Top

Published in:

01-04-2015 | Original Paper

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

Authors: 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 Wesseling, Jaap C. Reijneveld, Susan M. Chang, Bauke Ylstra, Joseph F. Costello

Published in: Acta Neuropathologica | Issue 4/2015

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 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.

Available only for authorised users

Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068

Bady P, Sciuscio D, Diserens AC, Bloch J, van den Bent MJ, Marosi C, Dietrich PY, Weller M, Mariani L, Heppner FL, Mcdonald DR, Lacombe D, Stupp R, Delorenzi M, Hegi ME (2012) MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status. Acta Neuropathol 124:547–560CrossRefPubMedCentralPubMed

Baumert B, Mason WP, Ryan G, Bromberg JE, van den Bent M, Hoang-Xuan K, Brandes AA, Kantor G, Taphoorn MJ, Ben Hassel M, Rees J, Wick W, von DA, Hartmann C, Kros JM, Hegi ME, Dif N, Lacombe D, Gorlia T, Stupp R (2013) The international EORTC/NCIC-CTG/TROG/MRC-CTU low grade trial: temozolomide chemotherapy versus radiotherapy in molecularly characterized (1p loss) LGG. 4th Quadrennial Meeting of the World Federation of Neuro-Oncology. San Francisco, CA, USA

Beroukhim R, Getz G, Nghiemphu L, Barretina J, Hsueh T, Linhart D, Vivanco I, Lee JC, Huang JH, Alexander S, Du J, Kau T, Thomas RK, Shah K, Soto H, Perner S, Prensner J, Debiasi RM, Demichelis F, Hatton C, Rubin MA, Garraway LA, Nelson SF, Liau L, Mischel PS, Cloughesy TF, Meyerson M, Golub TA, Lander ES, Mellinghoff IK, Sellers WR (2007) Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proc Natl Acad Sci 104:20007–20012CrossRefPubMedCentralPubMed

Bodell WJ, Gaikwad NW, Miller D, Berger MS (2003) Formation of DNA adducts and induction of lacI mutations in Big Blue Rat-2 cells treated with temozolomide: implications for the treatment of low-grade adult and pediatric brain tumors. Cancer Epidemiol Biomarkers Prev 12:545–551PubMed

Brada M, Viviers L, Abson C, Hines F, Britton J, Ashley S, Sardell S, Traish D, Gonsalves A, Wilkins P, Westbury C (2003) Phase II study of primary temozolomide chemotherapy in patients with WHO grade II gliomas. Ann Oncol 14:1715–1721CrossRefPubMed

Brandes AA, Franceschi E, Tosoni A, Bartolini S, Bacci A, Agati R, Ghimenton C, Turazzi S, Talacchi A, Skrap M, Marucci G, Volpin L, Morandi L, Pizzolitto S, Gardiman M, Andreoli A, Calbucci F, Ermani M (2010) O(6)-methylguanine DNA-methyltransferase methylation status can change between first surgery for newly diagnosed glioblastoma and second surgery for recurrence: clinical implications. Neuro Oncol 12:283–288CrossRefPubMedCentralPubMed

Cahill DP, Levine KK, Betensky RA, Codd PJ, Romany CA, Reavie LB, Batchelor TT, Futreal PA, Stratton MR, Curry WT, Iafrate AJ, Louis DN (2007) Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clin Cancer Res 13:2038–2045CrossRefPubMedCentralPubMed

Cankovic M, Mikkelsen T, Rosenblum ML, Zarbo RJ (2007) A simplified laboratory validated assay for MGMT promoter hypermethylation analysis of glioma specimens from formalin-fixed paraffin-embedded tissue. Lab Invest 87:392–397PubMed

10.

Chao EC, Velasquez JL, Witherspoon MS, Rozek LS, Peel D, Ng P, Gruber SB, Watson P, Rennert G, Anton-Culver H, Lynch H, Lipkin SM (2008) Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). Hum Mutat 29:852–860CrossRefPubMed

11.

Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C, Gabriel S, Meyerson M, Lander ES, Getz G (2013) Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol 31:213–219CrossRefPubMed

12.

