TY - JOUR
T1 - Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment
AU - van Thuijl, Hinke F.
AU - Mazor, Tali
AU - Johnson, Brett E.
AU - Fouse, Shaun D.
AU - Aihara, Koki
AU - Hong, Chibo
AU - Malmström, Annika
AU - Hallbeck, Martin
AU - Heimans, Jan J.
AU - Kloezeman, Jenneke J.
AU - Stenmark-Askmalm, Marie
AU - Lamfers, Martine L. M.
AU - Saito, Nobuhito
AU - Aburatani, Hiroyuki
AU - Mukasa, Akitake
AU - Berger, Mitchell S.
AU - Söderkvist, Peter
AU - Taylor, Barry S.
AU - Molinaro, Annette M.
AU - Wesseling, Pieter
AU - Reijneveld, Jaap C.
AU - Chang, Susan M.
AU - Ylstra, Bauke
AU - Costello, Joseph F.
AU - Johnson, BE
AU - Malmstrom, A.
AU - Soderkvist, P.
PY - 2015
Y1 - 2015
N2 - 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
AB - 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
U2 - https://doi.org/10.1007/s00401-015-1403-6
DO - https://doi.org/10.1007/s00401-015-1403-6
M3 - Article
C2 - 25724300
SN - 0001-6322
VL - 129
SP - 597
EP - 607
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 4
ER -