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IDH1 mutation is prognostic for diffuse astrocytoma but not low-grade oligodendrogliomas in patients not treated with early radiotherapy

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Abstract

Despite accumulating knowledge regarding molecular backgrounds, the optimal management strategy for low-grade gliomas remains controversial. One reason is the marked heterogeneity in the clinical course. To establish an accurate subclassification of low-grade gliomas, we retrospectively evaluated isocitrate dehydrogenase-1 (IDH1) mutation in clinical specimens of diffuse astrocytomas (DA) and oligodendroglial tumors separately. No patients were treated with early radiotherapy, and modified PCV chemotherapy was used for postoperative residual tumors or recurrence in oligodendroglial tumors. Immunohistochemical evaluation of IDH status, p53 status, O6-methylguanine methyltransferase expression, and the MIB-1 index were performed. The 1p and 19q status was analyzed with fluorescence in situ hybridization. Ninety-four patients were followed for a median period of 8.5 years. For DAs, p53 was prognostic for progression- free survival (PFS) and IDH1 was significant for overall survival (OS) with multivariate analysis. In contrast, for oligodendroglial tumors, none of the parameters was significant for PFS or OS. Thus, the significance of IDH1 mutation is not clear in oligodendroglial tumors that are homogeneously indolent and chemosensitive. In contrast, DAs are heterogeneous tumors including some potentially malignant tumors that can be predicted by examining the IDH1 mutation status.

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References

  1. Karim AB, Afra D, Cornu P et al (2002) Randomized trial on the efficacy of radiotherapy for cerebral low-grade gliomas in the adult: European Organization for Research and Treatment of Cancer Study 22845 with Medical Research Council Study BRO4: an interim analysis. Int J Radiat Oncol Biol Phys 52:316–324

    Article  PubMed  Google Scholar 

  2. Shaw E, Arusell R, Scheithauer B et al (2002) Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Group study. J Clin Oncol 20:2267–2276

    Article  CAS  PubMed  Google Scholar 

  3. van den Bent MJ, Afra D, de Witte O et al (2005) EORTC Radiotherapy and Brain Tumor Groups and the UK Medical Research Council. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 366:985–990

    Article  PubMed  Google Scholar 

  4. Papagikos MA, Shaw EG, Stieber VW (2005) Lessons from randomized clinical trials in adult low grade glioma. Lancet Oncol 6:240–244

    Article  PubMed  Google Scholar 

  5. Behin A, Hoang-Xuan K, Carpentier AF, Delattre J-Y (2003) Primary brain tumors in adults. Lancet 361:323–331

    Article  PubMed  Google Scholar 

  6. Wessels PH, Weber WE, Raven G et al (2003) Supratentorial grade II astrocytoma: biological features and clinical course. Lancet Neurol 2:395–403

    Article  PubMed  Google Scholar 

  7. Okamoto Y, Di Patre PL, Burkhard C et al (2004) Population-based study on incidence, survival rates, and genetic alterations of low-grade diffuse astrocytomas and oligodendrogliomas. Acta Neuropathol 108:49–56

    Article  PubMed  Google Scholar 

  8. Peraud A, Kreth FW, Wiestler OD, Kleihues P, Reulen HJ (2002) Prognostic impact of TP53 mutations and P53 protein overexpression in supratentorial WHO grade II astrocytomas and oligoastrocytomas. Clin Cancer Res 8:1117–1124

    CAS  PubMed  Google Scholar 

  9. Ständer M, Peraud A, Leroch B, Kreth FW (2004) Prognostic impact of TP53 mutation status for adult patients with supratentorial World Health Organization Grade II astrocytoma or oligoastrocytoma: a long-term analysis. Cancer 101:1028–1035

