Journal of Neuro-Oncology

, Volume 83, Issue 2, pp 173–179 | Cite as

MGMT prognostic impact on glioblastoma is dependent on therapeutic modalities

  • Emmanuelle Crinière
  • Gentian Kaloshi
  • Florence Laigle-Donadey
  • Julie Lejeune
  • Nathalie Auger
  • Alexandra Benouaich-Amiel
  • Sibille Everhard
  • Karima Mokhtari
  • Marc Polivka
  • Jean-Yves Delattre
  • Khê Hoang-Xuan
  • Joëlle Thillet
  • Marc Sanson
Lab Investigation

Abstract

MGMT promoter methylation, which has been correlated with the response to alkylating agents, was investigated in a retrospective series of 219 glioblastomas (GBMs) treated with various modalities. MGMT methylation had no impact on survival for the whole group, but showed a significant advantage (17.1 months vs. 13.1) for patients treated with RT+ adjuvant chemotherapy (relative risk of death (RR) = 0.53; P = 0.041), particularly when patients received CT during the course of RT (MS = 19.9 months vs. 12.5 months; RR = 0.227, P = 0.001). This suggests that the prognostic impact of MGMT methylation is dependent on therapeutic modalities and schedules. MGMT methylation was not correlated with the main molecular alterations, such as 10q loss and p53 expression.

Keywords

Glioblastoma Markers Prognosis MGMT Chemotherapy 

Notes

Acknowledgments

This research was supported by grants from the Institut National du Cancer (PL 046), the Délégation à la Recherche Clinique (AP-HP ; grant n° MUL 03012) and the Ligue Nationale contre le Cancer, comité d’Ile et Villaine. The authors gratefully thank Dr Philippe Broët for statistical expertise, Dr Michèle Kujas for providing histological samples, and Anne-Marie Lekieffre, Muriel Brandel, Marc Ouzounian and Tristan Salmon-Legagneur from the ARTC for their precious assistance.

