Skip to main content
NCBI home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1997 Sep;151(3):853–857.

Molecular genetic analysis of giant cell glioblastomas.

B Meyer-Puttlitz 1, Y Hayashi 1, A Waha 1, B Rollbrocker 1, J Boström 1, O D Wiestler 1, D N Louis 1, G Reifenberger 1, A von Deimling 1
PMCID: PMC1857850  PMID: 9284834

Abstract

Glioblastomas (GBMs) are a heterogeneous group of tumors. Recently, distinct molecular genetic alterations have been linked to subgroups of patients with GBM. Giant cell (gc)GBMs are a rare variant of GBM characterized by a marked preponderance of multinucleated giant cells. Several reports have associated this entity with a more favorable prognosis than the majority of GBMs. To evaluate whether gcGBM may also represent a genetically defined subgroup of GBM, we analyzed a series of 19 gcGBMs for mutations in the TP53 gene for amplification of the EGFR and CDK4 genes and for homozygous deletions in the CDKN2A (p16/MTS1) gene. Seventeen of nineteen gcGBMs carried TP53 mutations whereas EGFR and CDK4 gene amplification was seen in only one tumor each and homozygous deletion of CDKN2A was not observed at all. The strikingly high incidence of TP53 mutations and the relative absence of other genetic alterations groups gcGBM together with a previously recognized molecular genetic variant of GBM (type 1 GBM). It is tempting to speculate that the better prognosis of gcGBM patients may result from the low incidence of EGFR amplification and CDKN2A deletion, changes known for their growth-promoting potential.