Costello JF, Futscher BW, Kroes RA, Pieper RO (1994) Methylation-related chromatin structure is associated with exclusion of transcription factors from and suppressed expression of the O-6-methylguanine DNA methyltransferase gene in human glioma cell lines. Mol Cell Biol 14:6515–6521PubMedCentralPubMed

13.

Costello JF, Futscher BW, Tano K, Graunke DM, Pieper RO (1994) Graded methylation in the promoter and body of the O6-methylguanine DNA methyltransferase (MGMT) gene correlates with MGMT expression in human glioma cells. J Biol Chem 269:17228–17237PubMed

14.

Douw L, Klein M, Fagel SS, van den Heuvel J, Taphoorn MJ, Aaronson NK, Postma TJ, Vandertop WP, Mooij JJ, Boerman RH, Beute GN, Sluimer JD, Slotman BJ, Reijneveld JC, Heimans JJ (2009) Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up. Lancet Neurol 8:810–818CrossRefPubMed

15.

Dunn J, Baborie A, Alam F, Joyce K, Moxham M, Sibson R, Crooks D, Husband D, Shenoy A, Brodbelt A, Wong H, Liloglou T, Haylock B, Walker C (2009) Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy. Br J Cancer 101:124–131CrossRefPubMedCentralPubMed

16.

Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG (1999) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 59:793–797PubMed

17.

Everhard S, Tost J, El AH, Criniere E, Busato F, Marie Y, Gut IG, Sanson M, Mokhtari K, Laigle-Donadey F, Hoang-Xuan K, Delattre JY, Thillet J (2009) Identification of regions correlating MGMT promoter methylation and gene expression in glioblastomas. Neuro Oncol 11:348–356CrossRefPubMedCentralPubMed

18.

Felsberg J, Thon N, Eigenbrod S, Hentschel B, Sabel MC, Westphal M, Schackert G, Kreth FW, Pietsch T, Loffler M, Weller M, Reifenberger G, Tonn JC (2011) Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas. Int J Cancer 129:659–670CrossRefPubMed

19.

Fritz G, Kaina B (1992) Genomic differences between O6-methylguanine-DNA methyltransferase proficient (Mex+) and deficient (Mex−) cell lines: possible role of genetic and epigenetic changes in conversion of Mex+ into Mex−. Biochem Biophys Res Commun 183:1184–1190CrossRefPubMed

20.

Giraldo A, Gomez A, Salguero G, Garcia H, Aristizabal F, Gutierrez O, Angel LA, Padron J, Martinez C, Martinez H, Malaver O, Florez L, Barvo R (2005) MLH1 and MSH2 mutations in Colombian families with hereditary nonpolyposis colorectal cancer (Lynch syndrome)–description of four novel mutations. Fam Cancer 4:285–290CrossRefPubMed

21.

Grasbon-Frodl EM, Kreth FW, Ruiter M, Schnell O, Bise K, Felsberg J, Reifenberger G, Tonn JC, Kretzschmar HA (2007) Intratumoral homogeneity of MGMT promoter hypermethylation as demonstrated in serial stereotactic specimens from anaplastic astrocytomas and glioblastomas. Int J Cancer 121:2458–2464CrossRefPubMed

22.

Groenendijk FH, Taal W, Dubbink HJ, Haarloo CR, Kouwenhoven MC, van den Bent MJ, Kros JM, Dinjens WN (2011) MGMT promoter hypermethylation is a frequent, early, and consistent event in astrocytoma progression, and not correlated with TP53 mutation. J Neurooncol 101:405–417CrossRefPubMedCentralPubMed

23.

Hamilton MG, Roldan G, Magliocco A, McIntyre JB, Parney I, Easaw JC (2011) Determination of the methylation status of MGMT in different regions within glioblastoma multiforme. J Neurooncol 102:255–260CrossRefPubMed

24.

Harris LC, Remack JS, Brent TP (1994) Identification of a 59 bp enhancer located at the first exon/intron boundary of the human O6-methylguanine DNA methyltransferase gene. Nucleic Acids Res 22:4614–4619CrossRefPubMedCentralPubMed

25.

Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003CrossRefPubMed

26.

