Artikel
Molecular profiling of initial versus recurrent glioblastoma: an attempt using different techniques including array technology, MGMT-status and immunohistochemistry
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Autoren
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Andreas M. Stark
- Janka Held-Feindt Klinik für Neurochirurgie im Universitätsklinikum Schleswig-Holstein, Campus Kiel, Deutschland
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Franziska Ruhland
- Janka Held-Feindt Klinik für Neurochirurgie im Universitätsklinikum Schleswig-Holstein, Campus Kiel, Deutschland
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Heinz-Herrmann Hugo
- Janka Held-Feindt Klinik für Neurochirurgie im Universitätsklinikum Schleswig-Holstein, Campus Kiel, Deutschland
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H. Maximilian Mehdorn
- Janka Held-Feindt Klinik für Neurochirurgie im Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel
| Veröffentlicht: | 16. September 2010 |
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Gliederung
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Objective: Glioblastoma is the most frequent and most malignant primary brain tumor in adults. It is regarded as the endpoint of diffusely infiltration gliomas. Its molecular profile is regarded heterogenous. However, systematic information on this issue is sparse. The aim of this study was to quantify genetic heterogeneity of glioblastoma comparing initial versus recurrent tumors of the same patients using different techniques.
Methods: In total, 55 patients were included who underwent surgical resection of glioblastoma (WHO grade IV) between 2003 and 2007 at our institution. Inclusion criteria were: (1) primary tumor genesis, (2) macroscopically total resection at initial craniotomy, (3) at least one re-craniotomy for GB recurrence, (4) supratentorial tumor location. Immunohistochemistry was performed in 55 patients using specific antibodies. Fresh frozen tumor material from 10 patients was used for real-time RT-PCR validation of GEOligoArray results. The MGMT-Status was evaluated in 4 patients. RT2Profiler real-time PCR Array (Human Cell Cycle) was performed in one patient. Wilcoxon test was used for statistical analysis of immunohistochemical data.
Results: Cluster-Analysis of GEOligoArray data revealed increased expression in recurrent glioblastoma for: Integrins, Matrix-metallo-proteinases (MMPs), Preotease inhibitors, and DNA-damage/-checkpoint factors. Real-time PCR validation identified increased expression of MMP-2, MMP-9 (5/10 patients), TIMP-3, and Bax. RT2Profiler real-time PCR Array revealed overexpression of BCCIP, CDKN2B, DNM2, and MKI67. MGMT promoter methylation was present in 2/4 cases. There were no changes from initial to recurrent tumors. Immunohistochemical staining revealed significant changes in the expression of p53, GFAP and Ki67 in initial versus recurrent lesions. The expression of EGFR, p53, MDM2 and GFAP was significantly associated with the Ki67 proliferation index in initial and recurrent lesions. There were no significant association between staining results and patients survival.
Conclusions: Systematic examination of paired probes from initial and recurrent glioblastoma revealed a relatively stabil gene expression profile. However, there are several genetic changes which can mainly be assigned to DNA-damage/-checkpoint factors and Proteases. MGMT promotor methylation seems to be a stable parameter.
