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Pathology and molecular genetics of astrocytic gliomas

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Abstract

Astrocytic gliomas are the most common primary brain tumours. Here we summarize the characteristic neuropathological features of the different types of astrocytic neoplasms according to the World Health Organization classification of tumours of the nervous system. In addition, we report on the present state of the art concerning the molecular genetics of these tumours. Over the past 20 years a number of recurrent chromosomal, genetic and epigenetic alterations have been found to be associated with the different histological types and malignancy grades of astrocytic tumours. However, we are still far from understanding the complex mechanisms that underly tumour initiation and progression in the individual case. Furthermore, the clinical significance of molecular parameters for the diagnostic and prognostic assessment of astrocytic gliomas is still limited. Therefore further investigation of the molecular mechanisms underlying oncogenesis and progression of these most common brain tumours is necessary to improve their diagnostic assessment and to devise novel, individually tailored treatment strategies.

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Abbreviations

CTMP :

Carboxyl-terminal modulator protein

EGFR :

Epidermal growth factor receptor

GFAP :

Glial fibrillary acidic protein

LOH :

Loss of heterozygosity

NF :

Neurofibromatosis

PDGFRA :

Platelet-derived growth factor receptor α

PXA :

Pleomorphic xanthoastrocytoma

WHO :

World Health Organization

References

  1. Surawicz TS, McCarthy BJ, Kupelian V, Jukich PJ, Bruner JM, Davis FG (1999) Descriptive epidemiology of primary brain and CNS tumors: results from the Central Brain Tumor Registry of the United States, 1990–1994. Neuro-oncol 1:14–25

    Google Scholar 

  2. Miller RW, Young JL, Novakovic B (1995) Childhood cancer. Cancer 75:395–405

    CAS  PubMed  Google Scholar 

  3. Legler JM, Ries LA, Smith MA, Warren JL, Heineman EF, Kaplan RS, Linet MS (1999) Cancer surveillance series [corrected]: brain and other central nervous system cancers: recent trends in incidence and mortality. J Natl Cancer Inst 91:1382–1390

    Article  CAS  PubMed  Google Scholar 

  4. Greig NH, Ries LG, Yancik R, Rapoport SI (1990) Increasing annual incidence of primary malignant brain tumors in the elderly. J Natl Cancer Inst 82:1621–1624

    CAS  PubMed  Google Scholar 

  5. Desmeules M, Mikkelsen T, Mao Y (1992) Increasing incidence of primary malignant brain tumors: influence of diagnostic methods. J Natl Cancer Inst 84:442–445

    Article  CAS  PubMed  Google Scholar 

  6. Jukich PJ, McCarthy BJ, Surawicz TS, Freels S, Davis FG (2001) Trends in incidence of primary brain tumors in the United States, 1985–1994. Neuro-oncol 3:141–151

    Google Scholar 

  7. Virchow R (1864/1865) Die krankhaften Geschwülste. Achtzehnte Vorlesung: Psammome, Melanome, Gliome. Hirschwald, Berlin, pp 106–169

    Google Scholar 

  8. Bailey P, Cushing H (1926) A classification of the tumors of the glioma group on a histogenetic basis with a correlated study of prognosis. Lippincott, Philadelphia

  9. Zülch KJ (1979) Histological typing of tumors of the central nervous system. International histological classification of tumors, no. 21. World Health Organization, Geneva

  10. Kleihues P, Burger PC, Scheithauer BW (1993) Histological typing of tumors of the central nervous system, 2nd edn. International histological classification of tumors. Springer, Berlin, Heidelberg, New York

  11. Kleihues P, Cavenee WK (2000) Pathology and genetics of tumors of the nervous system. World Health Organization classification of tumors. IARC, Lyon

  12. Ohgaki H, Peraud A, Nakazato Y, Watanabe K, von Deimling A (2000) Giant cell glioblastoma. In: Kleihues P, Cavenee WK (eds) Pathology and genetics of tumors of the nervous system. World Health Organization classification of tumors. IARC, Lyon, pp 40–41

