Skip to main content
SpringerLink
Log in

MGMT gene promoter methylation in pediatric glioblastomas

  • Original Paper
  • Published:
Child's Nervous System Aims and scope Submit manuscript

Abstract

Purpose

Relatively few studies have been performed on molecular properties of pediatric glioblastoma multiforme (GBM). Methylation of DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) promoter region has been associated with favorable prognosis and prolonged survival in adult GBM patients treated with temozolomide (TMZ). We explored the frequency of MGMT gene promoter methylation in pediatric glioblastomas and compared it with the known molecular alterations in p53.

Methods

Twenty pediatric GBM cases were selected. MGMT promoter methylation was assessed by methylation specific PCR. p53 expression was determined by immunohistochemistry.

Results

MGMT gene promoter methylation was observed in 50% of pediatric glioblastomas. p53 protein expression was detected in 60% of cases. Seventy percent of cases with methylated MGMT promoter were p53 immunopositive.

Conclusions

The frequency of MGMT gene promoter methylation in pediatric GBMs was similar to adult GBM patients. The pediatric GBMs should also be investigated for MGMT promoter methylation to identify a subset of patients likely to benefit from TMZ therapy. p53 protein overexpression was more common in pediatric primary GBMs. To the best of our knowledge this is only the second study on MGMT gene promoter methylation status in pediatric GBMs.

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

Similar content being viewed by others

References

  1. Nicholson HS, Kretschmar CS, Krailo M et al (2007) Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors. Cancer 110:1542–1549

    Article  CAS  PubMed  Google Scholar 

  2. Armstrong DD, Giangaspero F (2003) Pediatric brain tumors: introduction. Brain Pathol 13:373–375

    Article  PubMed  Google Scholar 

  3. Bleyer WA (1999) Epidemiological impact of children with brain tumors. Childs Nerv Syst 15:758–763

    Article  CAS  PubMed  Google Scholar 

  4. Cheng Y, Ng HK, Zhang SF et al (1999) Genetic alterations in pediatric high-grade astrocytomas. Hum Pathol 30:1284–1290

    Article  CAS  PubMed  Google Scholar 

  5. Ganigi PM, Santosh V, Anandh B, Chandramouli BA (2005) Expression of p53, EGFR, pRb and bcl-2 protein in pediatric glioblastoma multiforme: a study of 54 patients. Pediatr Neurosurg 41:292–299

    Article  CAS  PubMed  Google Scholar 

  6. Suri V, Das P, Jain A et al (2009) Pediatric glioblastomas: a histopathological and molecular genetic study. Neuro Oncol 11:274–280

    Article  PubMed  Google Scholar 

  7. Donson AM, Addo-Yobo SO, Handler MH, Gore L, Foreman NK (2007) MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glioblastomas. Pediatr Blood Cancer 48:403–407

    Article  PubMed  Google Scholar 

  8. Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for newly diagnosed glioblastoma. N Engl J Med 352:987–996

    Article  CAS  PubMed  Google Scholar 

  9. Yung WK, Albright RE, Olsen J (2000) A phase II study of temozolomide versus procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 85:588–593

    Article  Google Scholar 

  10. Brada M, Hoang-Xuan K, Rampling R et al (2001) Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse. Ann Oncol 12:259–266

    Article  CAS  PubMed  Google Scholar 

  11. Gilbert MR, Friedman HS, Kuttesch JF et al (2002) A phase II study of temozolomide in patients with newly diagnosed supratentorial malignant glioma before radiation therapy. Neuro Oncol 4:261–267

    CAS  PubMed  Google Scholar 

  12. Erickson LC, Laurent G, Sharkey NA, Kohn KW (1980) DNA cross-linking and monoadduct repair in nitrosourea-treated human tumour cells. Nature 288:727–729