    Article  PubMed  Google Scholar 

  10. Weller M, Stupp R, Reifenberger G et al (2010) MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 6:39–51

    Article  CAS  PubMed  Google Scholar 

  11. 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 

  12. Jenkins RB, Blair H, Ballman KV et al (2006) 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 66:9852–9861

    Article  CAS  PubMed  Google Scholar 

  13. Cairncross JG, Ueki K, Zlatescu MC et al (1998) Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90:1473–1479

    Article  CAS  PubMed  Google Scholar 

  14. Weller M, Berger H, Hartmann C et al (2007) German Glioma Network. Combined 1p/19q loss in oligodendroglial tumors: predictive or prognostic biomarker? Clin Cancer Res 13:6933–6937

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A (2008) Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116:597–602

    Article  CAS  PubMed  Google Scholar 

  19. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S et al (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19:17–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yang H, Liu Y, Bai F, Zhang JY, Ma SH, Liu J, Xu ZD, Zhu HG, Ling ZQ, Ye D, Guan KL, Xiong Y (2013) Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene 32:663–669

    Article  CAS  PubMed  Google Scholar 

  22. Weller M, Felsberg J, Hartmann C, Berger H, Steinbach JP, Schramm J, Westphal M 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 27:5743–5750

    Article  CAS  PubMed  Google Scholar 

  23. Van den Bent MJ, Dubbink HJ, Marie Y, Brandes AA, Taphoom MJB 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 16:1597–1604

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Houillier C, Wang X, Kaloshi G et al (2010) IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology 75:1560–1566

    Article  CAS  PubMed  Google Scholar 

  26. Sabha N, Knobbe CB, Maganti M et al (2014) Analysis of IDH mutation, 1p/19q deletion, and PTEN loss delineates prognosis in clinical low-grade diffuse gliomas. Neuro Oncol 16:914–923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kim YH, Nobusawa S, Mittelbronn M, Paulus W, Brokinkel B, Keyvani K, Sure U et al (2010) Molecular classification of low-grade diffuse gliomas. Am J Pathol 177:2708–2714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mukasa A, Takayanagi S, Saito K, Shibahara J, Tabei Y et al (2012) Significance of IDH mutations varies with tumor histology, grade, and genetics in Japanese glioma patients. Cancer Sci 103:587–592

    Article  CAS  PubMed  Google Scholar 

  29. Boots-Sprenger SHE, Sijben A, Rijntjes J et al (2013) Significance of complete 1p/19q co-deletion, IDH1 mutation and MGMT promoter methylation in gliomas: use with caution. Mod Pathol 26:922–929

    Article  CAS  PubMed  Google Scholar 

  30. Leu S, von Felten S, Frank S, Vassella E, Vajtai I et al (2013) IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival. Neuro Oncol 15:469–479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Okita Y, Narita Y, Miyakita Y, Ohno M, Matsushita Y et al (2012) IDH1/2 mutation is a prognostic marker for survival and predicts response to chemotherapy for grade II gliomas concomitantly treated with radiation therapy. Int J Oncol 41:1325–1336

    Article  CAS  PubMed  Google Scholar 

  32. Dubbink HJ, Taal W, van Marion R et al (2009) IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide. Neurology 73:1792–1795

    Article  CAS  PubMed  Google Scholar 

  33. Hartmann C, Hentschel B, Tatagiba M et al (2011) Molecular markers in low-grade gliomas: predictive or prognostic? Clin Cancer Res 17:4588–4599

    Article  CAS  PubMed  Google Scholar 

  34. Ahmadi R, Stockhammer F, Becker N, Hohlen K, Misch M, Christians A, Dictus C et al (2012) No prognostic value of IDH1 mutations in a series of 100 WHO grade II astrocytomas. J Neurooncol 109:15–22

    Article  CAS  PubMed  Google Scholar 

  35. Juratli TA, Kirsch M, Robel K et al (2012) IDH mutations as an early and consistent marker in low-grade astrocytomas WHO grade II and their consecutive secondary high-grade gliomas. J Neurooncol 108:403–410

    Article  CAS  PubMed  Google Scholar 

  36. Dahlrot RH, Kristensen BW, Hjelmborg J, Herrstedt J, Hansen S (2013) A population-based study of low-grade gliomas and mutated isocitrate dehydrogenase 1 (IDH1). J Neurooncol 114:309–317

