open access

Vol 6, No 2 (2010)
Review paper
Published online: 2010-06-25
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The molecular basis for treatment of gliomas

Piotr Potemski
Onkol. Prak. Klin 2010;6(2):73-78.

open access

Vol 6, No 2 (2010)
REVIEW ARTICLES
Published online: 2010-06-25

Abstract

Gliomas are the most common of all primary tumours of the central nervous system and account for 70% of them. Glioblastoma (GBM), the most frequent and the most lethal of all gliomas may develop de novo (primary GBM) or by progression from grade II or anaplastic astrocytoma. Those two types of GBM are distinct disease entities with clear differences in clinical outcome and molecular genetics. For example, almost all secondary GBMs harbor mutations in IDH1 gene, whereas in primary GBMs these mutations are very rarely seen. Primary GBMs form a very heterogenous group of tumours and are characterized by many genetics alterations. One of such alteration is the expression of mutated EGFR gene. The most common mutation is EGFR-vIII that constitutively activates the receptor. Advances in molecular biology of gliomas may also help to select patients who better respond to conventional chemotherapy. Silencing of MGMT gene by methylation of its promoter observed in 45% of GBMs is associated with better outcome of patients treated with temozolomide. 1p/19q codeletion is a favourable prognostic factor in oligodendrogliomas and also predicts response to PCV chemotherapy. However, so far in gliomas critical molecular targets for novel drugs have not been recognized.
Onkol. Prak. Klin. 2010; 6, 2: 73-78

Abstract

Gliomas are the most common of all primary tumours of the central nervous system and account for 70% of them. Glioblastoma (GBM), the most frequent and the most lethal of all gliomas may develop de novo (primary GBM) or by progression from grade II or anaplastic astrocytoma. Those two types of GBM are distinct disease entities with clear differences in clinical outcome and molecular genetics. For example, almost all secondary GBMs harbor mutations in IDH1 gene, whereas in primary GBMs these mutations are very rarely seen. Primary GBMs form a very heterogenous group of tumours and are characterized by many genetics alterations. One of such alteration is the expression of mutated EGFR gene. The most common mutation is EGFR-vIII that constitutively activates the receptor. Advances in molecular biology of gliomas may also help to select patients who better respond to conventional chemotherapy. Silencing of MGMT gene by methylation of its promoter observed in 45% of GBMs is associated with better outcome of patients treated with temozolomide. 1p/19q codeletion is a favourable prognostic factor in oligodendrogliomas and also predicts response to PCV chemotherapy. However, so far in gliomas critical molecular targets for novel drugs have not been recognized.
Onkol. Prak. Klin. 2010; 6, 2: 73-78
Get Citation

Keywords

gliomas; methylation of MGMT; 1p/19q codeletion; IDH1 mutations; EGFR-vIII

About this article
Title

The molecular basis for treatment of gliomas

Journal

Oncology in Clinical Practice

Issue

Vol 6, No 2 (2010)

Article type

Review paper

Pages

73-78

Published online

2010-06-25

Bibliographic record

Onkol. Prak. Klin 2010;6(2):73-78.

Keywords

gliomas
methylation of MGMT
1p/19q codeletion
IDH1 mutations
EGFR-vIII

Authors

Piotr Potemski

References (23)
  1. Kleihues P, Louis DN, Wiestler OD, Burger PC, Scheithauer BW. WHO grading of tumours of the central nervous system. In: Ohgaki H, Louis DN, Wiestler OD, Cavenee WK. ed. WHO classification of tumours of the central nervous system. WHO Press, Geneva 2007: 10–11.
  2. Ohgaki H, Dessen P, Jourde B, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res. 2004; 64(19): 6892–6899.
  3. Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol. 2005; 64(6): 479–489.
  4. Trivedi RN, Almeida KH, Fornsaglio JL, et al. The role of base excision repair in the sensitivity and resistance to temozolomide-mediated cell death. Cancer Res. 2005; 65(14): 6394–6400.
  5. Friedman HS, McLendon RE, Kerby T, et al. DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. J Clin Oncol. 1998; 16(12): 3851–3857.
  6. Hegi M, Diserens AC, Gorlia T, et al. MGMTGene Silencing and Benefit from Temozolomide in Glioblastoma. New England Journal of Medicine. 2005; 352(10): 997–1003.
  7. Zawlik I, Vaccarella S, Kita D, et al. Promoter methylation and polymorphisms of the MGMT gene in glioblastomas: a population-based study. Neuroepidemiology. 2009; 32(1): 21–29.
  8. van den Bent MJ, Dubbink HJ, Sanson M, et al. MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Group Study 26951. J Clin Oncol. 2009; 27(35): 5881–5886.
  9. Jenkins RB, Blair H, Ballman KV, et al. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res. 2006; 66(20): 9852–9861.
  10. Cairncross G, Berkey B, Shaw E, et al. Intergroup Radiation Therapy Oncology Group Trial 9402. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol. 2006; 24(18): 2707–2714.
  11. van den Bent MJ, Carpentier AF, Brandes AA, et al. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol. 2006; 24(18): 2715–2722.
  12. Reifenberger G, Kros JM, Louis DN, Collins VP. Oligodendroglioma. In: Ohgaki H, Wiestler OD, Louis DN. ed. WHO classification of tumours of the central nervous system. WHO Press, Geneva 2007: 54–59.
  13. Yan H, Bigner DD, Velculescu V, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009; 360(8): 765–773.
  14. Ohgaki H, Kleihues P. Genetic alterations and signaling pathways in the evolution of gliomas. Cancer Sci. 2009; 100(12): 2235–2241.
  15. Weidemann A, Johnson RS. Biology of HIF-1alpha. Cell Death Differ. 2008; 15(4): 621–627.
  16. Zhao S, Lin Y, Xu W, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 2009; 324(5924): 261–265.
  17. Ohgaki H, Kleihues P. Genetic Pathways to Primary and Secondary Glioblastoma. The American Journal of Pathology. 2007; 170(5): 1445–1453.
  18. Nicholas MK, Lukas RV, Jafri NF, et al. Epidermal growth factor receptor - mediated signal transduction in the development and therapy of gliomas. Clin Cancer Res. 2006; 12(24): 7261–7270.
  19. Shinojima N, Tada K, Shiraishi S, et al. Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res. 2003; 63(20): 6962–6970.
  20. Tohma Y, Gratas C, Biernat W, et al. PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. J Neuropathol Exp Neurol. 1998; 57(7): 684–689.
  21. Biernat W, Tohma Y, Yonekawa Y, et al. Alterations of cell cycle regulatory genes in primary (de novo) and secondary glioblastomas. Acta Neuropathol. 1997; 94(4): 303–309.
  22. Gravendeel LAM, Kouwenhoven MCM, Gevaert O, et al. Intrinsic gene expression profiles of gliomas are a better predictor of survival than histology. Cancer Res. 2009; 69(23): 9065–9072.
  23. Biernat W, Huang H, Yokoo H, et al. Predominant expression of mutant EGFR (EGFRvIII) is rare in primary glioblastomas. Brain Pathol. 2004; 14(2): 131–136.

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