    Article  CAS  PubMed  Google Scholar 

  13. Ludlum DB (1990) DNA alkylation by the haloethylnitrosoureas: nature of modifications produced and their enzymatic repair or removal. Mutat Res 233:117–126

    CAS  PubMed  Google Scholar 

  14. Pegg AE, Dolan ME, Moschel RC (1995) Structure, function, and inhibition of O6-alkylguanine-DNA alkyltransferase. Prog Nucleic Acid Res Mol Biol 51:167–223

    Article  CAS  PubMed  Google Scholar 

  15. Qian XC, Brent TP (1997) Methylation hot spots in the 5′ flanking region denote silencing of the O6-methylguanine-DNA methyltransferase gene. Cancer Res 57:3672–3677

    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. Brell M, Tortosa A, Verger E et al (2005) Prognostic significance of O6-methylguanine-DNA methyltransferase determined by promoter hypermethylation and immunohistochemical expression in anaplastic gliomas. Clin Cancer Res 11:5167–5174

    Article  CAS  PubMed  Google Scholar 

  18. Hegi ME, Diserens AC, Gorlia T et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 52:997–1003

    Article  Google Scholar 

  19. Esteller M, Gracia-Foncillas J, Andion E et al (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343:1350–1354

    Article  CAS  PubMed  Google Scholar 

  20. Eoli M, Menghi F, Bruzzone MG et al (2007) Methylation of O6-methylguanine DNA methyltransferase and loss of heterozygosity on 19q and/or 17p are overlapping features of secondary glioblastomas with prolonged survival. Clin Cancer Res 13:2606–2613

    Article  CAS  PubMed  Google Scholar 

  21. Friedman HS, McLendon RE, Kerby T et al (1998) DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. J Clin Oncol 16:3851–3857

    CAS  PubMed  Google Scholar 

  22. Hegi ME, Diserens A-C, Godard S et al (2004) Clinical trial substantiates the predictive value of O6 methyl guanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 10:1871–1874

    Article  CAS  PubMed  Google Scholar 

  23. Kleihues P, Burger PC, Aldape KD, Brat DJ, Biernat W, Bigner DD (2007) Glioblastoma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds) WHO classification of tumors of central nervous system, 4th edn. IARC, Lyon, pp 33–49

    Google Scholar 

  24. Paz MF, Yaya-Tur R, Rojas-Marcos I et al (2004) CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas. Clin Cancer Res 10:4933–4938

    Article  CAS  PubMed  Google Scholar 

  25. Broniscer A, Iacono L, Chintagumpala M et al (2005) Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children: results of a multiinstitutional study (SJHG-98). Cancer 103:133–139

    Article  CAS  PubMed  Google Scholar 

  26. Broniscer A, Chintagumpala M, Fouladi M et al (2006) Temozolomide after radiotherapy for newly diagnosed high-grade glioma and unfavorable low-grade glioma in children. J Neurooncol 76:313–319

    Article  PubMed  Google Scholar 

  27. Verschuur AC, Grill J, Lelouch-Tubiana A, Couanet D, Kalifa C, Vassal G (2004) Temozolomide in paediatric high-grade glioma: a key for combination therapy? Br J Cancer 91:425–429

    Article  CAS  PubMed  Google Scholar 

  28. Barone G, Maurizi P, Tamburrini G, Riccardi R (2006) Role of temozolomide in pediatric brain tumors. Childs Nerv Syst 22:652–661

    Article  PubMed  Google Scholar 

  29. Jakacki RI, Yates A, Blaney SM et al (2008) A phase I trial of temozolomide and lomustine in newly diagnosed high-grade gliomas of childhood. Neuro Oncol 10:569–576

    Article  CAS  PubMed  Google Scholar 

  30. Lashford LS, Thiesse P, Jouvet A et al (2002) Temozolomide in malignant gliomas of childhood: a United Kingdom Children's Cancer Study Group and French Society for Pediatric Oncology Intergroup study. J Clin Oncol 20:4684–4691

