Skip to main content
SpringerLink
Log in

Low-level microsatellite instability phenotype in sporadic glioblastoma multiforme

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Genetic instability is a hallmark of glioblastoma multiforme (GBM). Microsatellite instability (MSI) is a significant event in the tumorigenesis of many sporadic malignancies. The aim of our investigation was to study microsatellite instability in newly diagnosed glioblastomas.

Methods

MSI was investigated in 109 GBMs with 15 microsatellite markers. Immunohistochemistry was performed for the mismatch repair (MMR) proteins hMLH1, hMSH2, hPMS2, and hMSH6 in cases showing MSI. Sequence and promoter methylation status of hMLH1 were analyzed in the case of a decreased hMLH1 protein expression as well. To further investigate MSI(+) GBMs we carried out studies of LOH at selected chromosome regions, EGFR amplification, and sequence of p53 and PTEN.

Results

MSI was observed in six GBMs (5.5%) and it was more frequent in GBMs with a previous lower grade astrocytoma (18.8% vs. 3.2%). MMR protein staining was positive in all MSI(+) GBMs except in one case, which showed an aberrant expression of hMLH1 and hPMS2 without hMLH1 inactivation. Among MSI(+) GBMs, one tumor corresponded to the GBM molecular type 1 (p53 mutation, no EGFR amplification), another tumor to type 2 (wild-type p53, EGFR amplification), and four tumors to neither type (wild-type p53, no EGFR amplification). None of the six tumors carried a PTEN mutation.

Conclusions

MSI in GBM might be caused by inactivation of minor MMR genes rather than by a deficiency of hMLH1 or hMSH2 and it appears not to play a decisive role in the pathogenesis of these tumors. MSI(+) GBMs predominantly showed a profile which included wild-type of p53 and PTEN and absence of EGFR amplification but MSI occurred in all GBM molecular subtypes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Alonso M, Hamelin R, Kim M, Porwancher K, Sung T, Parhar P, Miler DC, Newcomb EW (2001) Microsatellite instability occurs in distinct subtypes of pediatric but not adult central nervous system tumors. Cancer Res 61:2124–2128

    CAS  PubMed  Google Scholar 

  2. Boland R, Thibodeau S, Hamilton S, Sidransky D, Eshleman J, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S A (1998) 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

    CAS  PubMed  Google Scholar 

  3. 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

    CAS  PubMed  Google Scholar 

  4. Dams E, van der Kelft EJ, Martin JJ, Verlooy J, Willems PJ (1995) Instability of microsatellites in human gliomas. Cancer Res 55:1547–1549

    CAS  PubMed  Google Scholar 

  5. Dietmaier W, Wallinger S, Bocker T, Kullman F, Fishel R, Ruschoff J (1997) Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res 57:4749–4756

    CAS  PubMed  Google Scholar 

  6. Hui AB, Lo KW, Yin XL, Poon WS, Ng HK (2001) Detection of multiple gene amplifications in glioblastoma multiforme using array-based comparative genomic hybridization. Lab Invest 81:717–723

    CAS  PubMed  Google Scholar 

  7. Hunter SB, Abbott K, Varma VA, Olson JJ, Barnett DW, James D (1995) Reliability of differential PCR for the detection of EGFR and MDM 2 gene amplification in DNA extracted from FFPE glioma tissue. J Neuropathol Exp Neurol 54:57–64

    CAS  PubMed  Google Scholar 

  8. Ionov Y, Peinado A, Malkhosyan D, Shibata D, Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561

    Article  CAS  PubMed  Google Scholar 

  9. Jass JR (1999) Towards a molecular classification of colorectal cancer. Int J Colorectal Dis 14:194–200

    Article  CAS  PubMed  Google Scholar 

  10. Kane MF, Loda M, Gaida G, Lipman J, Mishra R, Goldman H, Jessup JM, Kolodner R (1997) Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 57:808–811

    CAS  PubMed  Google Scholar 

  11. Katabuchi H, van Rees B, Lambers AR, Ronnett BM, Blazes MS, Leach FS, Cho KR, Hedrick L (1995) Mutations in DNA mismatch repair genes are not responsible for microsatellite instability in most sporadic endometrial carcinomas. Cancer Res 55:5556–5560

    CAS  PubMed  Google Scholar 

  12. Kinzler KW, Vogelstein B (1997) Cancer susceptibility genes. Gatekeepers and caretakers. Nature 386:761–763

    Article  CAS  PubMed  Google Scholar 

  13. Kleihues P, Louis DN, Scheithauer BW, Rorke L, Reifenberger G, Burger PC Cavenee WK (2002) The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61:215–225

    Google Scholar 

  14. Kolodner RD, Hall NR, Lipford J, Kane MF, Morrison PT, Finan PJ, Burn J, Chapman P, Earabino C, Merchant E (1995) Structure of the human MLH1 locus and analysis of a large hereditary nonpolyposis colorectal carcinoma kindred for mlh1 mutations. Cancer Res 55:242–248

    CAS  PubMed  Google Scholar 

  15. Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, De Monte 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

    CAS  Google Scholar 

  16. Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacock 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

    Article  CAS  PubMed  Google Scholar 

  17. Louis DN (1997) A molecular genetic model of astrocytoma histopathology. Brain Pathol 7:755–764

    CAS  PubMed  Google Scholar 

  18. Marra G, Iaccarino I, Lettieri T, Roscilli G, Delmastro P, Jiricny J (1998) Mismatch repair deficiency associated with overexpression of the MSH3 gene. Proc Natl Acad Sci USA 95:8568–8573

