Skip to main content

Advertisement

SpringerLink
Log in

IDH1/2 gene status defines the prognosis and molecular profiles in patients with grade III gliomas

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

The discovery of isocitrate dehydrogenase 1 and 2 gene (IDH1/2) mutations has enabled grade III glioma to be divided into mutated and wild-type IDH1/2 groups, which are known to carry different prognosis and molecular features. However, detailed subgroup analysis of grade III glioma is limited. To address this, we investigated molecular and prognostic features of grade III glioma with and without IDH1/2 mutation.

Methods

We retrospectively analyzed 115 grade III glioma patients. Clinical parameters were obtained from medical records. The mutation of IDH1/2 and TP53 was analyzed by direct sequencing. O6-methylguanine methyltransferase gene (MGMT) gene promoter methylation status was determined by methylation-specific polymerase chain reaction. Detection of chromosome copy number changes of 1p, 7p (EGFR), 9p (CDKN2A), 10q (PTEN), and 19q was carried out by multiple ligation-dependent probe amplification. Patients were divided into two groups, mutated IDH1/2 and wild-type IDH1/2, for correlation with the factors analyzed.

Results

In our series, as previously reported, IDH1/2 mutation was an independent prognostic marker for improved progression-free and overall survival (OS) (P < 0.0001 and P < 0.0001, respectively) in patients with grade III gliomas. Subgroup analysis found that incomplete resection, 7p gain, and TP53 mutation were independent prognostic factors of poor outcome in grade III glioma patients with mutated IDH1/2 (P = 0.0092, P = 0.015 and P = 0.026, respectively), while there were none in patients with wild-type IDH1/2.

Conclusions

IDH1/2 gene status was significantly associated with prognosis in grade III gliomas. Subgroup analysis found that poor prognostic factors existed even in patients with IDH1/2 mutation.

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

Similar content being viewed by others

References

  1. Balss J, Meyer J, Mueller W et al (2008) Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116(6):597–602

    Article  PubMed  CAS  Google Scholar 

  2. Parsons DW, Jones S, Zhang X et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321(5897):1807–1812

    Article  PubMed  CAS  Google Scholar 

  3. Yan H, Parsons DW, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360(8):765–773

    Article  PubMed  CAS  Google Scholar 

  4. Watanabe T, Nobusawa S, Kleihues P et al (2009) IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 174(4):1149–1153

    Article  PubMed  CAS  Google Scholar 

  5. Ohgaki H, Kleihues P (2009) Genetic alterations and signaling pathways in the evolution of gliomas. Cancer Sci 100(12):2235–2241

    Article  PubMed  CAS  Google Scholar 

  6. Yan H, Bigner DD, Velculescu V et al (2009) Mutant metabolic enzymes are at the origin of gliomas. Cancer Res 69(24):9157–9159

    Article  PubMed  CAS  Google Scholar 

  7. van den Bent MJ, Dubbink HJ, Marie Y et al (2010) IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Clin Cancer Res 16(5):1597–1604

    Article  PubMed  Google Scholar 

  8. Ichimura K, Pearson DM, Kocialkowski S et al (2009) IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro Oncol 11(4):341–347

    Article  PubMed  CAS  Google Scholar 

  9. Levin VA, Hess KR, Choucair A et al (2003) Phase III randomized study of postradiotherapy chemotherapy with combination alpha-difluoromethylornithine-PCV versus PCV for anaplastic gliomas. Clin Cancer Res 9(3):981–990

    PubMed  CAS  Google Scholar 

  10. van den Bent MJ, Carpentier AF, Brandes AA et al (2006) 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 24(18):2715–2722

    Article  PubMed  Google Scholar 

  11. Sanson M, Marie Y, Paris S et al (2009) Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27(25):4150–4154

    Article  PubMed  CAS  Google Scholar 

  12. Houillier C, Mokhtari K, Carpentier C et al (2010) Chromosome 9p and 10q losses predict unfavorable outcome in low-grade gliomas. Neuro Oncol 12(1):2–6

    Article  PubMed  CAS  Google Scholar 

  13. Sonoda Y, Kumabe T, Nakamura T et al (2009) Analysis of IDH1 and IDH2 mutations in Japanese glioma patients. Cancer Sci 100(10):1996–1998

    Article  PubMed  CAS  Google Scholar 

  14. Mashiyama S, Murakami Y, Yoshimoto T et al (1991) Detection of p53 gene mutations in human brain tumors by single-strand conformation polymorphism analysis of polymerase chain reaction products. Oncogene 6(8):1313–1318

    PubMed  CAS  Google Scholar 

  15. Sonoda Y, Kumabe T, Watanabe M et al (2009) Long-term survivors of glioblastoma: clinical features and molecular analysis. Acta Neurochir (Wien) 151(11):1349–1358

    Article  Google Scholar 

  16. Sonoda Y, Yokosawa M, Saito R, et al (2010) O(6)-Methylguanine DNA methyltransferase determined by promoter hypermethylation and immunohistochemical expression is correlated with progression-free survival in patients with glioblastoma. Int J Clin Oncol 15:352–358

    Google Scholar 

  17. Wick W, Hartmann C, Engel C et al (2009) NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol 27(35):5874–5880

    Article  PubMed  CAS  Google Scholar 

  18. Jeuken J, Sijben A, Alenda C et al (2009) Robust detection of EGFR copy number changes and EGFR variant III: technical aspects and relevance for glioma diagnostics. Brain Pathol 19(4):661–671

