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Mutational patterns and regulatory networks in epigenetic subgroups of meningioma

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Abstract

DNA methylation patterns delineate clinically relevant subgroups of meningioma. We previously established the six meningioma methylation classes (MC) benign 1–3, intermediate A and B, and malignant. Here, we set out to identify subgroup-specific mutational patterns and gene regulation. Whole genome sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic meningiomas and 22 meningiomas arising after radiation (Mrad). RNA sequencing was added for 18 of these cases and chromatin-immunoprecipitation for histone H3 lysine 27 acetylation (H3K27ac) followed by sequencing (ChIP-seq) for 16 samples. Besides the known mutations in meningioma, structural variants were found as the mechanism of NF2 inactivation in a small subset (5%) of sporadic meningiomas, similar to previous reports for Mrad. Aberrations of DMD were found to be enriched in MCs with NF2 mutations, and DMD was among the most differentially upregulated genes in NF2 mutant compared to NF2 wild-type cases. The mutational signature AC3, which has been associated with defects in homologous recombination repair (HRR), was detected in both sporadic meningioma and Mrad, but widely distributed across the genome in sporadic cases and enriched near genomic breakpoints in Mrad. Compared to the other MCs, the number of single nucleotide variants matching the AC3 pattern was significantly higher in the malignant MC, which also exhibited higher genomic instability, determined by the numbers of both large segments affected by copy number alterations and breakpoints between large segments. ChIP-seq analysis for H3K27ac revealed a specific activation of genes regulated by the transcription factor FOXM1 in the malignant MC. This analysis also revealed a super enhancer near the HOXD gene cluster in this MC, which, together with general upregulation of HOX genes in the malignant MC, indicates a role of HOX genes in meningioma aggressiveness. This data elucidates the biological mechanisms rendering different epigenetic subgroups of meningiomas, and suggests leveraging HRR as a novel therapeutic target.

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Acknowledgements

This project was supported by the German Cancer Aid (110983, 70112007), the Else Kröner-Fresenius Stiftung (2015_A060, 2017_EKES.24), and the Heidelberg Center for Personalized Oncology (DKFZ-HIPO). We further thank the DKFZ Omics IT and Data Management Core Facility (ODCF) and DKFZ Genomics and Proteomics Core Facility for technical support.

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Author notes

  1. Johannes Werner

    Present address: Department of Biological Oceanography, Leibniz Institute of Baltic Sea Research, Rostock, Germany

  2. Nagarajan Paramasivam, Daniel Hübschmann, Matthias Schlesner, and Felix Sahm shared first or shared last authorship.

Authors and Affiliations

  1. Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Nagarajan Paramasivam, Daniel Hübschmann, Naveed Ishaque, Zuguang Gu, Johannes Werner & Roland Eils

  2. Heidelberg Center for Personalized Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Nagarajan Paramasivam, Naveed Ishaque, Zuguang Gu & Katja Beck

  3. Division of Stem Cells and Cancer, DKFZ, Heidelberg, Germany

    Daniel Hübschmann

  4. Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany

    Daniel Hübschmann

  5. Department of Pediatric Oncology, Hematology and Immunology, University Hospital, Heidelberg, Germany

    Daniel Hübschmann & Stefan M. Pfister

  6. Division Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Umut H Toprak

  7. Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany

    Umut H Toprak, David T. W. Jones, Stefan M. Pfister & Felix Sahm

  8. Center for Digital Health, Berlin Institute of Health and Charité Universitätsmedizin Berlin, Berlin, Germany

    Naveed Ishaque & Roland Eils

  9. Department of Neurosurgery, University Hospital of Zürich, Zurich, Switzerland

    Marian Neidert

  10. Department of Neuropathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany

    Daniel Schrimpf, Damian Stichel, David Reuss, Philipp Sievers, Annekathrin Reinhardt, Annika K. Wefers, Andreas von Deimling & Felix Sahm

  11. Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Daniel Schrimpf, Damian Stichel, David Reuss, Philipp Sievers, Annekathrin Reinhardt, Annika K. Wefers, Andreas von Deimling & Felix Sahm

  12. Pediatric Glioma Research Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    David T. W. Jones

  13. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    David T. W. Jones & Stefan M. Pfister

  14. German Cancer Consortium (DKTK), Heidelberg, Germany

    David T. W. Jones

  15. Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Sebastian Uhrig

  16. Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland

    Hans-Georg Wirsching & Michael Weller

  17. Genomics and Proteomics Core Facility, Microarray Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Matthias Schick & Melanie Bewerunge-Hudler

  18. Department of Neurosurgery, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany

    Stephanie Brehmer, Marcel Seiz-Rosenhagen & Daniel Hänggi

  19. Department of Neurosurgery, University Hospital Homburg Saar, Homburg, Germany

    Steffi Urbschat & Ralf Ketter

  20. Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany

    Christel Herold-Mende

  21. Health Data Science Unit, Bioquant, Medical Faculty, University of Heidelberg, Heidelberg, Germany

    Roland Eils

  22. Department of Neurosurgery, Tel Aviv Medical Center, Tel Aviv, Israel

    Zvi Ram & Rachel Grossmann

  23. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Zvi Ram & Rachel Grossmann

  24. Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Wolfgang Wick

  25. Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany

    Wolfgang Wick

  26. Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Matthias Schlesner

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  1. Nagarajan Paramasivam
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Correspondence to Felix Sahm.

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Supplementary material 1 (XLSX 10 kb)

Online Resource 1: Supplementary Table 1 Cohort characteristics

Supplementary material 2 (XLSX 138 kb)

Online Resource 2: Supplementary Table 2 Functional exonic variants and small insertions/deletions.

Supplementary material 3 (XLSX 6 kb)

Online Resource 3: Supplementary Table 3 Association of methylation classes with functional exonic small variants

Supplementary material 4 (PDF 394 kb)

Online Resource 4: Supplementary Table 4 Quality control metrics of 16 ChIP-seq samples generated using the ChIPQC R package. Supplementary Figure 1 Volcano plot showing differential expression in NF2 mutant vs wild-type cases. Supplementary Figure 2 Mutational signature analysis (legend below figure). Supplementary Figure 3 Correlation between genomic instability and AC3 stratified for Mrad and sporadic cases. Supplementary Figure 4 HOX gene expression

Supplementary material 5 (CSV 15731 kb)

Online Resource 5 Expression data from RNA sequencing from FFPE samples

Supplementary material 6 (CSV 12660 kb)

Online Resource 6 Expression data from RNA sequencing from frozen samples

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Paramasivam, N., Hübschmann, D., Toprak, U.H. et al. Mutational patterns and regulatory networks in epigenetic subgroups of meningioma. Acta Neuropathol 138, 295–308 (2019). https://doi.org/10.1007/s00401-019-02008-w

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