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  20. Nicolaides NC, Littman SJ, Modrich P, Kinzler KW, Vogelstein B (1998) A naturally occurring hPMS2 mutation can confer a dominant negative mutator phenotype. Mol Cell Biol 18:1635–1641

    CAS  PubMed  Google Scholar 

  21. Parc YR, Halling HC, Wang L, Christensen ER, Cunningham JM, French AJ, Burgert LJ, Price-Troska TL, Roche PC, Thibodeau SN (2000) hMSH6 alterations in patients with microsatellite instability-low colorectal cancer. Cancer Res 60:2225–2231

    CAS  PubMed  Google Scholar 

  22. Peltomäki P, de la Chapelle A (1997) Mutations predisposing to hereditary nonpolyposis colorectal cancer. Adv Cancer Res 71:93–119

    CAS  PubMed  Google Scholar 

  23. 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

    Article  CAS  PubMed  Google Scholar 

  24. Reifenberger G, Liu L, Ichimur K, Schmidt KK, Collins VP (1993) Amplification and overexpression of the MDM 2 gene in a subset of human malignant gliomas without p53 mutations. Cancer Res 53:2736–2739

    CAS  PubMed  Google Scholar 

  25. Renault B, Calistri D, Buonsanti G, Nanni O, Amadosi D, Ranzani GN (1996) Microsatellite instability and mutations of p53 and TGF-ßRII genes in gastric cancers: Hum Genet 98:601–607

    Google Scholar 

  26. Smith JS, Tachibana I, Lee HK, Qian J, Pohl U, Mohrenweiser HW, Borell TJ, Hosek SM, Soderberg CL, von Deimling A, Perry A, Scheithauer BW, Louis DN, Jenkins RB (2001) Mapping of the chromosome 19 q-arm glioma tumor suppressor gene using fluorescence in situ hybridization and novell microsatellite markers. Genes Chromosomes Cancer 29:16–25

    Article  Google Scholar 

  27. Sobrido MJ, Rodriguez P, Barros F, Forteza J, Carracedo A, Lema M (2000) Low frequency of replication errors in primary nervous system tumors. J Neurol Neurosurg Psychiatry 69:369–375

    Google Scholar 

  28. 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

    Article  CAS  PubMed  Google Scholar 

  29. Strickler JG, Zheng J, Shu Q, Burgart LJ, Alberts SR, Shibata D (1994) p53 mutations and microsatellite instability in sporadic gastric cancer: when guardians fail. Cancer Res 54:4750–4755

    CAS  PubMed  Google Scholar 

  30. Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260:816–819

    CAS  PubMed  Google Scholar 

  31. Thibodeau SN, French AJ, Cunningham JM, Teter D, Burgart LJ, Roche PC, McDonnell SK, Schaid DJ, Vockley CW, Michels VV, Farr GH Jr, Connell MJ (1998) Microsatellite instability in colorectal cancers: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res 58:1713–1718

    CAS  PubMed  Google Scholar 

  32. 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

    PubMed  Google Scholar 

  33. Von Deimling A, Louis DN, Wiestler OD (1995) Molecular pathways in the formation of gliomas. Glia 15:328–338

    PubMed  Google Scholar 

  34. Wooster R, Cleton-Jansen AM, Collins VP, Mangion J, Cornelis RS, Cooper CS, von Deimling A, Wiestler OD, Stratton MR (1994) Instability of short tandem repeats (microsatellites) in human cancer. Nat Genet 6:152–156

    Article  CAS  PubMed  Google Scholar 

  35. Wu MS, Sheu JC, Shun CT, Lee WJ, Wang JT, Wang TH, Cheng AL, Lin JT (1997) Infrequent hMSH2 mutations in sporadic gastric adenocarcinoma with microsatellite instability. Cancer Lett 112:161–166

    Article  CAS  PubMed  Google Scholar 

  36. Zhu JJ, Guo SZ, Beggs AH, Muruyama, T, Santarius T, Dashner K, Olsen N, Wu J, Black PM (1996) Microsatellite instability analysis of primary human brain tumors. Oncogene 12:1417–1423

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank C. Voelter at ENT Department, University of Würzburg, Germany for helpful discussion, and L. Moser at ENT Department, University of Würzburg, Germany for assessment of statistical analyses. We also thank A. Serra for advice with the densitometry studies and M. Reichmann for technical assistance. The authors are indebted S. Scherneck at the Department of Surgery and Surgical Oncology, Robert-Roessle Clinic, Berlin, Germany for kindly providing the breast cancer cell line CAL51

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Klinikum Fulda, Academic Hospital University of Marburg, Pacelliallee 4, 36043, Fulda, Germany

    R. Martinez

  2. Department of Surgical Research, University of Dresden, Dresden, Germany

    H. K. Schackert, H. Appelt & J. Plaschke

  3. Institute of Pathology, University of Dresden, Dresden, Germany

    G. Baretton

  4. Department of Neurosurgery, University of Dresden, Dresden, Germany

    G. Schackert

Authors
  1. R. Martinez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. K. Schackert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Appelt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Plaschke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. Baretton
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. Schackert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. Martinez.

Additional information

Grant sponsor: supported by a grant from the Deutsche Forschungsgemeinschaft, DFG (MA 2448/1)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martinez, R., Schackert, H.K., Appelt, H. et al. Low-level microsatellite instability phenotype in sporadic glioblastoma multiforme. J Cancer Res Clin Oncol 131, 87–93 (2005). https://doi.org/10.1007/s00432-004-0592-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-004-0592-5

Keywords

Search

Navigation