    Article  CAS  PubMed  Google Scholar 

  31. Estlin EJ, Lashford L, Ablett S et al (1998) Phase I study of temozolomide in paediatric patients with advanced cancer. United Kingdom Children's Cancer Study Group. Br J Cancer 78:652–661

    CAS  PubMed  Google Scholar 

  32. Loh KC, Willert J, Meltzer H et al (2005) Temozolomide and radiation for aggressive pediatric central nervous system malignancies. J Pediatr Hematol Oncol 27:254–258

    Article  PubMed  Google Scholar 

  33. Belanich M, Pastor M, Randall T et al (1996) Retrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain tumor patients treated with carmustine. Cancer Res 56:783–788

    CAS  PubMed  Google Scholar 

  34. Hotta T, Saito Y, Fujita H et al (1994) O6-alkylguanine-DNA alkyltransferase activity of human malignant glioma and its clinical implications. J Neurooncol 21:135–140

    Article  CAS  PubMed  Google Scholar 

  35. Wiewrodt D, Nagel G, Dreimuller N, Hundsberger T, Perneczky A, Kaina B (2008) MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome. Int J Cancer 122:1391–1399

    Article  CAS  PubMed  Google Scholar 

  36. Pollack IF, Hamilton RL, Sobol RW et al (2006) O6-methylguanine-DNA methyltransferase expression strongly correlates with outcome in childhood malignant gliomas: results from the CCG-945 Cohort. J Clin Oncol 24:3431–3437

    Article  CAS  PubMed  Google Scholar 

  37. Stupp R, Hegi ME (2007) Methylguanine methyltransferase testing in glioblastoma: when and how? J Clin Oncol 25:1459–1460

    Article  PubMed  Google Scholar 

  38. Everhard S, Kaloshi G, Crinière E et al (2006) MGMT methylation: a marker of response to temozolomide in low-grade gliomas. Ann Neurol 60:740–743

    Article  CAS  PubMed  Google Scholar 

  39. Sure U, Ruedi D, Tachibana O et al (1997) Determination of p53 mutation, EGFR overexpression and loss of p16 expression in pediatric glioblastomas. J Neuropathol Exp Neurol 56:782–789

    CAS  PubMed  Google Scholar 

  40. Bhattacharjee MB, Bruner JM (1997) p53 protein in pediatric malignant astrocytoma. A study of 21 patients. J Neurooncol 32:225–233

    Article  CAS  PubMed  Google Scholar 

  41. Pollack IF, Finkelstein SD, Woods J et al (2002) Expression of p53 and prognosis in children with malignant gliomas. N Engl J Med 346:420–427

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

We are thankful to Dr. Monika E. Hegi from the Laboratory of Tumor Biology and Genetics, Department of Neurosurgery, University Hospital, Lausanne, Switzerland, who trained PJ in her laboratory on this technique.

Author information

Authors and Affiliations

  1. Department of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India

    Arti Srivastava, Ayushi Jain, Prerana Jha, Vaishali Suri, Mehar Chand Sharma & Chitra Sarkar

  2. Department of Radiotherapy, All India Institute of Medical Sciences (AIIMS), New Delhi, India

    Supriya Mallick & Tarun Puri

  3. Department of Neurosurgery, All India Institute of Medical Sciences (AIIMS), New Delhi, India

    Deepak Kumar Gupta & Aditya Gupta

Authors
  1. Arti Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ayushi Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Prerana Jha
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vaishali Suri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mehar Chand Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Supriya Mallick
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tarun Puri
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Deepak Kumar Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Aditya Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chitra Sarkar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chitra Sarkar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Srivastava, A., Jain, A., Jha, P. et al. MGMT gene promoter methylation in pediatric glioblastomas. Childs Nerv Syst 26, 1613–1618 (2010). https://doi.org/10.1007/s00381-010-1214-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00381-010-1214-y

Keywords

Search

Navigation