  13. Ohgaki H, Biernat W, Reis R, Hegi M, Kleihues P (2000) Gliosarcoma. In: Kleihues P, Cavenee WK (eds) Pathology and genetics of tumors of the nervous system. World Health Organization classification of tumors. IARC, Lyon, pp 42–44

  14. Kraus JA, Lamszus K, Glesmann N, Beck M, Wolter M, Sabel M, Krex D, Klockgether T, Reifenberger G, Schlegel U (2001) Molecular genetic alterations in glioblastomas with oligodendroglial component. Acta Neuropathol (Berl) 101:311–320

    Google Scholar 

  15. He J, Mokhtari K, Sanson M, Marie Y, Kujas M, Huguet S, Leuraud P, Capelle L, Delattre JY, Poirier J, Hoang-Xuan K (2001) Glioblastomas with an oligodendroglial component: a pathological and molecular study. J Neuropathol Exp Neurol 60:863–871

    CAS  PubMed  Google Scholar 

  16. Kleihues P, Ohgaki H (1999) Primary and secondary glioblastomas: from concept to clinical diagnosis. Neuro-oncol 1:44–51

    Google Scholar 

  17. Dropcho EJ, Soong SJ (1996) The prognostic impact of prior low grade histology in patients with anaplastic gliomas: a case-control study. Neurology 47:684–690

    CAS  PubMed  Google Scholar 

  18. Tihan T, Fisher PG, Kepner JL, Godfraind C, McComb RD, Goldthwaite PT, Burger PC (1999) Pediatric astrocytomas with monomorphous pilomyxoid features and a less favorable outcome. J Neuropathol Exp Neurol 58:1061–1068

    CAS  PubMed  Google Scholar 

  19. Kepes JJ, Rubinstein LJ, Eng LF (1979) Pleomorphic xanthoastrocytoma: a distinctive meningocerebral glioma of young subjects with relatively favorable prognosis. A study of 12 cases. Cancer 44:1839–1852

    CAS  PubMed  Google Scholar 

  20. Giannini C, Scheithauer BW, Lopes MB, Hirose T, Kros JM, VandenBerg SR (2002) Immunophenotype of pleomorphic xanthoastrocytoma. Am J Surg Pathol 26:479–485

    Article  PubMed  Google Scholar 

  21. Reifenberger G, Kaulich K, Wiestler OD, Blumcke I (2003) Expression of the CD34 antigen in pleomorphic xanthoastrocytomas. Acta Neuropathol (Berl) 105:358–364

    Google Scholar 

  22. Macdonald DR (2001) Temozolomide for recurrent high-grade glioma. Semin Oncol 28 [4 Suppl 13]:3–12

  23. Stupp R, Dietrich PY, Ostermann Kraljevic S, Pica A, Maillard I, Maeder P, Meuli R, Janzer R, Pizzolato G, Miralbell R, Porchet F, Regli L, de Tribolet N, Mirimanoff RO, Leyvraz S (2002) Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 20:1375–1382

    Article  CAS  PubMed  Google Scholar 

  24. Pignatti F, van den Bent M, Curran D, Debruyne C, Sylvester R, Therasse P, Afra D, Cornu P, Bolla M, Vecht C, Karim AB (2002) Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol 20:2076–2084

    Article  PubMed  Google Scholar 

  25. Shaw E, Arusell R, Scheithauer B, O’Fallon J, O’Neill B, Dinapoli R, Nelson D, Earle J, Jones C, Cascino T, Nichols D, Ivnik R, Hellman R, Curran W, Abrams R (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 Oncology Group study. J Clin Oncol 20:2267–2276

    Article  CAS  PubMed  Google Scholar 

  26. Cavenee WK, Furnari FB, Nagane M, Huang H-JS, Newcomb EW, Bigner DD, Weller M, Berens ME, Plate KH, Israel MA, Noble MD, Kleihues P (2000) Diffusely infiltrating astrocytomas. In: Kleihues P, Cavenee WK (eds) Pathology and genetics of tumors of the nervous system. WHO classification of tumors. Lyon, IARC, pp 10–21