Hunter C, Smith R, Cahill DP, Stephens P, Stevens C, Teague J, Greenman C, Edkins S, Bignell G, Davies H, O’Meara S, Parker A, Avis T, Barthorpe S, Brackenbury L, Buck G, Butler A, Clements J, Cole J, Dicks E, Forbes S, Gorton M, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Kosmidou V, Laman R, Lugg R, Menzies A, Perry J, Petty R, Raine K, Richardson D, Shepherd R, Small A, Solomon H, Tofts C, Varian J, West S, Widaa S, Yates A, Easton DF, Riggins G, Roy JE, Levine KK, Mueller W, Batchelor TT, Louis DN, Stratton MR, Futreal PA, Wooster R (2006) A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res 66:3987–3991CrossRefPubMed

27.

Jiricny J (2006) The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol 7:335–346CrossRefPubMed

28.

Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, Fouse SD, Yamamoto S, Ueda H, Tatsuno K, Asthana S, Jalbert LE, Nelson SJ, Bollen AW, Gustafson WC, Charron E, Weiss WA, Smirnov IV, Song JS, Olshen AB, Cha S, Zhao Y, Moore RA, Mungall AJ, Jones SJ, Hirst M, Marra MA, Saito N, Aburatani H, Mukasa A, Berger MS, Chang SM, Taylor BS, Costello JF (2014) Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 343:189–193CrossRefPubMedCentralPubMed

29.

Koekkoek JA, Dirven L, Heimans JJ, Postma TJ, Vos MJ, Reijneveld JC, Taphoorn MJ (2014) Seizure reduction in a low-grade glioma: more than a beneficial side effect of temozolomide. J Neurol Neurosurg Psychiatry. doi:10.1136/jnnp-2014-308136 PubMed

30.

Komine C, Watanabe T, Katayama Y, Yoshino A, Yokoyama T, Fukushima T (2003) Promoter hypermethylation of the DNA repair gene O6-methylguanine-DNA methyltransferase is an independent predictor of shortened progression free survival in patients with low-grade diffuse astrocytomas. Brain Pathol 13:176–184CrossRefPubMed

31.

Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760CrossRefPubMedCentralPubMed

32.

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109CrossRefPubMedCentralPubMed

33.

Malley DS, Hamoudi RA, Kocialkowski S, Pearson DM, Collins VP, Ichimura K (2011) A distinct region of the MGMT CpG island critical for transcriptional regulation is preferentially methylated in glioblastoma cells and xenografts. Acta Neuropathol 121:651–661CrossRefPubMed

34.

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA (2010) The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20:1297–1303CrossRefPubMedCentralPubMed

35.

Nakamura M, Watanabe T, Yonekawa Y, Kleihues P, Ohgaki H (2001) Promoter methylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G: C–>A: T mutations of the TP53 tumor suppressor gene. Carcinogenesis 22:1715–1719CrossRefPubMed

36.

Nguyen SA, Stechishin OD, Luchman HA, Lun XQ, Senger DL, Robbins SM, Cairncross G, Weiss S (2014) Novel MSH6 mutations in treatment naive glioblastoma and anaplastic oligodendroglioma influence temozolomide resistance independently of MGMT methylation. Clin Cancer Res

37.

Pace A, Vidiri A, Galie E, Carosi M, Telera S, Cianciulli AM, Canalini P, Giannarelli D, Jandolo B, Carapella CM (2003) Temozolomide chemotherapy for progressive low-grade glioma: clinical benefits and radiological response. Ann Oncol 14:1722–1726CrossRefPubMed

38.

Parkinson JF, Wheeler HR, Clarkson A, McKenzie CA, Biggs MT, Little NS, Cook RJ, Messina M, Robinson BG, McDonald KL (2008) Variation of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation in serial samples in glioblastoma. J Neurooncol 87:71–78CrossRefPubMed

39.

Peltomaki P (2003) Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 21:1174–1179CrossRefPubMed

40.

Pieper RO, Costello JF, Kroes RA, Futscher BW, Marathi U, Erickson LC (1991) Direct correlation between methylation status and expression of the human O-6-methylguanine DNA methyltransferase gene. Cancer Commun 3:241–253PubMed

41.

Pignatti F, van den Bent M, Curran D, Debruyne C, Sylvester R, Therasse P, Afra D, Cornu P, Bolla M, Vecht C, Karim AB (2002) Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol 20:2076–2084CrossRefPubMed

42.

