2009-4470]; foundation STOPHersentumoren; Edli foundation; LiU Cancer Research Network; Medical Research Council of Southeast Sweden; National Institute Of General Medical Sciences [T32GM008568]; National Institutes of Health [1T32CA15102201]; National Cancer Institute [R01CA169316]; Sontag Foundation; NCI RO1 [R01 CA163687]; Project for Development of Innovative Research on Cancer Therapeutics (P-Direct); Ministry of Education, Culture, Sports, Science and Technology of Japan [23134501, 24221011]2015-04-222015-04-212016-04-04