  27. Fine HA, Dear KB, Loeffler JS, Black PM, Canellos GP. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 71:2585–2597

  28. Stewart LA (2002) Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:1011–1018

    Article  CAS  PubMed  Google Scholar 

  29. Tortosa A, Vinolas N, Villa S, Verger E, Gil JM, Brell M, Caral L, Pujol T, Acebes JJ, Ribalta T, Ferrer I, Graus F (2003) Prognostic implication of clinical, radiologic, and pathologic features in patients with anaplastic gliomas. Cancer 97:1063–1071

    Article  PubMed  Google Scholar 

  30. Scott JN, Rewcastle NB, Brasher PM, Fulton D, Hagen NA, MacKinnon JA, Sutherland G, Cairncross JG, Forsyth P (1998) Long-term glioblastoma multiforme survivors: a population-based study. Can J Neurol Sci 25:197–201

    CAS  PubMed  Google Scholar 

  31. Burkhard C, Di Patre PL, Schuler D, Schuler G, Yasargil MG, Yonekawa Y, Lutolf UM, Kleihues P, Ohgaki H (2003) A population-based study of the incidence and survival rates in patients with pilocytic astrocytoma. J Neurosurg 98:1170–1174

    PubMed  Google Scholar 

  32. Giannini C, Scheithauer BW, Burger PC, Brat DJ, Wollan PC, Lach B, O’Neill BP (1999) Pleomorphic xanthoastrocytoma: what do we really know about it? Cancer 85:2033–2045

    CAS  PubMed  Google Scholar 

  33. Kepes JJ, Louis DN, Giannini C, Paulus W (2000) Pleomorphic xanthoastrocytoma. In: Kleihues P, Cavenee WK (eds) Pathology and genetics of tumors of the nervous system. WHO classification of tumors. Lyon, IARC, pp 52–54

  34. Schrock E, Blume C, Meffert MC, du Manoir S, Bersch W, Kiessling M, Lozanowa T, Thiel G, Witkowski R, Ried T, Cremer T (1996) Recurrent gain of chromosome arm 7q in low-grade astrocytic tumors studied by comparative genomic hybridization. Genes Chromosomes Cancer 15:199–205

    Article  CAS  PubMed  Google Scholar 

  35. Wessels PH, Twijnstra A, Kessels AG, Krijne-Kubat B, Theunissen PH, Ummelen MI, Ramaekers FC, Hopman AH (2002) Gain of chromosome 7, as detected by in situ hybridization, strongly correlates with shorter survival in astrocytoma grade 2. Genes Chromosomes Cancer 33:279–284

    Article  CAS  PubMed  Google Scholar 

  36. Kleihues P, Davis RL, Ohgaki H, Burger PC, Westphal M, Cavenee WK (2000) Diffuse astrocytoma. In: Kleihues P, Cavenee WK (eds) Pathology and genetics of tumors of the nervous system. World Health Organization classification of tumors. IARC, Lyon, pp 22–26

  37. 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

    CAS  PubMed  Google Scholar 

  38. Watanabe K, Peraud A, Gratas C, Wakai S, Kleihues P, Ohgaki H (1998) p53 and PTEN gene mutations in gemistocytic astrocytomas. Acta Neuropathol (Berl) 95:559–564

    Google Scholar 

  39. Nakamura M, Watanabe T, Klangby U, Asker C, Wiman K, Yonekawa Y, Kleihues P, Ohgaki H (2001) p14ARF deletion and methylation in genetic pathways to glioblastomas. Brain Pathol 11:159–168

    CAS  PubMed  Google Scholar 

  40. Hermanson M, Funa K, Hartman M, Claesson-Welsh L, Heldin CH, Westermark B, Nister M (1992) Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. Cancer Res 52:3213–3219

    CAS  PubMed  Google Scholar 

  41. Guha A, Dashner K, Black PM, Wagner JA, Stiles CD (1995) Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop. Int J Cancer 60:168–173

