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Low-level microsatellite instability phenotype in sporadic glioblastoma multiforme

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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.

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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

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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

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  1. R. Martinez
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  4. J. Plaschke
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Correspondence to R. Martinez.

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

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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

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

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