Brain Tumor Pathology

, Volume 29, Issue 3, pp 148–153 | Cite as

Molecular characteristics of glioblastoma with 1p/19q co-deletion

  • Masahiro Mizoguchi
  • Koji Yoshimoto
  • Xinlong Ma
  • Yanlei Guan
  • Nobuhiro Hata
  • Toshiyuki Amano
  • Akira Nakamizo
  • Satoshi O. Suzuki
  • Toru Iwaki
  • Tomio Sasaki
Original Article

Abstract

Recent developments in molecular analysis have revealed genetic alterations in human gliomas. Loss of heterozygosity (LOH) is a critical molecular marker for classification of human glioma, and is useful for predicting outcome. Our previous LOH study identified a small subgroup of glioblastoma (GBM), with 1p/19q co-deletion, with a favorable clinical outcome. In this study, we investigated molecular pathological features of eight GBM with 1p/19q co-deletion compared with “classic” GBM and anaplastic oligodendroglioma (AO). We estimated EGFR gene amplification, EGFRvIII expression, CDKN2A (p16) homozygous deletion, and isocitrate dehydrogenase 1/2 (IDH1/2) gene mutations. We also conducted an analysis of the expression of proneural genes (DLL3, OLIG2, SOX2). On histopathological review, only one GBM was diagnosed as glioblastoma with oligodendroglioma component (GBMO). Loss of chromosomes 10 and 17p is common, and neither IDH1/2 mutations nor EGFRvIII expression were detected in GBM with 1p/19q co-deletion. The expression profile revealed high expression of the OLIG2 gene in this subgroup. High expression of proneural gene OLIG2 without EGFRvIII expression may be associated with a favorable clinical outcome; however, IDH1/2 gene status and the extent of LOH regions may indicate that this small subgroup of GBM is a distinct genetic subgroup from oligodendroglial tumors.

Keywords

Glioblastoma Oligodendroglioma 1p/19q co-deletion IDH1/2 OLIG2 

Notes

Acknowledgments

Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; grant number: 2390280 (M. Mizoguchi).