    CAS  PubMed  Google Scholar 

  42. Hermanson M, Funa K, Koopmann J, Maintz D, Waha A, Westermark B, Heldin CH, Wiestler OD, Louis DN, von Deimling A, Nister M (1996) Association of loss of heterozygosity on chromosome 17p with high platelet-derived growth factor alpha receptor expression in human malignant gliomas. Cancer Res 56:164–171

    CAS  PubMed  Google Scholar 

  43. Ruas M, Peters G (1998) The p16INK4a/CDKN2A tumor suppressor and its relatives. Biochim Biophys Acta 1378:F115–F177

    Article  CAS  PubMed  Google Scholar 

  44. Roussel MF (1999) The Ink4 family of cell cycle inhibitors in cancer. Oncogene 18:5311–5317

    Article  CAS  PubMed  Google Scholar 

  45. Reifenberger G, Reifenberger J, Ichimura K, Meltzer PS, Collins VP (1994) Amplification of multiple genes from chromosomal region 12q13–14 in human malignant gliomas: preliminary mapping of the amplicons shows preferential involvement of CDK4, SAS, and MDM 2. Cancer Res 54:4299–4303

    CAS  PubMed  Google Scholar 

  46. Ichimura K, Schmidt EE, Goike HM, Collins VP (1996) Human glioblastomas with no alterations of the CDKN2A (p16INK4A, MTS1) and CDK4 genes have frequent mutations of the retinoblastoma gene. Oncogene 13:1065–1072

    CAS  PubMed  Google Scholar 

  47. Smith JS, Tachibana I, Passe SM, Huntley BK, Borell TJ, Iturria N, O’Fallon JR, Schaefer PL, Scheithauer BW, James CD, Buckner JC, Jenkins RB (2001) PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst 93:1246–1256

    Article  CAS  PubMed  Google Scholar 

  48. Bigner SH, Vogelstein B (1990) Cytogenetics and molecular genetics of malignant gliomas and medulloblastoma. Brain Pathol 1:12–18

    CAS  PubMed  Google Scholar 

  49. Riemenschneider MJ, Buschges R, Wolter M, Reifenberger J, Bostrom J, Kraus JA, Schlegel U, Reifenberger G (1999) Amplification and overexpression of the MDM 4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM 2 amplification. Cancer Res 59:6091–6096

    CAS  PubMed  Google Scholar 

  50. Kleihues P, Burger PC, Collins VP, Newcomb EW, Ohgaki H, Cavenee WK (2000) Glioblastoma. In: Kleihues P, Cavenee WK (eds) Pathology and genetics of tumors of the nervous system. WHO classification of tumors. Lyon, IARC, pp 29–39

  51. Nakamura M, Yonekawa Y, Kleihues P, Ohgaki H (2001) Promoter hypermethylation of the RB1 gene in glioblastomas. Lab Invest 81:77–82

    CAS  PubMed  Google Scholar 

  52. Nakamura M, Yang F, Fujisawa H, Yonekawa Y, Kleihues P, Ohgaki H (2000) Loss of heterozygosity on chromosome 19 in secondary glioblastomas. J Neuropathol Exp Neurol 59:539–543

    CAS  PubMed  Google Scholar 

  53. Fujisawa H, Reis RM, Nakamura M, Colella S, Yonekawa Y, Kleihues P, Ohgaki H (2000) Loss of heterozygosity on chromosome 10 is more extensive in primary (de novo) than in secondary glioblastomas. Lab Invest 80:65–72

    CAS  PubMed  Google Scholar 

  54. Meyer-Puttlitz B, Hayashi Y, Waha A, Rollbrocker B, Bostrom J, Wiestler OD, Louis DN, Reifenberger G, von Deimling A (1997) Molecular genetic analysis of giant cell glioblastomas. Am J Pathol 151:853–857