Quinn JA, Reardon DA, Friedman AH, Rich JN, Sampson JH, Provenzale JM, McLendon RE, Gururangan S, Bigner DD, Herndon JE, Avgeropoulos N, Finlay J, Tourt-Uhlig S, Affronti ML, Evans B, Stafford-Fox V, Zaknoen S, Friedman HS (2003) Phase II trial of temozolomide in patients with progressive low-grade glioma. J Clin Oncol 21:646–651CrossRefPubMed

43.

Raevaara TE, Korhonen MK, Lohi H, Hampel H, Lynch E, Lonnqvist KE, Holinski-Feder E, Sutter C, McKinnon W, Duraisamy S, Gerdes AM, Peltomaki P, Kohonen-Ccorish M, Mangold E, Macrae F, Greenblatt M, de la Chapelle A, Nystrom M (2005) Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1. Gastroenterology 129:537–549PubMed

44.

Ramalho-Carvalho J, Pires M, Lisboa S, Graca I, Rocha P, Barros-Silva JD, Savva-Bordalo J, Mauricio J, Resende M, Teixeira MR, Honavar M, Henrique R, Jeronimo C (2013) Altered expression of MGMT in high-grade gliomas results from the combined effect of epigenetic and genetic aberrations. PLoS One 8:e58206CrossRefPubMedCentralPubMed

45.

Reijneveld JC, Bottomley A, Taphoorn MJ, Coens C, Bromberg JE, Mason, Hoang-Xuan K, Brandes AA, Stupp R, Kantor G, Ben Hassel M, Ryan G, Wick W, Theissen B, Lacombe D, Gorlia T, Baumert B. (2013) Health related Quality of Life results from temozolomide chemotherapy vs. radiotherapy in molecularly characterized (1p loss) low-grade glioma. A randomized phase III Intergroup study by the EORTC/NCIC-CTG/TROG/MRC-CTU (EORTC 22033-26033). Neuro Oncol 15. 4th Quadrennial Meeting of the World Federation of Neuro-Oncology. San Francisco, CA, USA

46.

Rodriguez-Hernandez I, Garcia JL, Santos-Briz A, Hernandez-Lain A, Gonzalez-Valero JM, Gomez-Moreta JA, Toldos-Gonzalez O, Cruz JJ, Martin-Vallejo J, Gonzalez-Sarmiento R (2013) Integrated analysis of mismatch repair system in malignant astrocytomas. PLoS One 8:e76401CrossRefPubMedCentralPubMed

47.

Rohde C, Zhang Y, Reinhardt R, Jeltsch A (2010) BISMA–fast and accurate bisulfite sequencing data analysis of individual clones from unique and repetitive sequences. BMC Bioinform 11:230CrossRef

48.

Ruda R, Magliola U, Bertero L, Trevisan E, Bosa C, Mantovani C, Ricardi U, Castiglione A, Monagheddu C, Soffietti R (2013) Seizure control following radiotherapy in patients with diffuse gliomas: a retrospective study. Neuro Oncol 15:1739–1749CrossRefPubMedCentralPubMed

49.

Scheinin I, Sie D, Bengtsson H, van de Wiel MA, Olshen AB, van Thuijl HF, van Essen HF, Eijk PP, Rustenburg F, Meijer GA, Reijneveld JC, Wesseling P, Pinkel D, Albertson DG, Ylstra B (2014) DNA copy number analysis of fresh and formalin-fixed specimens by shallow whole-genome sequencing with identification and exclusion of problematic regions in the genome assembly. Genome Res 24:2022–2032CrossRefPubMedCentralPubMed

50.

Shaw EG, Wang M, Coons SW, Brachman DG, Buckner JC, Stelzer KJ, Barger GR, Brown PD, Gilbert MR, Mehta MP (2012) Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: initial results of RTOG 9802. J Clin Oncol 30:3065–3070CrossRefPubMedCentralPubMed

51.

Shin YK, Heo SC, Shin JH, Hong SH, Ku JL, Yoo BC, Kim IJ, Park JG (2004) Germline mutations in MLH1, MSH2 and MSH6 in Korean hereditary non-polyposis colorectal cancer families. Hum Mutat 24:351CrossRefPubMed

52.

Silber JR, Blank A, Bobola MS, Ghatan S, Kolstoe DD, Berger MS (1999) O6-methylguanine-DNA methyltransferase-deficient phenotype in human gliomas: frequency and time to tumor progression after alkylating agent-based chemotherapy. Clin Cancer Res 5:807–814PubMed

53.

Taal W, Dubbink HJ, Zonnenberg CB, Zonnenberg BA, Postma TJ, Gijtenbeek JM, Boogerd W, Groenendijk FH, Kros JM, Kouwenhoven MC, van Marion R, van Heuvel I, van der Holt B, Bromberg JE, Sillevis Smitt PA, Dinjens WN, van den Bent MJ (2011) First-line temozolomide chemotherapy in progressive low-grade astrocytomas after radiotherapy: molecular characteristics in relation to response. Neuro Oncol 13:235–241CrossRefPubMedCentralPubMed

54.

van de Wiel MA, Kim KI, Vosse SJ, van Wieringen WN, Wilting SM, Ylstra B (2007) CGHcall: calling aberrations for array CGH tumor profiles. Bioinformatics 23:892–894CrossRefPubMed

55.

van Thuijl HF, Scheinin I, Sie D, Alentorn A, van Essen HF, Cordes M, Fleischeuer R, Gijtenbeek AM, Beute G, van den Brink WA, Meijer GA, Havenith M, Idbaih A, Hoang-Xuan K, Mokhtari K, Verhaak R, van der Valk P, van de Wiel MA, Heimans JJ, Aronica E, Reijneveld JC, Wesseling P, Ylstra B (2014) Spatial and temporal evolution of distal 10q deletion, a prognostically unfavorable event in diffuse low-grade gliomas. Genome Biol 15:471CrossRefPubMedCentralPubMed

56.

Venkatraman ES, Olshen AB (2007) A faster circular binary segmentation algorithm for the analysis of array CGH data. Bioinformatics 23:657–663CrossRefPubMed

57.

Weber RG, Sabel M, Reifenberger J, Sommer C, Oberstrass J, Reifenberger G, Kiessling M, Cremer T (1996) Characterization of genomic alterations associated with glioma progression by comparative genomic hybridization. Oncogene 13:983–994PubMed

58.

Wick W, Meisner C, Hentschel B, Platten M, Schilling A, Wiestler B, Sabel MC, Koeppen S, Ketter R, Weiler M, Tabatabai G, von DA, Gramatzki D, Westphal M, Schackert G, Loeffler M, Simon M, Reifenberger G, Weller M (2013) Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. Neurology 81:1515–1522CrossRefPubMed

59.

www.clinicaltrials.gov (2013) NCT00003375, observation or radiation therapy with or without combination chemotherapy in treating patients with low-grade glioma

60.

www.clinicaltrialsregister.eu (2013) EORTC 22022-26033, evaluating primary chemotherapy with temozolomide continuative low dose in patients with low grade gliomas grade II WHO

61.

Ye K, Schulz MH, Long Q, Apweiler R, Ning Z (2009) Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads. Bioinformatics 25:2865–2871CrossRefPubMedCentralPubMed

62.

Yip S, Miao J, Cahill DP, Iafrate AJ, Aldape K, Nutt CL, Louis DN (2009) MSH6 mutations arise in glioblastomas during temozolomide therapy and mediate temozolomide resistance. Clin Cancer Res 15:4622–4629CrossRefPubMedCentralPubMed

Title: Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment
Authors: 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 Wesseling
Jaap C. Reijneveld
Susan M. Chang
Bauke Ylstra
Joseph F. Costello
Publication date: 01-04-2015
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 4/2015
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-015-1403-6

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

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

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2015

High rate of concurrent BRAF-KIAA1549 gene fusion and 1p deletion in disseminated oligodendroglioma-like leptomeningeal neoplasms (DOLN)

Isoglutaminyl cyclase contributes to CCL2-driven neuroinflammation in Alzheimer’s disease

Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer’s and Parkinson’s disease

Physiological and pathophysiological functions of cell cycle proteins in post-mitotic neurons: implications for Alzheimer’s disease

One is the deadliest number: the detrimental effects of social isolation on cerebrovascular diseases and cognition

IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II–III diffuse gliomas