References

  1. 1.
    Louis DN, Ohgaki H, Weistler OD et al (2007) WHO Classification of tumours of the central nervous system: International Agency for Research on Cancer (IARC), LyonGoogle Scholar
  2. 2.
    Ohgaki H, Kleihues P (2009) Genetic alterations and signaling pathways in the evolution of gliomas. Cancer Sci 100:2235–2241PubMedCrossRefGoogle Scholar
  3. 3.
    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 90:1473–1479PubMedCrossRefGoogle Scholar
  4. 4.
    Louis DN, Holland EC, Cairncross JG (2001) Glioma classification: a molecular reappraisal. Am J Pathol 159:779–786PubMedCrossRefGoogle Scholar
  5. 5.
    Cairncross G (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 24:2707–2714PubMedCrossRefGoogle Scholar
  6. 6.
    van den Bent MJ (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 24:2715–2722PubMedCrossRefGoogle Scholar
  7. 7.
    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 66:9852–9861PubMedCrossRefGoogle Scholar
  8. 8.
    Griffin CA, Burger P, Morsberger L et al (2006) Identification of der(1;19)(q10;p10) in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss. J Neuropathol Exp Neurol 65:988–994PubMedCrossRefGoogle Scholar
  9. 9.
    Ohgaki H, Kleihues P (2007) Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170:1445–1453PubMedCrossRefGoogle Scholar
  10. 10.
    Nakamura M, Yang F, Fujisawa H et al (2000) Loss of heterozygosity on chromosome 19 in secondary glioblastomas. J Neuropathol Exp Neurol 59:539–543PubMedGoogle Scholar
  11. 11.
    Idbaih A, Marie Y, Pierron G et al (2005) Two types of chromosome 1p losses with opposite significance in gliomas. Ann Neurol 58:483–487PubMedCrossRefGoogle Scholar
  12. 12.
    Hartmann C, Johnk L, Kitange G et al (2002) Transcript map of the 3.7-Mb D19S112-D19S246 candidate tumor suppressor region on the long arm of chromosome 19. Cancer Res 62:4100–4108PubMedGoogle Scholar
  13. 13.
    Mizoguchi M, Betensky RA, Batchelor TT et al (2006) Activation of STAT3, MAPK, and AKT in malignant astrocytic gliomas: correlation with EGFR status, tumor grade, and survival. J Neuropathol Exp Neurol 65:1181–1188PubMedCrossRefGoogle Scholar
  14. 14.
    Ducray F, Idbaih A, de Reynies A et al (2008) Anaplastic oligodendrogliomas with 1p19q codeletion have a proneural gene expression profile. Molecular Cancer 7:41PubMedCrossRefGoogle Scholar
  15. 15.
    Mukasa A, Ueki K, Matsumoto S et al (2002) Distinction in gene expression profiles of oligodendrogliomas with and without allelic loss of 1p. Oncogene 21:3961–3968PubMedCrossRefGoogle Scholar
  16. 16.
    Beroukhim R, Getz G, Nghiemphu L et al (2007) Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proc Natl Acad Sci 104:20007–20012PubMedCrossRefGoogle Scholar
  17. 17.
    Vogazianou AP, Chan R, Backlund LM et al (2010) Distinct patterns of 1p and 19q alterations identify subtypes of human gliomas that have different prognoses. NeuroOncology 12:664–678Google Scholar
  18. 18.
    Mizoguchi M, Kuga D, Guan Y et al (2011) Loss of heterozygosity analysis in malignant gliomas. Brain Tumor Pathol 28:191–196PubMedCrossRefGoogle Scholar
  19. 19.
    Yoshimoto K, Iwaki T, Inamura T et al (2002) Multiplexed analysis of post-PCR fluorescence-labeled microsatellite alleles and statistical evaluation of their imbalance in brain tumors. Jpn J Cancer Res 93:284–290PubMedCrossRefGoogle Scholar
  20. 20.
    Guan Y, Mizoguchi M, Yoshimoto K et al (2010) MiRNA-196 is upregulated in glioblastoma but not in anaplastic astrocytoma and has prognostic significance. Clin Cancer Res 16:4289–4297PubMedCrossRefGoogle Scholar
  21. 21.
    Mellinghoff IK, Wang MY, Vivanco I et al (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024PubMedCrossRefGoogle Scholar
  22. 22.
    Capper D, Weissert S, Balss J et al (2010) Characterization of R132H mutation-specific IDH1 antibody binding in brain tumors. Brain Pathol 20:245–254PubMedCrossRefGoogle Scholar
  23. 23.
    Phillips HS, Kharbanda S, Chen R et al (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9:157–173PubMedCrossRefGoogle Scholar
  24. 24.
    Verhaak RGW, Hoadley KA, Purdom E et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110PubMedCrossRefGoogle Scholar
  25. 25.
    Miller CR, Dunham CP, Scheithauer BW et al (2006) Significance of necrosis in grading of oligodendroglial neoplasms: a clinicopathologic and genetic study of newly diagnosed high-grade gliomas. J Clin Oncol Off J Am Soc Clin Oncol 24:5419–5426CrossRefGoogle Scholar
  26. 26.
    Pinto LW, Araujo MB, Vettore AL et al (2008) Glioblastomas: correlation between oligodendroglial components, genetic abnormalities, and prognosis. Virchows Archiv Int J Pathol 452:481–490CrossRefGoogle Scholar
  27. 27.
    Hegi ME, Janzer RC, Lambiv WL et al (2012) Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial. Acta Neuropathol 123:841–852PubMedCrossRefGoogle Scholar
  28. 28.
    Yan H, Parsons DW, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773PubMedCrossRefGoogle Scholar
  29. 29.
    Kuga D, Mizoguchi M, Guan Y et al (2008) Prevalence of copy-number neutral LOH in glioblastomas revealed by genomewide analysis of laser-microdissected tissues. Neuro Oncol 10:995–1003PubMedCrossRefGoogle Scholar
  30. 30.
    Mizoguchi M, Nutt CL, Louis DN (2004) Mutation analysis of CBL-C and SPRED3 on 19q in human glioblastoma. Neurogenetics 5:81–82PubMedCrossRefGoogle Scholar

Copyright information

© The Japan Society of Brain Tumor Pathology 2012

Authors and Affiliations

  • Masahiro Mizoguchi
    • 1
  • Koji Yoshimoto
    • 1
  • Xinlong Ma
    • 1
  • Yanlei Guan
    • 1
  • Nobuhiro Hata
    • 1
  • Toshiyuki Amano
    • 1
  • Akira Nakamizo
    • 1
  • Satoshi O. Suzuki
    • 2
  • Toru Iwaki
    • 2
  • Tomio Sasaki
    • 1
  1. 1.Department of Neurosurgery, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  2. 2.Department of Neuropathology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan

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