    CAS  PubMed  Google Scholar 

  55. Peraud A, Watanabe K, Schwechheimer K, Yonekawa Y, Kleihues P, Ohgaki H (1999) Genetic profile of the giant cell glioblastoma. Lab Invest 79:123–129

    CAS  PubMed  Google Scholar 

  56. Reis RM, Konu-Lebleblicioglu D, Lopes JM, Kleihues P, Ohgaki H (2000) Genetic profile of gliosarcomas. Am J Pathol 156:425–432

    CAS  PubMed  Google Scholar 

  57. Actor B, Cobbers JM, Buschges R, Wolter M, Knobbe CB, Reifenberger G, Weber RG (2002) Comprehensive analysis of genomic alterations in gliosarcoma and its two tissue components. Genes Chromosomes Cancer 34:416–427

    Article  CAS  PubMed  Google Scholar 

  58. Sanoudou D, Tingby O, Ferguson-Smith MA, Collins VP, Coleman N (2000) Analysis of pilocytic astrocytoma by comparative genomic hybridization. Br J Cancer 82:1218–1222

    Article  CAS  PubMed  Google Scholar 

  59. Kluwe L, Hagel C, Tatagiba M, Thomas S, Stavrou D, Ostertag H, von Deimling A, Mautner VF (2001) Loss of NF1 alleles distinguish sporadic from NF1-associated pilocytic astrocytomas. J Neuropathol Exp Neurol 60:917–620

    CAS  PubMed  Google Scholar 

  60. Wimmer K, Eckart M, Meyer-Puttlitz B, Fonatsch C, Pietsch T (2002) Mutational and expression analysis of the NF1 gene argues against a role as tumor suppressor in sporadic pilocytic astrocytomas. J Neuropathol Exp Neurol 61:896–902

    CAS  PubMed  Google Scholar 

  61. Ohgaki H, Eibl RH, Schwab M, Reichel MB, Mariani L, Gehring M, Petersen I, Holl T, Wiestler OD, Kleihues P (1993) Mutations of the p53 tumor suppressor gene in neoplasms of the human nervous system. Mol Carcinog 8:74–80

    CAS  PubMed  Google Scholar 

  62. Lang FF, Miller DC, Pisharody S, Koslow M, Newcomb EW (1994) High frequency of p53 protein accumulation without p53 gene mutation in human juvenile pilocytic, low grade and anaplastic astrocytomas. Oncogene 9:949–954

    CAS  PubMed  Google Scholar 

  63. Hayes VM, Dirven CM, Dam A, Verlind E, Molenaar WM, Mooij JJ, Hofstra RM, Buys CH (1999) High frequency of TP53 mutations in juvenile pilocytic astrocytomas indicates role of TP53 in the development of these tumors. Brain Pathol 9:463–467

    CAS  PubMed  Google Scholar 

  64. Giannini C, Hebrink D, Scheithauer BW, Dei Tos AP, James CD (2001) Analysis of p53 mutation and expression in pleomorphic xanthoastrocytoma. Neurogenetics 3:159–162

    Article  CAS  PubMed  Google Scholar 

  65. Kaulich K, Blaschke B, Numann A, von Deimling A, Wiestler OD, Weber RG, Reifenberger G (2002) Genetic alterations commonly found in diffusely infiltrating cerebral gliomas are rare or absent in pleomorphic xanthoastrocytomas. J Neuropathol Exp Neurol 61:1092–1099

    CAS  PubMed  Google Scholar 

  66. Feinberg AP, Tycko B (2004) The history of cancer epigenetics. Nat Rev Cancer 4:143–153

    Article  CAS  PubMed  Google Scholar 

  67. Gonzalez-Gomez P, Bello MJ, Arjona D, Lomas J, Alonso ME, De Campos JM, Vaquero J, Isla A, Gutierrez M, Rey JA (2003) Promoter hypermethylation of multiple genes in astrocytic gliomas. Int J Oncol 22:601–608

