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The intra-tumoral heterogeneity in glioblastoma — a limitation for prognostic value of epigenetic markers?

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Abstract

Objective

Epigenetic tumor features are getting into focus as prognostic markers in glioblastoma. Whether intra-tumoral heterogeneity in these epigenetic characteristics may influence prognostic value remains unclear.

Methods

Of 154 patients suffering from glioblastoma, 120 patients served as reference collective, while 34 patients were compiled as test collective. MGMT, p15, and p16 promoter methylation and miRNA expression levels (miRNA-21, miRNA-24, miRNA-26a, and miRNA-181d) were measured in each tumor specimen. Serving as a statistical baseline, epigenetic heterogeneity between tumors (inter-tumoral) was estimated within a triplet of three tumor specimens from three different reference patients. For estimation of epigenetic heterogeneity within a tumor (intra-tumoral), previous results were compared to three tumor specimens within one glioblastoma of patients of the test collective. Resulting levels of heterogeneity were then correlated with survival and validated by an external TCGA data set.

Results

Heterogeneity in MGMT promoter methylation occurred less likely in the test group compared to the reference group. No difference in heterogeneity was observed between test and reference group regarding p15 and p16 methylation. Intra-tumoral heterogeneity within the test group regarding miRNA-21, miRNA-24, miRNA-26a, and miRNA-181d expression was not distinguishable from inter-tumoral heterogeneity. A homogenously increased miRNA-21 expression was associated with reduced overall survival in the test collective. The findings could be validated by comparison with TCGA datasets.

Conclusion

Heterogeneity of epigenetic characteristics in one glioblastoma may be of the same magnitude as heterogeneity between different patients. Not only the extent of epigenetic characteristics but also the extent of intra-tumoral heterogeneity may influence survival in glioblastoma.

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Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

FC:

Fold change

GBM:

Glioblastoma multiforme

IDH:

Isocitrate dehydrogenase

MGMT:

O6-Methylguanine-DNA methyltransferase

miRNA:

microRNA

MS-PCR:

Methylation-specific polymerase chain reaction

qRT-PCR:

Quantitative reverse-transcription polymerase chain reaction

TCGA:

The Cancer Genome Atlas

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Authors and Affiliations

  1. Department of Neurosurgery, Faculty of Medicine, University of Saarland, Homburg/Saar, Germany

    Sippl Christoph, Saenz Alicia, Teping Fritz, Trenkpohl Vanessa, Ketter Ralf, Linsler Stefan & Oertel Joachim

  2. Institute of Pathology, Faculty of Medicine, University of Saarland, Glockenstraße 54, Kaiserslautern, Germany

    Kim Yoo Jin

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  1. Sippl Christoph
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  2. Saenz Alicia
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Correspondence to Sippl Christoph.

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Ethics approval and consent to participate

This study was approved by the local German ethical board (Ethikkommission der Ärztekammer des Saarlandes, Saarbrücken, Germany). All procedures performed in this study were in accordance with the ethical standards of the 1964 Helsinki Declaration, and informed consent was obtained from all participants. This article does not contain any animal studies performed by any of the authors.

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Written informed consent was obtained from all patients (General Medical Council of the State of Saarland, NO 93/16).

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The authors declare no competing interests.

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Christoph, S., Alicia, S., Fritz, T. et al. The intra-tumoral heterogeneity in glioblastoma — a limitation for prognostic value of epigenetic markers?. Acta Neurochir 165, 1635–1644 (2023). https://doi.org/10.1007/s00701-023-05594-7

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  • DOI: https://doi.org/10.1007/s00701-023-05594-7

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