Full text

PDF
853

Images in this article

855Figure 1
on p.855

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Brooks W. H., Markesbery W. R., Gupta G. D., Roszman T. L. Relationship of lymphocyte invasion and survival of brain tumor patients. Ann Neurol. 1978 Sep;4(3):219–224. doi: 10.1002/ana.410040305. [DOI] [PubMed] [Google Scholar]
  2. Burger P. C., Green S. B. Patient age, histologic features, and length of survival in patients with glioblastoma multiforme. Cancer. 1987 May 1;59(9):1617–1625. doi: 10.1002/1097-0142(19870501)59:9<1617::aid-cncr2820590916>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  3. Burger P. C., Vollmer R. T. Histologic factors of prognostic significance in the glioblastoma multiforme. Cancer. 1980 Sep 1;46(5):1179–1186. doi: 10.1002/1097-0142(19800901)46:5<1179::aid-cncr2820460517>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
  4. Bögler O., Huang H. J., Kleihues P., Cavenee W. K. The p53 gene and its role in human brain tumors. Glia. 1995 Nov;15(3):308–327. doi: 10.1002/glia.440150311. [DOI] [PubMed] [Google Scholar]
  5. Fukasawa K., Choi T., Kuriyama R., Rulong S., Vande Woude G. F. Abnormal centrosome amplification in the absence of p53. Science. 1996 Mar 22;271(5256):1744–1747. doi: 10.1126/science.271.5256.1744. [DOI] [PubMed] [Google Scholar]
  6. Fults D., Brockmeyer D., Tullous M. W., Pedone C. A., Cawthon R. M. p53 mutation and loss of heterozygosity on chromosomes 17 and 10 during human astrocytoma progression. Cancer Res. 1992 Feb 1;52(3):674–679. [PubMed] [Google Scholar]
  7. Giangaspero F., Doglioni C., Rivano M. T., Pileri S., Gerdes J., Stein H. Growth fraction in human brain tumors defined by the monoclonal antibody Ki-67. Acta Neuropathol. 1987;74(2):179–182. doi: 10.1007/BF00692849. [DOI] [PubMed] [Google Scholar]
  8. Giani C., Finocchiaro G. Mutation rate of the CDKN2 gene in malignant gliomas. Cancer Res. 1994 Dec 15;54(24):6338–6339. [PubMed] [Google Scholar]
  9. Hayashi Y., Ueki K., Waha A., Wiestler O. D., Louis D. N., von Deimling A. Association of EGFR gene amplification and CDKN2 (p16/MTS1) gene deletion in glioblastoma multiforme. Brain Pathol. 1997 Jul;7(3):871–875. doi: 10.1111/j.1750-3639.1997.tb00890.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Henson J. W., Schnitker B. L., Correa K. M., von Deimling A., Fassbender F., Xu H. J., Benedict W. F., Yandell D. W., Louis D. N. The retinoblastoma gene is involved in malignant progression of astrocytomas. Ann Neurol. 1994 Nov;36(5):714–721. doi: 10.1002/ana.410360505. [DOI] [PubMed] [Google Scholar]
  11. Jen J., Harper J. W., Bigner S. H., Bigner D. D., Papadopoulos N., Markowitz S., Willson J. K., Kinzler K. W., Vogelstein B. Deletion of p16 and p15 genes in brain tumors. Cancer Res. 1994 Dec 15;54(24):6353–6358. [PubMed] [Google Scholar]
  12. Levine A. J. p53, the cellular gatekeeper for growth and division. Cell. 1997 Feb 7;88(3):323–331. doi: 10.1016/s0092-8674(00)81871-1. [DOI] [PubMed] [Google Scholar]
  13. Louis D. N., Gusella J. F. A tiger behind many doors: multiple genetic pathways to malignant glioma. Trends Genet. 1995 Oct;11(10):412–415. doi: 10.1016/s0168-9525(00)89125-8. [DOI] [PubMed] [Google Scholar]
  14. Louis D. N., Rubio M. P., Correa K. M., Gusella J. F., von Deimling A. Molecular genetics of pediatric brain stem gliomas. Application of PCR techniques to small and archival brain tumor specimens. J Neuropathol Exp Neurol. 1993 Sep;52(5):507–515. doi: 10.1097/00005072-199309000-00009. [DOI] [PubMed] [Google Scholar]
  15. Louis D. N. The p53 gene and protein in human brain tumors. J Neuropathol Exp Neurol. 1994 Jan;53(1):11–21. doi: 10.1097/00005072-199401000-00002. [DOI] [PubMed] [Google Scholar]
  16. Minn A. J., Boise L. H., Thompson C. B. Expression of Bcl-xL and loss of p53 can cooperate to overcome a cell cycle checkpoint induced by mitotic spindle damage. Genes Dev. 1996 Oct 15;10(20):2621–2631. doi: 10.1101/gad.10.20.2621. [DOI] [PubMed] [Google Scholar]
  17. Müller W., Slowik F., Firsching R., Afra D., Sanker P. Contribution to the problem of giant cell astrocytomas. Neurosurg Rev. 1987;10(3):213–219. doi: 10.1007/BF01782050. [DOI] [PubMed] [Google Scholar]
  18. Nagane M., Coufal F., Lin H., Bögler O., Cavenee W. K., Huang H. J. A common mutant epidermal growth factor receptor confers enhanced tumorigenicity on human glioblastoma cells by increasing proliferation and reducing apoptosis. Cancer Res. 1996 Nov 1;56(21):5079–5086. [PubMed] [Google Scholar]