    CAS  PubMed  Google Scholar 

  68. Watanabe T, Hirota Y, Arakawa Y, Fujisawa H, Tachibana O, Hasegawa M, Yamashita J, Hayashi Y (2003) Frequent LOH at chromosome 12q22–23 and Apaf-1 inactivation in glioblastoma. Brain Pathol 13:431–439

    CAS  PubMed  Google Scholar 

  69. Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343:1350–1354

    Article  CAS  PubMed  Google Scholar 

  70. Horiguchi K, Tomizawa Y, Tosaka M, Ishiuchi S, Kurihara H, Mori M, Saito N (2003) Epigenetic inactivation of RASSF1A candidate tumor suppressor gene at 3p21.3 in brain tumors. Oncogene 22:7862–7865

    Article  CAS  PubMed  Google Scholar 

  71. Hesson L, Bieche I, Krex D, Criniere E, Hoang-Xuan K, Maher ER, Latif F (2004) Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas. Oncogene 23:2408–2419

    Article  CAS  PubMed  Google Scholar 

  72. Konduri SD, Srivenugopal KS, Yanamandra N, Dinh DH, Olivero WC, Gujrati M, Foster DC, Kisiel W, Ali-Osman F, Kondraganti S, Lakka SS, Rao JS (2003) Promoter methylation and silencing of the tissue factor pathway inhibitor-2 (TFPI-2), a gene encoding an inhibitor of matrix metalloproteinases in human glioma cells. Oncogene 22:4509–4516

    Article  CAS  PubMed  Google Scholar 

  73. Dallol A, Krex D, Hesson L, Eng C, Maher ER, Latif F (2003) Frequent epigenetic inactivation of the SLIT2 gene in gliomas. Oncogene 22:4611–4616

    Article  CAS  PubMed  Google Scholar 

  74. Knobbe CB, Reifenberger J, Blaschke B, Reifenberger G (2004) Hypermethylation and transcriptional downregulation of the carboxyl-terminal modulator protein gene in glioblastomas. J Natl Cancer Inst 96:483–486

    Article  CAS  PubMed  Google Scholar 

  75. Costello JF (2003) DNA methylation in brain development and gliomagenesis. Front Biosci 8:s175–s184

    CAS  PubMed  Google Scholar 

  76. Reifenberger G, Louis DN (2003) Oligodendroglioma: toward molecular definitions in diagnostic neuro-oncology. J Neuropathol Exp Neurol 62:111–126

    CAS  PubMed  Google Scholar 

  77. 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 

  78. Ribom D, Andrae J, Frielingsdorf M, Hartman M, Nister M, Smits A (2002) Prognostic value of platelet derived growth factor alpha receptor expression in grade 2 astrocytomas and oligoastrocytomas. J Neurol Neurosurg Psychiatry 72:782–787

    Article  CAS  PubMed  Google Scholar 

  79. Hilton DA, Penney M, Evans B, Sanders H, Love S (2002) Evaluation of molecular markers in low-grade diffuse astrocytomas: loss of p16 and retinoblastoma protein expression is associated with short survival. Am J Surg Pathol 26:472–478

    Article  PubMed  Google Scholar 

  80. Kunwar S, Mohapatra G, Bollen A, Lamborn KR, Prados M, Feuerstein BG (2001) Genetic subgroups of anaplastic astrocytomas correlate with patient age and survival. Cancer Res 61:7683–7688

    CAS  PubMed  Google Scholar 

  81. Huncharek M, Kupelnick B (2000) Epidermal growth factor receptor gene amplification as a prognostic marker in glioblastoma multiforme: results of a meta-analysis. Oncol Res 12:107–112

    CAS  PubMed  Google Scholar 

  82. Schmidt MC, Antweiler S, Urban N, Mueller W, Kuklik A, Meyer-Puttlitz B, Wiestler OD, Louis DN, Fimmers R, von Deimling A (2002) Impact of genotype and morphology on the prognosis of glioblastoma. J Neuropathol Exp Neurol 61:321–328

