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Adult grade II diffuse astrocytomas are genetically distinct from and more aggressive than their paediatric counterparts

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Abstract

Diffuse astrocytomas (WHO grade II) typically present as slow-growing tumours showing significant cellular differentiation, but possessing a tendency towards malignant progression. They account for ~10% of all astrocytic tumours, with a peak incidence between 30 and 40 years of age. Median survival is reported as around 6–8 years. Mutations of TP53 and IDH1 have been described as genetic hallmarks, while copy number alterations are also relatively common. However, there is some evidence to suggest that these characteristics may vary with age. Here, we present an integrated clinicopathologic, genomic and transcriptomic analysis suggesting that paediatric and adult tumours are associated with distinct genetic signatures. For example, no childhood tumour showed mutation of IDH1/2 or TP53, virtually no copy number changes were seen, and MGMT methylation was absent. In contrast, adult tumours showed IDH1/2 mutation in 94% and TP53 mutation in 69% of cases, with multiple copy number alterations per case and hypermethylation of MGMT in the majority of tumours. These differences were associated with a worse prognosis in the adult patients. The expression array data also revealed a significant difference in the expression of a number of genes putatively involved in neural stem cell maintenance and CNS development, including DLL3, HES5, BMP2, TIMP1 and BAMBI. Genes involved in DNA replication and the cell cycle were also enriched in the adult tumours, suggesting that their more aggressive behaviour may be due to derivation from a more rapidly dividing, less differentiated cell type.

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References

  1. Arslantas A, Artan S, Oner U et al (2007) Genomic alterations in low-grade, anaplastic astrocytomas and glioblastomas. Pathol Oncol Res 13:39–46

    Article  PubMed  CAS  Google Scholar 

  2. 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  PubMed  CAS  Google Scholar 

  3. Canzoniere D, Farioli-Vecchioli S, Conti F et al (2004) Dual control of neurogenesis by PC3 through cell cycle inhibition and induction of Math1. J Neurosci 24:3355–3369

    Article  PubMed  CAS  Google Scholar 

  4. Central Brain Tumor Registry of the United States (2010) Statistical report: primary brain and central nervous system tumors diagnosed in the United States, 2004–2006. CBTRUS, Hinsdale, IL

  5. Du P, Kibbe WA, Lin SM (2008) lumi: a pipeline for processing Illumina microarray. Bioinformatics 24:1547–1548

    Article  PubMed  CAS  Google Scholar 

  6. Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG (1999) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 59:793–797

    PubMed  CAS  Google Scholar 

  7. Felix CA, Slavc I, Dunn M et al (1995) p53 gene mutations in pediatric brain tumors. Med Pediatr Oncol 25:431–436

    Article  PubMed  CAS  Google Scholar 

  8. 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 118:469–474

    Article  PubMed  Google Scholar 

  9. Hirose Y, Aldape KD, Chang S, Lamborn K, Berger MS, Feuerstein BG (2003) Grade II astrocytomas are subgrouped by chromosome aberrations. Cancer Genet Cytogenet 142:1–7

    Article  PubMed  CAS  Google Scholar 

  10. 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  PubMed  CAS  Google Scholar 

  11. Ichimura K, Bolin MB, Goike HM, Schmidt EE, Moshref A, Collins VP (2000) Deregulation of the p14ARF/MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with G1-S transition control gene abnormalities. Cancer Res 60:417–424

    PubMed  CAS  Google Scholar 

  12. 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 11:341–347

    Article  PubMed  CAS  Google Scholar 

  13. Imayoshi I, Sakamoto M, Yamaguchi M, Mori K, Kageyama R (2010) Essential roles of Notch signaling in maintenance of neural stem cells in developing and adult brains. J Neurosci 30:3489–3498

    Article  PubMed  CAS  Google Scholar 

  14. Jones DTW, Kocialkowski S, Liu L et al (2008) Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68:8673–8677

    Article  PubMed  CAS  Google Scholar 

  15. Kageyama R, Ohtsuka T, Kobayashi T (2008) Roles of Hes genes in neural development. Dev Growth Differ 50(Suppl 1):S97–S103

    Article  PubMed  CAS  Google Scholar 

  16. Kullar PJ, Pearson DM, Malley DS, Collins VP, Ichimura K (2010) CpG island hypermethylation of the NF2 gene is rare in sporadic vestibular schwannomas. Neuropathol Appl Neurobiol 36:505–514

    Article  PubMed  CAS  Google Scholar 

  17. Lei W, Rushton JJ, Davis LM, Liu F, Ness SA (2004) Positive and negative determinants of target gene specificity in myb transcription factors. J Biol Chem 279:29519–29527

    Article  PubMed  CAS  Google Scholar 

  18. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2007) WHO classification of tumours of the central nervous system. IARC Press, Lyon

    Google Scholar 

  19. McCabe MG, Ichimura K, Liu L et al (2006) High-resolution array-based comparative genomic hybridization of medulloblastomas and supratentorial primitive neuroectodermal tumors. J Neuropathol Exp Neurol 65:549–561

    Article  PubMed  CAS  Google Scholar 

  20. 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 

  21. Mootha VK, Lindgren CM, Eriksson KF et al (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273

    Article  PubMed  CAS  Google Scholar 

  22. Nakamura M, Shimada K, Ishida E et al (2007) Molecular pathogenesis of pediatric astrocytic tumors. Neuro Oncol 9:113–123

    Article  PubMed  CAS  Google Scholar 

  23. Nakashima K, Takizawa T, Ochiai W et al (2001) BMP2-mediated alteration in the developmental pathway of fetal mouse brain cells from neurogenesis to astrocytogenesis. Proc Natl Acad Sci USA 98:5868–5873

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  25. 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 

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

    Article  PubMed  CAS  Google Scholar 

  27. Paugh BS, Qu C, Jones C et al (2010) Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 28:3061–3068

    Article  PubMed  Google Scholar 

  28. Pollack IF, Hamilton RL, Sobol RW et al (2011) IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children’s Oncology Group. Childs Nerv Syst 27:87–94

    Article  PubMed  Google Scholar 

  29. R Development Core Team (2008) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria

  30. Smyth G (2005) Limma: linear models for microarray data. In: Gentleman R, Carey VJ, Dudoit S, Irizarry R, Huber W (eds) Bioinformatics and computational biology solutions using R and bioconductor. Springer, New York, pp 397–420

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

    Article  PubMed  CAS  Google Scholar 

  32. Subramanian A, Tamayo P, Mootha VK et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102:15545–15550

    Article  PubMed  CAS  Google Scholar 

  33. Sun H, Li L, Vercherat C et al (2007) Stra13 regulates satellite cell activation by antagonizing Notch signaling. J Cell Biol 177:647–657

    Article  PubMed  CAS  Google Scholar 

  34. Tatevossian RG, Tang B, Dalton J et al (2010) MYB upregulation and genetic aberrations in a subset of pediatric low-grade gliomas. Acta Neuropathol 120:731–743

    Article  PubMed  Google Scholar 

  35. Therneau T, Lumley T (2009) Survival analysis, including penalised likelihood. R package 2.35-7

  36. Ward SJ, Karakoula K, Phipps KP et al (2010) Cytogenetic analysis of paediatric astrocytoma using comparative genomic hybridisation and fluorescence in situ hybridisation. J Neurooncol 98:305–318

    Article  PubMed  Google Scholar 

  37. 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  39. Zhao X, D’Arca D, Lim WK et al (2009) The N-Myc-DLL3 cascade is suppressed by the ubiquitin ligase Huwe1 to inhibit proliferation and promote neurogenesis in the developing brain. Dev Cell 17:210–221

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank Cambridge Genomic Services (University of Cambridge) for microarray assistance, and also Professor Andreas von Deimling (University of Heidelberg), Professor Felice Giangaspero (University of Rome), Dr Yukihiko Sonoda (Tohoku University), Dr Marc Sanson (INSERM, Paris) and Professor Hai Yan (Duke University Medical Centre) for providing TP53/IDH mutation data from their paediatric cases for the meta-analysis. Funding: Cancer Research UK, the Samantha Dickson Brain Tumour Trust and the Addenbrooke’s Charitable Trust.

Conflict of interest

The authors declare that they have no conflict of interest.

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Author notes

  1. David T. W. Jones

    Present address: German Cancer Research Centre (DKFZ), Molecular Genetics of Paediatric Brain Tumours (B062), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

Authors and Affiliations

  1. Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, CB2 0QQ, UK

    David T. W. Jones, Shani A. Mulholland, Danita M. Pearson, Deborah S. Malley, Samuel W. S. Openshaw, Sally R. Lambert, Lu Liu, Koichi Ichimura & V. Peter Collins

  2. Department of Oncology-Pathology, Karolinska Hospital, 171 76, Stockholm, Sweden

    L. Magnus Bäcklund

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  1. David T. W. Jones
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Correspondence to David T. W. Jones.

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Jones, D.T.W., Mulholland, S.A., Pearson, D.M. et al. Adult grade II diffuse astrocytomas are genetically distinct from and more aggressive than their paediatric counterparts. Acta Neuropathol 121, 753–761 (2011). https://doi.org/10.1007/s00401-011-0810-6

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  • DOI: https://doi.org/10.1007/s00401-011-0810-6

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