    Article  CAS  PubMed  Google Scholar 

  37. Thon N, Eigenbrod S, Kreth S et al (2012) IDH1 mutations in grade II astrocytomas are associated with unfavorable progression-free survival and prolonged postrecurrence survival. Cancer 118:452–460

    Article  CAS  PubMed  Google Scholar 

  38. Lee D, Suh YL, Kang SY, Park TI, Jeong JY, Kim SH (2013) IDH1 mutations in oligodendroglial tumors: comparative analysis of direct sequencing, pyrosequencing, immunohistochemistry, nested PCR and PNA-mediated clamping PCR. Brain Pathol 23:285–293

    Article  CAS  PubMed  Google Scholar 

  39. Myung JK, Cho HJ, Park CK, Kim SK, Phi JH, Park SH (2012) IDH1 mutation of gliomas with long-term survival analysis. Oncol Rep 28:1639–1644

    Article  CAS  PubMed  Google Scholar 

  40. Figarella-Branger D, Bouvier C, de Paula AM et al (2012) Molecular genetics of adult grade II gliomas: towards a comprehensive tumor classification system. J Neurooncol 110:205–213

    Article  CAS  PubMed  Google Scholar 

  41. Metellus P, Coulibaly B, Colin C et al (2010) Absence of IDH mutation identifies a novel radiologic and molecular subtype of WHO grade II gliomas with dismal prognosis. Acta Neuropathol 120:719–729

    Article  PubMed  Google Scholar 

  42. Caincross G, Berkey B, Shaw E et al (2006) 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 24:2707–2714

    Article  Google Scholar 

  43. 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 Organization for Research and Treatment of Cancer phase III trial. J Clin Oncol 24:2715–2722

    Article  PubMed  Google Scholar 

  44. Iwadate Y, Matsutani T, Hasegawa Y, Shinozaki N, Higuchi Y, Saeki N (2011) Favorable long-term outcome of low-grade oligodendrogliomas irrespective of 1p/19q status when treated without radiotherapy. J Neurooncol 102:443–449

    Article  PubMed  Google Scholar 

  45. Kanner AA, Staugaitis SM, Castilla EA et al (2006) The impact of genotype on outcome in oligodendroglioma: validation of the loss of chromosome arm 1p as an important factor in clinical decision making. J Neurosurg 104:542–550

    Article  PubMed  Google Scholar 

  46. Mariani L, Deiana G, Vassella E et al (2006) Loss of heterozygosity 1p36 and 19q13 is a prognostic factor for overall survival in patients with diffuse WHO grade 2 gliomas treated without chemotherapy. J Clin Oncol 24:4758–4763

    Article  CAS  PubMed  Google Scholar 

  47. Jaeckle KA, Ballman KV, Rao RD, Jenkins RB, Buckner JC (2006) Current strategies in treatment of oligodendroglioma: evolution of molecular signature of response. J Clin Oncol 24:1246–1252

    Article  CAS  PubMed  Google Scholar 

  48. Weller M, Berger H, Hartmann C et al (2007) Combined 1p/19q loss in oligodendroglial tumors: predictive or prognostic biomarker? Clin Cancer Res 13:6933–6937

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurological Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan

    Yasuo Iwadate, Tomoo Matsutani, Seiichiro Hirono, Shiro Ikegami & Naokatsu Saeki

  2. Department of Neurosurgery, Narita Red-Cross Hospital, 90-1 Iida-cho, Narita, Chiba, 286-8523, Japan

    Natsuki Shinozaki

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  1. Yasuo Iwadate
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  2. Tomoo Matsutani
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  3. Seiichiro Hirono
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Correspondence to Yasuo Iwadate.

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Iwadate, Y., Matsutani, T., Hirono, S. et al. IDH1 mutation is prognostic for diffuse astrocytoma but not low-grade oligodendrogliomas in patients not treated with early radiotherapy. J Neurooncol 124, 493–500 (2015). https://doi.org/10.1007/s11060-015-1863-5

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  • DOI: https://doi.org/10.1007/s11060-015-1863-5

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