    CAS  PubMed  Google Scholar 

  83. Galanis E, Buckner J, Kimmel D, Jenkins R, Alderete B, O’Fallon J, Wang CH, Scheithauer BW, James CD (1998) Gene amplification as a prognostic factor in primary and secondary high-grade malignant gliomas. Int J Oncol 13:717–724

    CAS  PubMed  Google Scholar 

  84. James CD, Galanis E, Frederick L, Kimmel DW, Cunningham JM, Atherton-Skaff PJ, O’Fallon JR, Jenkins RB, Buckner JC, Hunter SB, Olson JJ, Scheithauer BW (1999) Tumor suppressor gene alterations in malignant gliomas: histopathological associations and prognostic evaluation. Int J Oncol 15:547–553

    CAS  PubMed  Google Scholar 

  85. Kraus JA, Glesmann N, Beck M, Krex D, Klockgether T, Schackert G, Schlegel U (2000) Molecular analysis of the PTEN, TP53 and CDKN2A tumor suppressor genes in long-term survivors of glioblastoma multiforme. J Neurooncol 48:89–94

    Article  CAS  PubMed  Google Scholar 

  86. Newcomb EW, Cohen H, Lee SR, Bhalla SK, Bloom J, Hayes RL, Miller DC (1998) Survival of patients with glioblastoma multiforme is not influenced by altered expression of p16, p53, EGFR, MDM 2 or Bcl-2 genes. Brain Pathol 8:655–667

    CAS  PubMed  Google Scholar 

  87. Simmons ML, Lamborn KR, Takahashi M, Chen P, Israel MA, Berger MS, Godfrey T, Nigro J, Prados M, Chang S, Barker FG 2nd, Aldape K (2001) Analysis of complex relationships between age, p53, epidermal growth factor receptor, and survival in glioblastoma patients. Cancer Res 61:1122–1128

    CAS  PubMed  Google Scholar 

  88. Zhou XP, Li YJ, Hoang-Xuan K, Laurent-Puig P, Mokhtari K, Longy M, Sanson M, Delattre JY, Thomas G, Hamelin R (1999) Mutational analysis of the PTEN gene in gliomas: molecular and pathological correlations. Int J Cancer 84:150–154

    Article  CAS  PubMed  Google Scholar 

  89. Sano T, Lin H, Chen X, Langford LA, Koul D, Bondy ML, Hess KR, Myers JN, Hong YK, Yung WK, Steck PA (1999) Differential expression of MMAC/PTEN in glioblastoma multiforme: relationship to localization and prognosis. Cancer Res 59:1820–1824

    CAS  PubMed  Google Scholar 

  90. Backlund LM, Nilsson BR, Goike HM, Schmidt EE, Liu L, Ichimura K, Collins VP (2003) Short postoperative survival for glioblastoma patients with a dysfunctional Rb1 pathway in combination with no wild-type PTEN. Clin Cancer Res 9:4151–4158

    PubMed  Google Scholar 

  91. Gerson SL (2004) MGMT: its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer 4:296–307

    Article  CAS  PubMed  Google Scholar 

  92. Hegi ME, Diserens AC, Godard S, Dietrich PY, Regli L, Ostermann S, Otten P, Van Melle G, de Tribolet N, Stupp R (2004) Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 10:1871–1874

    CAS  PubMed  Google Scholar 

  93. Balana C, Ramirez JL, Taron M, Roussos Y, Ariza A, Ballester R, Sarries C, Mendez P, Sanchez JJ, Rosell R (2003) O6-methyl-guanine-DNA methyltransferase methylation in serum and tumor DNA predicts response to 1:3-bis (2-chloroethyl)-1-nitrosourea but not to temozolamide plus cisplatin in glioblastoma multiforme. Clin Cancer Res 9:1461–1468

    CAS  PubMed  Google Scholar 

  94. 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

    CAS  PubMed  Google Scholar 

  95. Nutt CL, Mani DR, Betensky RA, Tamayo P, Cairncross JG, Ladd C, Pohl U, Hartmann C, McLaughlin ME, Batchelor TT, Black PM, von Deimling A, Pomeroy SL, Golub TR, Louis DN (2003) Gene expression-based classification of malignant gliomas correlates better with survival than histological classification. Cancer Res 63:1602–1607

