Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment.
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.
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
Hinke F
HF
van Thuijl
Tali
T
Mazor
Brett E
BE
Johnson
Shaun D
SD
Fouse
Koki
K
Aihara
Chibo
C
Hong
Annika
A
Malmström
Martin
M
Hallbeck
Jan J
JJ
Heimans
Jenneke J
JJ
Kloezeman
Marie
M
Stenmark-Askmalm
Martine L M
ML
Lamfers
Nobuhito
N
Saito
Hiroyuki
H
Aburatani
Akitake
A
Mukasa
Mitchell S
MS
Berger
Peter
P
Söderkvist
Barry S
BS
Taylor
Annette M
AM
Molinaro
Pieter
P
Wesseling
Jaap C
JC
Reijneveld
Susan M
SM
Chang
Bauke
B
Ylstra
Joseph F
JF
Costello
D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000150:complications* / Q000188:drug therapy; D015331:Cohort Studies; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D049914:DNA Repair-Deficiency Disorders / Q000188:drug therapy* / Q000209:etiology; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018450:Disease Progression; D005260:Female; D005910:Glioma / Q000150:complications* / Q000188:drug therapy; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics; D018709:Statistics, Nonparametric; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics
D018906:Antineoplastic Agents, Alkylating; D011971:Receptors, Immunologic; D025521:Tumor Suppressor Proteins; C573592:macrophage MHC receptor 1, human; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide