Skip to main content
SpringerLink
Log in

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

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

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

  2. 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 124:547–560

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. 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

  4. 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 104:20007–20012

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. 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 12:545–551

    CAS  PubMed  Google Scholar 

  6. 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 14:1715–1721

    Article  CAS  PubMed  Google Scholar 

  7. 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 12:283–288

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. 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 13:2038–2045

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. 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 87:392–397

    CAS  PubMed  Google Scholar 

  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 29:852–860

    Article  CAS  PubMed  Google Scholar 

  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 31:213–219

    Article  CAS  PubMed  Google Scholar 

  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 14:6515–6521

    PubMed Central  CAS  PubMed  Google Scholar 

  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 269:17228–17237

    CAS  PubMed  Google Scholar 

  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 8:810–818

    Article  PubMed  Google Scholar 

  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 101:124–131

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 59:793–797

    CAS  PubMed  Google Scholar 

  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 11:348–356

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 129:659–670

    Article  CAS  PubMed  Google Scholar 

  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 183:1184–1190

    Article  CAS  PubMed  Google Scholar 

  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 4:285–290

    Article  CAS  PubMed  Google Scholar 

  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 121:2458–2464

    Article  CAS  PubMed  Google Scholar 

  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 101:405–417

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 102:255–260

    Article  CAS  PubMed  Google Scholar 

  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 22:4614–4619

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 352:997–1003

    Article  CAS  PubMed  Google Scholar 

  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 66:3987–3991

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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 343:189–193

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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  Google Scholar 

  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 13:176–184

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 114:97–109

    Article  PubMed Central  PubMed  Google Scholar 

  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 121:651–661

    Article  CAS  PubMed  Google Scholar 

  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 20:1297–1303

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 22:1715–1719

    Article  CAS  PubMed  Google Scholar 

  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 14:1722–1726

    Article  CAS  PubMed  Google Scholar 

  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 87:71–78

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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 3:241–253

    CAS  PubMed  Google Scholar 

  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 20:2076–2084

    Article  PubMed  Google Scholar 

  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 21:646–651

    Article  CAS  PubMed  Google Scholar 

  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 129:537–549

    CAS  PubMed  Google Scholar 

  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:e58206

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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:e76401

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 11:230

    Article  Google Scholar 

  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 15:1739–1749

    Article  PubMed Central  PubMed  Google Scholar 

  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 24:2022–2032

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 30:3065–3070

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 24:351

    Article  PubMed  Google Scholar 

  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 5:807–814

    CAS  PubMed  Google Scholar 

  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 13:235–241

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 23:892–894

    Article  PubMed  Google Scholar 

  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 15:471

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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 13:983–994

    CAS  PubMed  Google Scholar 

  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 81:1515–1522

    Article  CAS  PubMed  Google Scholar 

  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 25:2865–2871

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 15:4622–4629

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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 ‘STOPHersentumoren’, 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, Linköping Charlotte Bratthäll, Kalmar and Michael Strandéus, Jönköping.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA

    Hinke F. van Thuijl, Tali Mazor, Brett E. Johnson, Shaun D. Fouse, Chibo Hong, Mitchell S. Berger, Annette M. Molinaro, Susan M. Chang & Joseph F. Costello

  2. Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands

    Hinke F. van Thuijl, Jan J. Heimans & Jaap C. Reijneveld

  3. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands

    Hinke F. van Thuijl, Pieter Wesseling & Bauke Ylstra

  4. Department of Neurosurgery, The University of Tokyo, Tokyo, Japan

    Koki Aihara, Nobuhito Saito & Akitake Mukasa

  5. Genome Science Laboratory, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan

    Koki Aihara & Hiroyuki Aburatani

  6. Department of Advanced Home Care, Linköping University, Linköping, Sweden

    Annika Malmström

  7. Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden

    Annika Malmström, Martin Hallbeck, Marie Stenmark-Askmalm & Peter Söderkvist

  8. Department of Neurosurgery, Brain Tumor Center, Erasmus Medical Center, Rotterdam, The Netherlands

    Jenneke J. Kloezeman & Martine L. M. Lamfers

  9. Department of Clinical Pathology and Clinical Genetics, University Hospital, Linköping, Sweden

    Marie Stenmark-Askmalm

  10. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Barry S. Taylor

  11. Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA

    Annette M. Molinaro

  12. Department of Pathology, Radboud University Nijmegen, Nijmegen, The Netherlands

    Pieter Wesseling

  13. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Barry S. Taylor

  14. Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Jaap C. Reijneveld

Authors
  1. Hinke F. van Thuijl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tali Mazor
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brett E. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shaun D. Fouse
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Koki Aihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chibo Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Annika Malmström
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Martin Hallbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jan J. Heimans
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jenneke J. Kloezeman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Marie Stenmark-Askmalm
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Martine L. M. Lamfers
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Nobuhito Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hiroyuki Aburatani
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Akitake Mukasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Mitchell S. Berger
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Peter Söderkvist
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Barry S. Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Annette M. Molinaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Pieter Wesseling
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Jaap C. Reijneveld
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Susan M. Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Bauke Ylstra
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Joseph F. Costello
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joseph F. Costello.

Electronic supplementary material

Below is the link to the electronic supplementary material.

401_2015_1403_MOESM1_ESM.pdf

Supplementary material 1 (PDF 911 kb) Fig. S1. Methylation status of CpG sites in 10 individual clones of the PCR product from bisulfite-treated DNA from the initial tumor and the recurrent tumor of patient 296. Each row represents a single clone with each CpG site marked as either methylated (red) or unmethylated (blue). The total methylation percentage of all CpGs in all clones is presented to the left of each panel

401_2015_1403_MOESM2_ESM.pdf

Supplementary material 2 (PDF 4753 kb) Fig. S2. Hypermutated recurrent tumors show single copy loss and accompanying loss-of-heterozygosity (LOH) at loci encompassing MGMT and members of the DNA mismatch repair pathway. For each patient with a hypermutated recurrent tumor, the genomic location of genes of interest is indicated in purple on chromosomal plots. Somatic copy number alterations identified in each tumor are shown and the minor allele frequency of heterozygous germline SNPs is graphed. The presence of germline SNPs with low variant allele frequencies indicates genomic regions of allelic imbalance and LOH

Supplementary material 3 (DOCX 26 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

van Thuijl, H.F., Mazor, T., Johnson, B.E. et al. Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment. Acta Neuropathol 129, 597–607 (2015). https://doi.org/10.1007/s00401-015-1403-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-015-1403-6

Keywords

Search

Navigation