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Acta Neuropathologica

, Volume 138, Issue 2, pp 295–308 | Cite as

Mutational patterns and regulatory networks in epigenetic subgroups of meningioma

  • Nagarajan Paramasivam
  • Daniel Hübschmann
  • Umut H Toprak
  • Naveed Ishaque
  • Marian Neidert
  • Daniel Schrimpf
  • Damian Stichel
  • David Reuss
  • Philipp Sievers
  • Annekathrin Reinhardt
  • Annika K. Wefers
  • David T. W. Jones
  • Zuguang Gu
  • Johannes Werner
  • Sebastian Uhrig
  • Hans-Georg Wirsching
  • Matthias Schick
  • Melanie Bewerunge-Hudler
  • Katja Beck
  • Stephanie Brehmer
  • Steffi Urbschat
  • Marcel Seiz-Rosenhagen
  • Daniel Hänggi
  • Christel Herold-Mende
  • Ralf Ketter
  • Roland Eils
  • Zvi Ram
  • Stefan M. Pfister
  • Wolfgang Wick
  • Michael Weller
  • Rachel Grossmann
  • Andreas von Deimling
  • Matthias Schlesner
  • Felix SahmEmail author
Original Paper

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.

Keywords

Meningioma Whole genome sequencing Molecular classification DNA methylation NF2 Mutational signatures 

Notes

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.

Supplementary material

401_2019_2008_MOESM1_ESM.xlsx (10 kb)
Supplementary material 1 (XLSX 10 kb)Online Resource 1: Supplementary Table 1 Cohort characteristics
401_2019_2008_MOESM2_ESM.xlsx (138 kb)
Supplementary material 2 (XLSX 138 kb)Online Resource 2: Supplementary Table 2 Functional exonic variants and small insertions/deletions.
401_2019_2008_MOESM3_ESM.xlsx (6 kb)
Supplementary material 3 (XLSX 6 kb)Online Resource 3: Supplementary Table 3 Association of methylation classes with functional exonic small variants
401_2019_2008_MOESM4_ESM.pdf (395 kb)
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
401_2019_2008_MOESM5_ESM.csv (15.4 mb)
Supplementary material 5 (CSV 15731 kb)Online Resource 5 Expression data from RNA sequencing from FFPE samples
401_2019_2008_MOESM6_ESM.csv (12.4 mb)
Supplementary material 6 (CSV 12660 kb)Online Resource 6 Expression data from RNA sequencing from frozen samples

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Nagarajan Paramasivam
    • 1
    • 2
  • Daniel Hübschmann
    • 1
    • 3
    • 4
    • 5
  • Umut H Toprak
    • 6
    • 7
  • Naveed Ishaque
    • 1
    • 2
    • 8
  • Marian Neidert
    • 9
  • Daniel Schrimpf
    • 10
    • 11
  • Damian Stichel
    • 10
    • 11
  • David Reuss
    • 10
    • 11
  • Philipp Sievers
    • 10
    • 11
  • Annekathrin Reinhardt
    • 10
    • 11
  • Annika K. Wefers
    • 10
    • 11
  • David T. W. Jones
    • 7
    • 12
    • 13
    • 14
  • Zuguang Gu
    • 1
    • 2
  • Johannes Werner
    • 1
    • 15
  • Sebastian Uhrig
    • 16
  • Hans-Georg Wirsching
    • 17
  • Matthias Schick
    • 18
  • Melanie Bewerunge-Hudler
    • 18
  • Katja Beck
    • 2
  • Stephanie Brehmer
    • 19
  • Steffi Urbschat
    • 20
  • Marcel Seiz-Rosenhagen
    • 19
  • Daniel Hänggi
    • 19
  • Christel Herold-Mende
    • 21
  • Ralf Ketter
    • 20
  • Roland Eils
    • 1
    • 8
    • 22
  • Zvi Ram
    • 23
    • 24
  • Stefan M. Pfister
    • 5
    • 7
    • 13
  • Wolfgang Wick
    • 25
    • 26
  • Michael Weller
    • 17
  • Rachel Grossmann
    • 23
    • 24
  • Andreas von Deimling
    • 10
    • 11
  • Matthias Schlesner
    • 27
  • Felix Sahm
    • 7
    • 10
    • 11
    Email author
  1. 1.Division of Theoretical BioinformaticsGerman Cancer Research Center (DKFZ)HeidelbergGermany
  2. 2.Heidelberg Center for Personalized Oncology (DKFZ-HIPO)German Cancer Research Center (DKFZ)HeidelbergGermany
  3. 3.Division of Stem Cells and CancerDKFZHeidelbergGermany
  4. 4.Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)HeidelbergGermany
  5. 5.Department of Pediatric Oncology, Hematology and ImmunologyUniversity HospitalHeidelbergGermany
  6. 6.Division Neuroblastoma GenomicsGerman Cancer Research Center (DKFZ)HeidelbergGermany
  7. 7.Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ)HeidelbergGermany
  8. 8.Center for Digital HealthBerlin Institute of Health and Charité Universitätsmedizin BerlinBerlinGermany
  9. 9.Department of NeurosurgeryUniversity Hospital of ZürichZurichSwitzerland
  10. 10.Department of NeuropathologyUniversity Hospital HeidelbergHeidelbergGermany
  11. 11.Clinical Cooperation Unit NeuropathologyGerman Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
  12. 12.Pediatric Glioma Research GroupGerman Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
  13. 13.Division of Pediatric NeurooncologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  14. 14.German Cancer Consortium (DKTK)HeidelbergGermany
  15. 15.Department of Biological OceanographyLeibniz Institute of Baltic Sea ResearchRostockGermany
  16. 16.Division of Applied BioinformaticsGerman Cancer Research Center (DKFZ)HeidelbergGermany
  17. 17.Department of NeurologyUniversity Hospital and University of ZurichZurichSwitzerland
  18. 18.Genomics and Proteomics Core Facility, Microarray UnitGerman Cancer Research Center (DKFZ)HeidelbergGermany
  19. 19.Department of Neurosurgery, University Hospital MannheimUniversity of HeidelbergMannheimGermany
  20. 20.Department of NeurosurgeryUniversity Hospital Homburg SaarHomburgGermany
  21. 21.Division of Experimental Neurosurgery, Department of NeurosurgeryUniversity Hospital HeidelbergHeidelbergGermany
  22. 22.Health Data Science Unit, Bioquant, Medical FacultyUniversity of HeidelbergHeidelbergGermany
  23. 23.Department of NeurosurgeryTel Aviv Medical CenterTel AvivIsrael
  24. 24.Sackler School of MedicineTel Aviv UniversityTel AvivIsrael
  25. 25.Clinical Cooperation Unit NeurooncologyGerman Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
  26. 26.Department of Neurology and Neurooncology Program, National Center for Tumor DiseasesHeidelberg University HospitalHeidelbergGermany
  27. 27.Bioinformatics and Omics Data AnalyticsGerman Cancer Research Center (DKFZ)HeidelbergGermany

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