    Article  PubMed  Google Scholar 

  19. Jeuken J, Cornelissen S, Boots-Sprenger S et al (2006) Multiplex ligation-dependent probe amplification: a diagnostic tool for simultaneous identification of different genetic markers in glial tumors. J Mol Diagn 8(4):433–443

    Article  PubMed  CAS  Google Scholar 

  20. Jeuken JW, Cornelissen SJ, Vriezen M et al (2007) MS-MLPA: an attractive alternative laboratory assay for robust, reliable, and semiquantitative detection of MGMT promoter hypermethylation in gliomas. Lab Invest 87(10):1055–1065

    Article  PubMed  CAS  Google Scholar 

  21. Kato H, Kato S, Kumabe T et al (2000) Functional evaluation of p53 and PTEN gene mutations in gliomas. Clin Cancer Res 6(10):3937–3943

    PubMed  CAS  Google Scholar 

  22. Kanamori M, Kumabe T, Sonoda Y et al (2009) Predictive factors for overall and progression-free survival, and dissemination in oligodendroglial tumors. J Neurooncol 93(2):219–228

    Article  PubMed  Google Scholar 

  23. Ohgaki H, Kleihues P (2005) Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 64(6):479–489

    PubMed  CAS  Google Scholar 

  24. Smith JS, Tachibana I, Passe SM et al (2001) PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst 93(16):1246–1256

    Article  PubMed  CAS  Google Scholar 

  25. Dehais C, Laigle-Donadey F, Marie Y et al (2006) Prognostic stratification of patients with anaplastic gliomas according to genetic profile. Cancer 107(8):1891–1897

    Article  PubMed  CAS  Google Scholar 

  26. Etienne MC, Formento JL, Lebrun-Frenay C et al (1998) Epidermal growth factor receptor and labeling index are independent prognostic factors in glial tumor outcome. Clin Cancer Res 4(10):2383–2390

    PubMed  CAS  Google Scholar 

  27. Zhou YH, Tan F, Hess KR et al (2003) The expression of PAX6, PTEN, vascular endothelial growth factor, and epidermal growth factor receptor in gliomas: relationship to tumor grade and survival. Clin Cancer Res 9(9):3369–3375

    PubMed  CAS  Google Scholar 

  28. Hartmann C, Meyer J, Balss J et al (2009) Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol 118(4):469–474

    Article  PubMed  Google Scholar 

  29. Weller M, Felsberg J, Hartmann C et al (2009) Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J Clin Oncol 27(34):5743–5750

    Article  PubMed  CAS  Google Scholar 

  30. Ohgaki H, Dessen P, Jourde B et al (2004) Genetic pathways to glioblastoma: a population-based study. Cancer Res 64(19):6892–6899

    Article  PubMed  CAS  Google Scholar 

  31. Ueki K, Ono Y, Henson JW et al (1996) CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer Res 56(1):150–153

    PubMed  CAS  Google Scholar 

  32. Gan HK, Kaye AH, Luwor RB (2009) The EGFRvIII variant in glioblastoma multiforme. J Clin Neurosci 16(6):748–754

    Article  PubMed  CAS  Google Scholar 

  33. Aldape KD, Ballman K, Furth A et al (2004) Immunohistochemical detection of EGFRvIII in high malignancy grade astrocytomas and evaluation of prognostic significance. J Neuropathol Exp Neurol 63(7):700–707

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Health and Welfare in Japan to T. T. We thank T. Matsuki and M. Fue for assistance in extracting genomic DNA and PCR analysis.

Conflict of interest

There is no conflict of interest to declare.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan

    Ichiyo Shibahara, Yukihiko Sonoda, Masayuki Kanamori, Ryuta Saito, Yoji Yamashita, Toshihiro Kumabe & Teiji Tominaga

  2. Department of Clinical Oncology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan

    Shunsuke Kato & Chikashi Ishioka

  3. Pathological Division, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan

    Mika Watanabe

  4. Department of Pathology, Sendai Medical Center, 2-8-8 Miyagino, Miyagino-ku, Sendai, 983-8520, Japan

    Hiroyoshi Suzuki

Authors
  1. Ichiyo Shibahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yukihiko Sonoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masayuki Kanamori
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ryuta Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoji Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Toshihiro Kumabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mika Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiroyoshi Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shunsuke Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chikashi Ishioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Teiji Tominaga
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yukihiko Sonoda.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Fig. 1: Overall survival of patients with grade III gliomas based on either MGMT gene promoter status or chromosome 1p19q status with and without IDH1/2 mutation. In all univariate analyses, IDH1/2 mutation subgroups presented longer survival with statistical significance except for 1p19q codeletion with IDH1/2 mutation.

Supplementary material 1 (TIFF 189 kb)

Supplementary material 2 (DOC 21.0 kb)

About this article

Cite this article

Shibahara, I., Sonoda, Y., Kanamori, M. et al. IDH1/2 gene status defines the prognosis and molecular profiles in patients with grade III gliomas. Int J Clin Oncol 17, 551–561 (2012). https://doi.org/10.1007/s10147-011-0323-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-011-0323-2

Keywords

Search

Navigation