References

  1. 1.
    Stupp R, Mason W, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research, Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group. (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996PubMedCrossRefGoogle Scholar
  2. 2.
    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 352:997–1003PubMedCrossRefGoogle Scholar
  3. 3.
    Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343:1350–1354PubMedCrossRefGoogle Scholar
  4. 4.
    Blan JL, Wager M, Guilhot J, Kusy S, Bataille B, Chantereau T, Lapierre F, Larsen CJ, Karayan-Tapon L (2004) Correlation of clinical features and methylation status of MGMT gene promoter in glioblastomas. J Neurooncol 68:275–283CrossRefGoogle Scholar
  5. 5.
    Paz MF, Yaya-Tur R, Rojas-Marcos I, Reynes G, Pollan M, Aguirre-Cruz L, Garcia-Lopez JL, Piquer J, Safont MJ, Balana C, Sanchez-Cespedes M, Garcia-Villanueva M, Arribas L, Esteller M (2004) CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas. Clin Cancer Res 10:4933–4938PubMedCrossRefGoogle Scholar
  6. 6.
    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 5:807–814PubMedGoogle Scholar
  7. 7.
    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 13:176–184PubMedCrossRefGoogle Scholar
  8. 8.
    Watanabe T, Katayama Y, Komine C, Yoshino A, Ogino A, Ohta T, Fukushima T (2005) O6-methylguanine-DNA methyltransferase methylation and TP53 mutation in malignant astrocytomas and their relationships with clinical course. Int J Cancer 113:581–587PubMedCrossRefGoogle Scholar
  9. 9.
    Palmisano WA, Divine KK, Saccomanno G, Gilliland FD, Baylin SB, Herman JG, Belinsky SA (2000) Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer Res 60:5954–5958PubMedGoogle Scholar
  10. 10.
    He J, Mokhtari K, Sanson M, Marie Y, Kujas M, Huguet S, Leuraud P, Capelle L, Delattre JY, Poirier J, Hoang-Xuan K (2001) Glioblastomas with an oligodendroglial component: a pathological and molecular study. J Neuropathol Exp Neurol 60:863–871PubMedGoogle Scholar
  11. 11.
    Houillier C, Lejeune J, Benouaich-Amiel A, Laigle-Donadey F, Criniere E, Mokhtari K, Thillet J, Delattre JY, Hoang-Xuan K, Sanson M (2006) Prognostic impact of molecular markers in a series of 220 primary glioblastomas. Cancer 106(10):2218–2223Google Scholar
  12. 12.
    Berggren P, Kumar R, Sakano S, Hemminki L, Wada T, Steineck G, Adolfsson J, Larsson P, Norming U, Wijkstrom H, Hemminki K (2003) Detecting homozygous deletions in the CDKN2A(p16(INK4a))/ARF(p14(ARF)) gene in urinary bladder cancer using real-time quantitative PCR. Clin Cancer Res 9:235–242PubMedGoogle Scholar
  13. 13.
    Mokhtari K, Paris S, Aguirre-Cruz L, Privat N, Criniere E, Marie Y, Hauw JJ, Kujas M, Rowitch D, Hoang-Xuan K, Delattre JY, Sanson M (2005) Olig2 expression, GFAP, p53 and 1p loss analysis contribute to glioma subclassification. Neuropathol Appl Neurobiol 31:62–69PubMedCrossRefGoogle Scholar
  14. 14.
    Kleinberg L, Grossman SA, Piantadosi S, Zeltzman M, Wharam M (1999) The effects of sequential versus concurrent chemotherapy and radiotherapy on survival and toxicity in patients with newly diagnosed high-grade astrocytoma. Int J Radiat Oncol Biol Phys 44:535–543PubMedCrossRefGoogle Scholar
  15. 15.
    Vigliani MC, Sichez N, Poisson M, Delattre JY (1996) A prospective study of cognitive functions following conventional radiotherapy for supratentorial gliomas in young adults: 4-year results. Int J Radiat Oncol Biol Phys 35:527–533PubMedCrossRefGoogle Scholar
  16. 16.
    Tolcher AW, Gerson SL, Denis L, Geyer C, Hammond LA, Patnaik A, Goetz AD, Schwartz G, Edwards T, Reyderman L, Statkevich P, Cutler DL, Rowinsky EK (2003) Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer 88:1004–1011PubMedCrossRefGoogle Scholar
  17. 17.
    Grombacher T, Mitra S, Kaina B (1996) Induction of the alkyltransferase (MGMT) gene by DNA damaging agents and the glucocorticoid dexamethasone and comparison with the response of base excision repair genes. Carcinogenesis 17:2329–2336PubMedCrossRefGoogle Scholar
  18. 18.
    Grombacher T, Eichhorn U, Kaina B (1998) p53 is involved in regulation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) by DNA damaging agents. Oncogene 17:845–851PubMedCrossRefGoogle Scholar
  19. 19.
    Hermisson M, Klumpp A, Wick W, Wischhusen J, Nagel G, Roos W, Kaina B, Weller M (2006) O6-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells. J Neurochem 96:766–776PubMedCrossRefGoogle Scholar
  20. 20.
    Koga Y, Kitajima Y, Miyoshi A, Sato K, Kitahara K, Soejima H, Miyazaki K (2005) Tumor progression through epigenetic gene silencing of O(6)-methylguanine-DNA methyltransferase in human biliary tract cancers. Ann Surg Oncol 12:354–363PubMedCrossRefGoogle Scholar
  21. 21.
    Kitajima Y, Miyazaki K, Matsukura S, Tanaka M, Sekiguchi M (2003) Loss of expression of DNA repair enzymes MGMT, hMLH1, and hMSH2 during tumor progression in gastric cancer. Gastric Cancer 6:86–95PubMedGoogle Scholar
  22. 22.
    Osanai T, Takagi Y, Toriya Y, Nakagawa T, Aruga T, Iida S, Uetake H, Sugihara K (2005) Inverse correlation between the expression of O6-methylguanine-DNA methyl transferase (MGMT) and p53 in breast cancer. Jpn J Clin Oncol 35:121–125PubMedCrossRefGoogle Scholar
  23. 23.
    Rolhion C, Penault-Llorca F, Kemeny JL, Kwiatkowski F, Lemaire JJ, Chollet P, Finat-Duclos F, Verrelle P (1999) O(6)-methylguanine-DNA methyltransferase gene (MGMT) expression in human glioblastomas in relation to patient characteristics and p53 accumulation. Int J Cancer 84:416–420PubMedCrossRefGoogle Scholar
  24. 24.
    Curran WJSC, Horton J, et al. (1993) Recursive partitioning analysis of prognosis factors in the three Radiation Therapy Oncology group malignant gliomas trials. J Natl Cancer Inst 85:704–710PubMedCrossRefGoogle Scholar
  25. 25.
    Takagi Y, Takahashi M, Sanada M, Ito R, Yamaizumi M, Sekiguchi M (2003) Roles of MGMT and MLH1 proteins in alkylation-induced apoptosis and mutagenesis. DNA Repair (Amst) 2:1135–1146CrossRefGoogle Scholar
  26. 26.
    Sanada M, Takagi Y, Ito R, Sekiguchi M (2004) Killing and mutagenic actions of dacarbazine, a chemotherapeutic alkylating agent, on human and mouse cells: effects of Mgmt and Mlh1 mutations. DNA Repair (Amst) 3:413–420CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Emmanuelle Crinière
    • 1
  • Gentian Kaloshi
    • 2
  • Florence Laigle-Donadey
    • 2
  • Julie Lejeune
    • 2
  • Nathalie Auger
    • 1
  • Alexandra Benouaich-Amiel
    • 2
  • Sibille Everhard
    • 1
  • Karima Mokhtari
    • 1
    • 3
  • Marc Polivka
    • 4
  • Jean-Yves Delattre
    • 1
    • 2
  • Khê Hoang-Xuan
    • 1
    • 2
  • Joëlle Thillet
    • 1
  • Marc Sanson
    • 1
    • 2
    • 5
  1. 1.INSERM, U711, Biologie des Interactions Neurones & GlieUniversité Pierre et Marie Curie, Faculté de MédecineParisFrance
  2. 2.Service de Neurologie Mazarin, Groupe Hospitalier Pitié-SalpêtrièreAssistance-Publique Hôpitaux de ParisParis cedex 13France
  3. 3.Laboratoire de Neuropathologie R. EscourolleGroupe Hospitalier Pitié-SalpêtrièreParisFrance
  4. 4.Service d’anatomopathologieHôpital LariboisièreParisFrance
  5. 5.Service de Neurologie MazarinGroupe Hospitalier Pitié-SalpêtrièreParisFrance

Personalised recommendations