    CAS  PubMed  Google Scholar 

  96. Holland EC (2001) Gliomagenesis: genetic alterations and mouse models. Nat Rev Genet 2:120–129

    Article  CAS  PubMed  Google Scholar 

  97. Reilly KM, Jacks TG (2001) Genetically engineered mouse models of astrocytoma: GEMs in the rough? Semin Cancer Biol 11:177–179

    Article  CAS  PubMed  Google Scholar 

  98. Begemann M, Fuller GN, Holland EC (2002) Genetic modeling of glioma formation in mice. Brain Pathol 12:117–132

    CAS  PubMed  Google Scholar 

  99. Hesselager G, Holland EC (2003) Using mice to decipher the molecular genetics of brain tumors. Neurosurgery 53:685–694

    PubMed  Google Scholar 

  100. Gutmann DH, Baker SJ, Giovannini M, Garbow J, Weiss W (2003) Mouse models of human cancer consortium symposium on nervous system tumors. Cancer Res 63:3001–3004

    CAS  PubMed  Google Scholar 

  101. Weiss WA, Israel M, Cobbs C, Holland E, James CD, Louis DN, Marks C, McClatchey AI, Roberts T, Van Dyke T, Wetmore C, Chiu IM, Giovannini M, Guha A, Higgins RJ, Marino S, Radovanovic I, Reilly K, Aldape K (2002) Neuropathology of genetically engineered mice: consensus report and recommendations from an international forum. Oncogene 21:7453–7463

    Article  CAS  PubMed  Google Scholar 

  102. Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN (2000) Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25:55–57

    Article  CAS  PubMed  Google Scholar 

  103. Bachoo RM, Maher EA, Ligon KL, Sharpless NE, Chan SS, You MJ, Tang Y, DeFrances J, Stover E, Weissleder R, Rowitch DH, Louis DN, DePinho RA (2002) Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 1:269–277

    Article  CAS  PubMed  Google Scholar 

  104. Uhrbom L, Dai C, Celestino JC, Rosenblum MK, Fuller GN, Holland EC (2002) Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. Cancer Res 62:5551–5558

    CAS  PubMed  Google Scholar 

  105. Xiao A, Wu H, Pandolfi PP, Louis DN, Van Dyke T (2002) Astrocyte inactivation of the pRb pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN mutation. Cancer Cell 1:157–168

    Article  CAS  PubMed  Google Scholar 

  106. Rajasekhar VK, Viale A, Socci ND, Wiedmann M, Hu X, Holland EC (2003) Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Mol Cell 12:889–901

    Article  CAS  PubMed  Google Scholar 

  107. Gutmann DH, Huang ZY, Hedrick NM, Ding H, Guha A, Watson MA (2002) Mouse glioma gene expression profiling identifies novel human glioma-associated genes. Ann Neurol 51:393–405

    Article  CAS  PubMed  Google Scholar 

  108. Koutcher JA, Hu X, Xu S, Gade TP, Leeds N, Zhou XJ, Zagzag D, Holland EC (2002) MRI of mouse models for gliomas shows similarities to humans and can be used to identify mice for preclinical trials. Neoplasia 4:480–485

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neuropathology, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany

    Guido Reifenberger

  2. Department of Pathology, Division of Molecular Histopathology, Addenbrooke’s Hospital, University of Cambridge, Hills Road, Box 235, Cambridge, CB2 2QQ, UK

    Vincent Peter Collins

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  1. Guido Reifenberger
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  2. Vincent Peter Collins
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Correspondence to Vincent Peter Collins.

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Reifenberger, G., Collins, V.P. Pathology and molecular genetics of astrocytic gliomas. J Mol Med 82, 656–670 (2004). https://doi.org/10.1007/s00109-004-0564-x

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  • DOI: https://doi.org/10.1007/s00109-004-0564-x

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