@article{324f6bcfb16c45e0aea79c2848128881,
title = "Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment",
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-na{\"i}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.",
keywords = "Hypermutator, Low-grade glioma, MGMT, Mismatch repair, Temozolomide",
author = "{van Thuijl}, {Hinke F.} and Tali Mazor and Johnson, {Brett E.} and Fouse, {Shaun D.} and Koki Aihara and Chibo Hong and Annika Malmstr{\"o}m and Martin Hallbeck and Heimans, {Jan J.} and Kloezeman, {Jenneke J.} and Marie Stenmark-Askmalm and Lamfers, {Martine L.M.} and Nobuhito Saito and Hiroyuki Aburatani and Akitake Mukasa and Berger, {Mitchell S.} and Peter S{\"o}derkvist and Taylor, {Barry S.} and Molinaro, {Annette M.} and Pieter Wesseling and Reijneveld, {Jaap C.} and Chang, {Susan M.} and Bauke Ylstra and Costello, {Joseph F.}",
note = "Funding Information: This project was generously supported by Accelerate Brain Cancer Cure; The Grove Foundation; The TDC Foundation; The Anne and Jason Farber Foundation; and a generous gift from the Dabbiere family, UCSF Brain Tumor SPORE grant (NIH P50CA097257) (A.M., J.F.C., B.T., S.M.C., M.S.B.), the Dutch Cancer Society (KWF) grant number 2009-4470 and personal travel grant (H.F.v.T), foundation {\textquoteleft}STOPHersentumoren{\textquoteright}, Edli foundation, LiU Cancer Research Network, The Medical Research Council of Southeast Sweden. Additional support by the National Institute Of General Medical Sciences T32GM008568 (T.M.), the National Institutes of Health 1T32CA15102201, the National Cancer Institute R01CA169316 (J.F.C.), Sontag Foundation (B.T.), NCI RO1 (R01 CA163687) (A.M.). This project was supported in part by a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct) (A.M., N.S., and H.A.), Grant-in-Aid for Scientific Research on Innovative Areas (No. 23134501) (A.M.), and Grant-in-Aid for Scientific Research (No. 24221011) (H.A.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. We are grateful to our Dutch collaborators Guus Beute and Ruth Fleischeuer from St. Elisabeth hospital, Wimar van den Brink and Miek Havenith from Isala hospital, Hans Baayen, David Noske and Philip de Witt Hamer from VU University Medical Center and Anja M. Gijtenbeek from the Radboud University Medical Center Nijmegen for providing samples and clinical data. We thank collaborators from the South-East Sweden Brain Tumor Group for providing samples and clinical data; neurosurgeon Peter Milos, clinical oncologists Anna-Lotta Hallbeck, Link{\"o}ping Charlotte Bratth{\"a}ll, Kalmar and Michael Strand{\'e}us, J{\"o}nk{\"o}ping. Publisher Copyright: {\textcopyright} 2015, Springer-Verlag Berlin Heidelberg.",
year = "2015",
month = apr,
day = "1",
doi = "10.1007/s00401-015-1403-6",
language = "English (US)",
volume = "129",
pages = "597--607",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "4",
}