gms | German Medical Science

63rd Annual Meeting of the German Society of Neurosurgery (DGNC)
Joint Meeting with the Japanese Neurosurgical Society (JNS)

German Society of Neurosurgery (DGNC)

13 - 16 June 2012, Leipzig

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DNA Mismatch repair gene expression in recurrent glioblastoma – association to MGMT status and survival

Meeting Abstract

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  • A.M. Stark - Klinik für Neurochirurgie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel
  • A. Doukas - Klinik für Neurochirurgie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel
  • H.H. Hugo - Klinik für Neurochirurgie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel
  • H.M. Mehdorn - Klinik für Neurochirurgie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel
  • J.H. Held-Feindt - Klinik für Neurochirurgie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel

Deutsche Gesellschaft für Neurochirurgie. Japanische Gesellschaft für Neurochirurgie. 63. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie (JNS). Leipzig, 13.-16.06.2012. Düsseldorf: German Medical Science GMS Publishing House; 2012. DocFR.01.06

doi: 10.3205/12dgnc170, urn:nbn:de:0183-12dgnc1708

Published: June 4, 2012

© 2012 Stark et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.

Outline

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Objective: Glioblastoma patients containing a methylated MGMT promotor region show prolonged survival under combined chemo/radiotherapy with temozolomide. There is current evidence that further Mismatch genes, namely MLH1, MSH2 and MSH6, play a pivotal role in the tumor's response to treatment. We previously found prognostic impact of MSH2 and MSH6 expression in initial glioblastoma in a series of 42 patients based on immunohistochemical.

Methods: 211 patients were included who underwent macroscopically total glioblastoma (WHO grade IV) removal and at least one re-craniotomy for recurrence. Immunohistochemical staining was performed on paraffin-embedded specimens from 211 patients (initial tumors) with specific antibodies against MLH1, MSH2 and MSH6. Results were compared to the Ki67 proliferation index and patient survival (univariate and multivariate analysis). Fresh frozen samples from 9 patients treated with combined chemo-/ radiotherapy (paired initial and recurrent specimens) were examined using real-time RT-PCR with specific primers against MLH1, MSH2 and MSH6. Results were compared to MGMT status and survival.

Results: Immunohistochemistry: (1) Wilcoxon analysis revealed a highly significant association between MLH1, MSH2 and MSH6 expression in initial glioblastoma and the Ki67 proliferation index (p < 0.001). Real-time RT-PCR revealed significantly different expression (defined as ≥ 2fold over- or ≤ 0,5fold underexpression in recurrent lesions) in two patients. In one case we found overexpression of MLH1, MSH2 and MSH6 in the recurrent tumor accompanied by negative MGMT methylation and survival of 17.4 months. In the other case, we found underexpression of MLH1, MSH2 and MSH6 accompanied by positive MGMT methylation and survival of only 11.7 months.

Conclusions: Our data indicate that (1) a subpopulation of glioblastoma patients shows genetic alterations in mismatch repair genes beyond from MGMT that may affect the response to treatment. (2) Multivariate analysis revealed a significant association between MLH1, MSH2 and MSH6 immunohistochemical staining and the Ki67 proliferation index. (3) The protein expression of MLH1, MSH2 and MSH6 is not associated with survival examined in a large series treated before the temozolomide era.

This work was supported by the “Familie Mehdorn Stiftung” in Kiel.