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60th Annual Meeting of the German Society of Neurosurgery (DGNC)
Joint Meeting with the Benelux countries and Bulgaria

German Society of Neurosurgery (DGNC)

24 - 27 May 2009, Münster

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Accumulation of genetic and epigenetic alterations in glioblastoma during progression

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  • R. Martinez - Klinik für Neurochirurgie, Universitätsklinikum Göttingen
  • V. Rohde - Klinik für Neurochirurgie, Universitätsklinikum Göttingen
  • G. Schackert - Klinik für Neurochirurgie, Universitätsklinikum Carl Gustav Carus der TU Dresden
  • M. Esteller - Spanish National Cancer Centre, Madrid

Deutsche Gesellschaft für Neurochirurgie. 60. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit den Benelux-Ländern und Bulgarien. Münster, 24.-27.05.2009. Düsseldorf: German Medical Science GMS Publishing House; 2009. DocMI.05-02

doi: 10.3205/09dgnc193, urn:nbn:de:0183-09dgnc1930

Published: May 20, 2009

© 2009 Martinez et al.
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Objective: Glioblastoma, the most frequent primary brain tumor in adults has an inherent tendency to recur. The molecular basis of the recurrence process in GBM is still poorly understood. We aimed to analyze both genetic and epigenetic alterations occurring in GBM during disease progression.

Methods: We have analyzed 20 match-paired GBM. Genetic analysis was performed by: a) sequencing of p53 and PTEN; b) EGFR amplification by semiquantitative PCR and c) wide-genome LOH analysis at chromosome regions 17p13, 1p35, 19q13, 13q14, 9p21 and 10q24 by microsatellite analysis. Epigenetic patterns were determinated by investigating genes with a key role in DNA repair (MGMT), apoptosis (CASP8, CASP3, CASP9, DcR 1, DR4, DR5, and TMS1/ASC), and cell adherence (CDH1, CDH13) as well as the cell cycle check-point regulator CHFR and tumor suppressor genes RASSF1A and BLU. The CpG island promoter hypermethylation status was assessed by methylation-specific PCR.

Results: Among primary GBM, we observed 12 type 2 GBM, four type 1 GBM and four GBM showing neither p53 mutations nor EGFR amplification (non type 1-non type 2 GBM). Upon recurrence, we have found two patterns of progression: tumors showing either type 1 or type 2 profiles conserved them. In contrast, non type 1-non type 2 GBM acquired a type 2 GBM profile. Both type 1 and type 2 GBM showed a less methylated profile when compared to the non type1-non type 2 GBM. The promoter hypermethylation pattern of relapsed GBM in comparison with their corresponding primary tumors was different in 50% of type 1 GBM, in 58.3% of type 2 GBM and in 100% of non type 1-non type 2 GBM. The most prominent distinction was the presence of a previously undetected CASP8 hypermethylation in GBM relapses (P= 0.031, Fisher's exact test). This difference was even more marked in non type 1-non type 2 GBM, which showed significantly higher rates of hypermethylation of RASFF1A and BLU as well.

Conclusions: Our data strongly suggest that GBM accumulates genetic and epigenetic alterations during disease progression. Relapses of GBM showed different profiles of epigenetic aberrations depending on the genetic subtype, which was more patent in non type 1-non type 2 GBM.