  19. Oda H., Zhang S., Tsurutani N., Shimizu S., Nakatsuru Y., Aizawa S., Ishikawa T. Loss of p53 is an early event in induction of brain tumors in mice by transplacental carcinogen exposure. Cancer Res. 1997 Feb 15;57(4):646–650. [PubMed] [Google Scholar]
  20. Ono Y., Tamiya T., Ichikawa T., Kunishio K., Matsumoto K., Furuta T., Ohmoto T., Ueki K., Louis D. N. Malignant astrocytomas with homozygous CDKN2/p16 gene deletions have higher Ki-67 proliferation indices. J Neuropathol Exp Neurol. 1996 Oct;55(10):1026–1031. [PubMed] [Google Scholar]
  21. Palma L., Celli P., Maleci A., Di Lorenzo N., Cantore G. Malignant monstrocellular brain tumours. A study of 42 surgically treated cases. Acta Neurochir (Wien) 1989;97(1-2):17–25. doi: 10.1007/BF01577735. [DOI] [PubMed] [Google Scholar]
  22. Palma L., Di Lorenzo N., Guidetti B. Lymphocytic infiltrates in primary glioblastomas and recidivous gliomas. Incidence, fate, and relevance to prognosis in 228 operated cases. J Neurosurg. 1978 Dec;49(6):854–861. doi: 10.3171/jns.1978.49.6.0854. [DOI] [PubMed] [Google Scholar]
  23. Reifenberger G., Liu L., Ichimura K., Schmidt E. E., Collins V. P. Amplification and overexpression of the MDM2 gene in a subset of human malignant gliomas without p53 mutations. Cancer Res. 1993 Jun 15;53(12):2736–2739. [PubMed] [Google Scholar]
  24. Reifenberger G., Reifenberger J., Ichimura K., Meltzer P. S., Collins V. P. 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 MDM2. Cancer Res. 1994 Aug 15;54(16):4299–4303. [PubMed] [Google Scholar]
  25. Reifenberger J., Ring G. U., Gies U., Cobbers L., Oberstrass J., An H. X., Niederacher D., Wechsler W., Reifenberger G. Analysis of p53 mutation and epidermal growth factor receptor amplification in recurrent gliomas with malignant progression. J Neuropathol Exp Neurol. 1996 Jul;55(7):822–831. doi: 10.1097/00005072-199607000-00007. [DOI] [PubMed] [Google Scholar]
  26. Rollbrocker B., Waha A., Louis D. N., Wiestler O. D., von Deimling A. Amplification of the cyclin-dependent kinase 4 (CDK4) gene is associated with high cdk4 protein levels in glioblastoma multiforme. Acta Neuropathol. 1996 Jul;92(1):70–74. doi: 10.1007/s004010050491. [DOI] [PubMed] [Google Scholar]
  27. Safdari H., Hochberg F. H., Richardson E. P., Jr Histological correlations with survival in malignant gliomas. Acta Neurochir Suppl (Wien) 1979;28(2):485–488. [PubMed] [Google Scholar]
  28. Ueki K., Ono Y., Henson J. W., Efird J. T., von Deimling A., Louis D. N. CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer Res. 1996 Jan 1;56(1):150–153. [PubMed] [Google Scholar]
  29. Waha A., Rollbrocker B., Wiestler O. D., von Deimling A. A polymerase chain reaction-based assay for the rapid detection of gene amplification in human tumors. Diagn Mol Pathol. 1996 Jun;5(2):147–150. doi: 10.1097/00019606-199606000-00010. [DOI] [PubMed] [Google Scholar]
  30. Watanabe K., Tachibana O., Sata K., Yonekawa Y., Kleihues P., Ohgaki H. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol. 1996 Jul;6(3):217–24. doi: 10.1111/j.1750-3639.1996.tb00848.x. [DOI] [PubMed] [Google Scholar]
  31. Wellenreuther R., Kraus J. A., Lenartz D., Menon A. G., Schramm J., Louis D. N., Ramesh V., Gusella J. F., Wiestler O. D., von Deimling A. Analysis of the neurofibromatosis 2 gene reveals molecular variants of meningioma. Am J Pathol. 1995 Apr;146(4):827–832. [PMC free article] [PubMed] [Google Scholar]
  32. Winger M. J., Macdonald D. R., Cairncross J. G. Supratentorial anaplastic gliomas in adults. The prognostic importance of extent of resection and prior low-grade glioma. J Neurosurg. 1989 Oct;71(4):487–493. doi: 10.3171/jns.1989.71.4.0487. [DOI] [PubMed] [Google Scholar]
  33. van Meyel D. J., Ramsay D. A., Casson A. G., Keeney M., Chambers A. F., Cairncross J. G. p53 mutation, expression, and DNA ploidy in evolving gliomas: evidence for two pathways of progression. J Natl Cancer Inst. 1994 Jul 6;86(13):1011–1017. doi: 10.1093/jnci/86.13.1011. [DOI] [PubMed] [Google Scholar]
  34. von Deimling A., Eibl R. H., Ohgaki H., Louis D. N., von Ammon K., Petersen I., Kleihues P., Chung R. Y., Wiestler O. D., Seizinger B. R. p53 mutations are associated with 17p allelic loss in grade II and grade III astrocytoma. Cancer Res. 1992 May 15;52(10):2987–2990. [PubMed] [Google Scholar]
  35. von Deimling A., von Ammon K., Schoenfeld D., Wiestler O. D., Seizinger B. R., Louis D. N. Subsets of glioblastoma multiforme defined by molecular genetic analysis. Brain Pathol. 1993 Jan;3(1):19–26. doi: 10.1111/j.1750-3639.1993.tb00721.x. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES