Skip to main content
PMC home page
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;13(4):598–607. doi: 10.1111/j.1750-3639.2003.tb00488.x

Independent Molecular Development of Metachronous Glioblastomas with Extended Intervening Recurrence‐free Interval

Ramon Martinez 1,✉, Hans‐K Schackert 2, Stephanie von Kannen 1, Peter Lichter 3, Stefan Joos 3, Gabriele Schackert 1
PMCID: PMC8095935  PMID: 14655763

Abstract

Two metachronous glioblastomas with different cerebral locations in a 53‐year‐old long‐term survival patient were analyzed by multiple genetic approaches. Using comparative genomic hybridization a different pattern of chromosomal aberrations was observed, with 19 imbalances in the first tumor and only 2 imbalances in the second. Sequence analysis revealed a distinct mutation profile in each tumor, with amino acid substitutions in the p53 and PTEN genes only in the first tumor, ie, p53 in codon 273 (CGT→TGT, Arg→Cys) and PTEN in codon 336 (TAC→TTC, Tyr→Phe). A splicing acceptor site PTEN mutation (IVS8‐2A>G) was observed only in the second GBM. EGFR amplification, mutations of p16 INK4a/CDKN2A or p14 ARF were not observed. According to the results of p53 mutational analysis and EGFR amplification studies, the first tumor is classified as a type 1 GBM, whereas the alterations in the second one are different from those typically encountered in type 1 or type 2 tumors. In conclusion, our data strongly suggest that the metachronous tumors in this patient are exceptional in that they developed independently from each other. Whether the molecular features of the first glioblastoma are associated with the notably extended recurrence‐free period of 5 years remains to be elucidated.

Full Text

The Full Text of this article is available as a PDF (977.6 KB).

References

  • 1. Bigner SH, Schröck E (1997) Molecular cytogenetics of brain tumors. J Neuropathol Exp Neurol 56:1173–1181. [DOI] [PubMed] [Google Scholar]
  • 2. Boland R, Thibodeau S, Hamilton S, Sidransky D, Eshleman J, Rodriguez‐Bigas M, Fodde R, Ranzani GN, Srivastava S (1998) A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination for microsatellite instability in colorectal cancer. Cancer Res 58:5248–5257. [PubMed] [Google Scholar]
  • 3. Bonneau D, Longy M (2000) Mutations of the human PTEN gene. Human Mutat 16:109–122. [DOI] [PubMed] [Google Scholar]
  • 4. Burton EC, Lamborn KR, Forsyth P, Scott J, O'Campo J, Uyehara‐Lock J, Prados M, Berger M, Passe S, Uhm J, O'Neill B, Jenkins RB, Aldape KD (2002) Aberrant p53, mdm2 and proliferation differ in glioblastomas from longterm compared with typical survivors. Clin Cancer Res 8:180–187. [PubMed] [Google Scholar]
  • 5. Cawkwell L, Lewis FA, Quirke P (1994) Frequency of allele loss of DCC, p53, RB1, WT1, NF1, NM23 and APC/MCC in colorectal cancer assayed by fluorescent multiplex polymerase chain reaction. Br J Cancer 70:813–818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. Cho Y, Gorina S, Jeffrey P Pavletich NP (1994) Crystal structure of a p53 tumor suppressor DNA complex: a framework for understanding how mutations inactivate p53. Science 265:346–355. [DOI] [PubMed] [Google Scholar]
  • 7. Collins VP (1998) Gliomas. Cancer Survey 32:37–51. [PubMed] [Google Scholar]
  • 8. Dietmaier W, Wallinger S, Bocker T, Kullman F, Fishel R and Ruschoff J (1997) Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res 57:4749–4756. [PubMed] [Google Scholar]
  • 9. Du Manoir S, Schröck E, Bentz M, Speicher MR, Joos S, Ried T, Lichter P, Cremer T (1995) Quantitative analysis of comparative genomic hybridization. Cytometry 19:27–41. [DOI] [PubMed] [Google Scholar]
  • 10. Duerr EM, Rollbrocker B, Hayashi Y, Peters N, Meyer‐Puttlitz B, Louis DN, Schramm J, Wiestler OD, Parsons R, Eng C, von Deimling A (1998) PTEN mutations in gliomas and glioneuronal tumors. Oncogene 16:2259–2264. [DOI] [PubMed] [Google Scholar]
  • 11. Fujisawa H, Kurrer M, Reis RM, Yonekawa Y, Kleihues P, Ohgaki H (1999) Acquisition of the glioblastoma phenotype during astrocytoma progression is associated with loss of heterozygosity on 10q25‐qter. Am J Pathol 155:387–394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Greenblatt MS, Bennett M, Hollstein M, Harris CC (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54:4855–4878. [PubMed] [Google Scholar]
  • 13. Hahn M, Wieland I, Koufaki ON, Görgens H, Sobottka SB, Schackert G, Schackert HK (1999) Genetic alterations of the tumor suppressor gene PTEN/MMAC1 in human brain metastases. Clin Cancer Res 5:2431–2437. [PubMed] [Google Scholar]
  • 14. Hainaut P, Soussi T, Shomer B, Hollstein M, Greenblatt M, Hovig E, Harris CC, Montesano R (1997) Database of p53 gene somatic mutations in human tumors and cell lines: updated compilation and future prospects. Nucleic Acids Res 25:151–157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. Hayashi Y, Ueki K, Waha A, Wiestler OD, Louis DN, von Deimling A (1997) Association of gene amplification and CDKN2A(p16/MTS1) gene deletion in glioblastoma multiforme. Brain Pathol 7:871–875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Joos S, Bergerheim USR, Pan Y, Matsuyama H, Bentz M, du Manoir S, Lichter P (1995) Mapping of chromosomal gains and losses in prostate cancer by comparative genomic hybridization. Genes Chromosomes Cancer 14:267–276. [DOI] [PubMed] [Google Scholar]
  • 17. Joos S, Otaño‐Joos MI, Ziegler S, Brüderlein S, du Manoir S, Bentz M, Möller P, Lichter P (1996) Primary mediastinal (thymic) B‐cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene. Blood 87:1571–1578. [PubMed] [Google Scholar]
  • 18. Kleihues P, Ohgaki H (1999) Primary and secondary glioblastomas: from concept to clinical diagnosis. Neurooncol 1:44–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. 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 101:311–320. [DOI] [PubMed] [Google Scholar]
  • 20. Lacroix M, Abi‐Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, Lang FF, McCutcheon IE, Hassenbusch SJ, Holland E, Hess K, Michael C, Miller D, Sawaya R (2001) A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection and survival. J Neurosurg 95:190–198. [DOI] [PubMed] [Google Scholar]
  • 21. Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C, Parsons R (1997) Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 16:64–67. [DOI] [PubMed] [Google Scholar]
  • 22. Louis DN (1997) A molecular genetic model of astrocytoma histopathology. Brain Pathol 7:755–764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Morse RP, Darras BT, Ye Z, Wu JK (1994) Clonal analysis of human astrocytomas. J Neurooncol 21:151–157. [DOI] [PubMed] [Google Scholar]
  • 24. Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, Bigner SH, Davidson N, Baylin S, Devilee P, Glover T, Collins FS, Weston A, Modali R, Harris CC, Vogelstein B (1989) Mutations in the p53 gene occur in diverse human tumor types. Nature 342:705–708. [DOI] [PubMed] [Google Scholar]
  • 25. Plaschke J, Kruger S, Pistorius S, Theissig F, Saeger HD, Schackert HK (2002) Involvement of hMSH6 in the development of hereditary and sporadic colorectal cancer revealed by immunostaining is based on germline mutations, but rarely on somatic inactivation. Int J Cancer 97:643–648. [DOI] [PubMed] [Google Scholar]
  • 26. Reis RM, Herva R, Brandner S, Koivukangas J, Mironov N, Bär W, Kleihues P, Ohgaki H (2001) Second primary glioblastoma. J Neuropathol Exp Neurol 60:208–215. [DOI] [PubMed] [Google Scholar]
  • 27. Rollbrocker B, Waha A, Louis DN, Wiestler OD, von Deimling A (1996) Amplification of the cyclin dependent kinase 4 (CDK4) gene is associated with high cdk4 protein levels in glioblastoma multiforme. Acta Neuropathol 92:70–74. [DOI] [PubMed] [Google Scholar]
  • 28. Saxena A, Shriml L, Dean M, Ali IU (1999) Comparative molecular genetic profiles of anaplastic astrocytomas/glioblastomas multiforme and their subsequent recurrences. Oncogene 18:1385–1390. [DOI] [PubMed] [Google Scholar]
  • 29. Scott JN, Rewcastle NB, Brasher PMA, Fulton D, Hagen NA, MacKinnon JA, Hamilton M, Cairncross JC, Forsyth P (1999) Which glioblastoma multiforme patient will become a long‐term survivor? A population based study. Ann Neurol 46:183–188. [PubMed] [Google Scholar]
  • 30. Smith JS, Perry A, Borell TJ, Lee HK, O'Fallon J, Hosek SM, Kimmel D, Yates A, Burger PC, Scheithauer BW, Jenkins RB (2000) Alterations of chromosome arms 1 p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. J Clin Oncol 18:636–645. [DOI] [PubMed] [Google Scholar]
  • 31. Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV (1997) Identification of a candidate tumor suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advances cancers. Nat Genet 15:356–362. [DOI] [PubMed] [Google Scholar]
  • 32. Tada M, Sawamura Y, Abe H, Iggo R (1997) Homozygous p53 gene mutation in a radiation‐induced glioblastoma 10 years after treatment for an intracranial germ‐cell tumor: case report. Neurosurgery 40:393–396. [DOI] [PubMed] [Google Scholar]
  • 33. Von Deimling A, Louis DN, Wiestler OD (1995) Molecular pathways in the formation of gliomas. Glia 15:328–338. [DOI] [PubMed] [Google Scholar]
  • 34. Von Deimling A, von Ammon K, Schoenfeld D, Wiestler OD, Seizinger BR, Louis DN (1993) Subsets of glioblastoma multiforme defined by molecular genetic analysis. Brain Pathol 3:19–26. [DOI] [PubMed] [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES