gms | German Medical Science

70. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Skandinavischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

12.05. - 15.05.2019, Würzburg

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Influence of individual CpG methylation status on outcome in adult patients with glioblastoma multiforme receiving alkylating agent treatment

Der Einfluss des individuellen Methylierungsstatus für die Prognose von Glioblastom-Patienten unter alkylierender Chemotherapie

Meeting Abstract

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  • presenting/speaker Sebastian Siller - Klinikum der Universität München (Ludwig-Maximilians-Universität), Campus Großhadern, Neurochirurgische Klinik, München, Deutschland
  • Michael Lauseker - Klinikum der Universität München (Ludwig-Maximilians-Universität), Campus Großhadern, Institut für medizinische Informationsverarbeitung, Biometrie und Epidemiologie (IBE), München, Deutschland; Klinikum der Universität München (Ludwig-Maximilians-Universität), Campus Großhadern, Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie (IBE), München, Deutschland
  • Armin Giese - Klinikum der Universität München (Ludwig-Maximilians-Universität), Campus Großhadern, Zentrum für Neuropathologie und Prionforschung, München, Deutschland
  • Jörg-Christian Tonn - Klinikum der Universität München (Ludwig-Maximilians-Universität), Campus Großhadern, Neurochirurgische Klinik, München, Deutschland
  • Karim-Maximilian Niyazi - Klinikum der Universität München (Ludwig-Maximilians-Universität), Campus Großhadern, Radioonkologische Klinik, München, Deutschland
  • Niklas Thon - Klinikum der Universität München (Ludwig-Maximilians-Universität), Campus Großhadern, Neurochirurgische Klinik, München, Deutschland
  • Bogdana Suchorska - Klinikum der Universität München (Ludwig-Maximilians-Universität), Campus Großhadern, Neurochirurgische Klinik, München, Deutschland
  • Friedrich-Wilhelm Kreth - Klinikum der Universität München (Ludwig-Maximilians-Universität), Campus Großhadern, Neurochirurgische Klinik, München, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 70. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Skandinavischen Gesellschaft für Neurochirurgie. Würzburg, 12.-15.05.2019. Düsseldorf: German Medical Science GMS Publishing House; 2019. DocV127

doi: 10.3205/19dgnc142, urn:nbn:de:0183-19dgnc1428

Veröffentlicht: 8. Mai 2019

© 2019 Siller et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.

Gliederung

Text

Objective: Methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) promotor causes gene silencing and has been associated with a favourable prognosis in patients with glioblastoma multiforme (GBM) receiving alkylating chemotherapy. However, analysis of MGMT promotor methylation is usually reported as a cut-off depending on the results of the correspondent CpG site testing. This approach disregards a possible heterogeneity concerning the methylation status within the individual CpG sites and its possible association with prognosis in GBM patients. The current study aimed at elucidating the association between methylation of CpG sites 74-98 within the MGMT promotor region and outcome in GBM patients receiving alkylating agents.

Methods: Individual methylation status of 230 patients with histologically proven GBM following concomitant radio-chemotherapy with TMZ after stereotactic biopsy or open tumor resection (OTR) was assessed by the Sanger sequencing (Sseq) approach. Methylation of CpG sites 74–98 within the MGMT promotor region was defined according to a ratio of cytosine/thymine peak >50%. The total number of methylated CpG sites as well as clinical factors such as age, Karnofsky Performance Score (KPS) and mode of surgical procedure were correlated with outcome using proportional hazards models.

Results: Median progression-free (PFS) and overall survival (OS) were 7.8 and 14.6 months, respectively. Alongside younger age, KPS> 80 and OTR, the cumulative total number of methylated loci within the CpG sites 74–98 was strongly associated with both PFS and OS and retained its prognostic influence on outcome in multivariate models (p<0.001). Furthermore, a linear coherence between the total number of methylated CpG sites 74–98 and survival parameters could be observed.

Conclusion: In contrast to the concept of dichotomizing the MGMT promotor status into “methylated” and “non-methylated”, our approach shows a clear heterogeneity within the methylation status of the CpG sites 74-98 within the GBM tumor specimens. Our data suggest a strong correlation between outcome and the total number of methylated CpG sites, thus an up-front analysis of the individual CpG site methylation status prior to initiation of alkylating chemotherapy might help to improve treatment response in GBM patients.