Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Acta Neuropathologica
Published in: Acta Neuropathologica 2/2019

01-08-2019 | Meningioma | Original Paper

Mutational patterns and regulatory networks in epigenetic subgroups of meningioma

Authors: 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 Sahm

Published in: Acta Neuropathologica | Issue 2/2019

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Abedalthagafi MS, Bi WL, Merrill PH et al (2015) ARID1A and TERT promoter mutations in dedifferentiated meningioma. Cancer Genet 208:345–350PubMedPubMedCentral
2.
Abkevich V, Timms KM, Hennessy BT et al (2012) Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 107:1776–1782PubMedPubMedCentral
3.
Alexandrov LB, Nik-Zainal S, Wedge DC et al (2013) Signatures of mutational processes in human cancer. Nature 500:415–421PubMedPubMedCentral
4.
Birkbak NJ, Wang ZC, Kim JY et al (2012) Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov 2:366–375PubMedPubMedCentral
5.
Brastianos PK, Horowitz PM, Santagata S et al (2013) Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet 45:285–289PubMedPubMedCentral
6.
Carroll TS, Liang Z, Salama R, Stark R, de Santiago I (2014) Impact of artifact removal on ChIP quality metrics in ChIP-seq and ChIP-exo data. Front Genet 5:75PubMedPubMedCentral
7.
Chen X, Muller GA, Quaas M et al (2013) The forkhead transcription factor FOXM1 controls cell cycle-dependent gene expression through an atypical chromatin binding mechanism. Mol Cell Biol 33:227–236PubMedPubMedCentral
8.
Chudasama P, Mughal SS, Sanders MA et al (2018) Integrative genomic and transcriptomic analysis of leiomyosarcoma. Nat Commun 9:144PubMedPubMedCentral
9.
Clark VE, Erson-Omay EZ, Serin A et al (2013) Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science 339:1077–1080PubMedPubMedCentral
10.
Clark VE, Harmanci AS, Bai H et al (2016) Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. Nat Genet 48:1253–1259PubMedPubMedCentral
11.
Collord G, Tarpey P, Kurbatova N et al (2018) An integrated genomic analysis of anaplastic meningioma identifies prognostic molecular signatures. Sci Rep 8:13537PubMedPubMedCentral
12.
Di Vinci A, Brigati C, Casciano I et al (2012) HOXA7, 9, and 10 are methylation targets associated with aggressive behavior in meningiomas. Transl Res 160:355–362PubMed
13.
Engert F, Kovac M, Baumhoer D, Nathrath M, Fulda S (2017) Osteosarcoma cells with genetic signatures of BRCAness are susceptible to the PARP inhibitor talazoparib alone or in combination with chemotherapeutics. Oncotarget 8:48794–48806PubMed
14.
Engert F, Schneider C, Weibeta LM, Probst M, Fulda S (2015) PARP inhibitors sensitize Ewing sarcoma cells to temozolomide-induced apoptosis via the mitochondrial pathway. Mol Cancer Ther 14:2818–2830PubMed
15.
Gallia GL, Zhang M, Ning Y, Haffner MC, Batista D, Binder ZA (2018) Genomic analysis identifies frequent deletions of Dystrophin in olfactory neuroblastoma. Nat Commun. 9(1):5410PubMedPubMedCentral
16.
17.
Georgiou G, van Heeringen SJ (2016) fluff: exploratory analysis and visualization of high-throughput sequencing data. PeerJ 4:e2209PubMedPubMedCentral
18.
Godlewski J, Kiezun J, Krazinski BE, Kozielec Z, Wierzbicki PM, Kmiec Z (2018) The immunoexpression of YAP1 and LATS1 proteins in clear cell renal cell carcinoma: impact on patients’ survival. Biomed Res Int 2018:2653623PubMedPubMedCentral
19.
Gu Z, Eils R, Schlesner M (2016) Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics 32:2847–2849PubMed
20.
Harmanci AS, Youngblood MW, Clark VE et al (2017) Integrated genomic analyses of de novo pathways underlying atypical meningiomas. Nat Commun 8:14433PubMedPubMedCentral
21.
Heining C, Horak P, Uhrig S et al (2018) NRG1 fusions in KRAS wild-type pancreatic cancer. Cancer Discov 8:1087–1095PubMed
22.
Helmrich A, Ballarino M, Tora L (2011) Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes. Mol Cell 44:966–977PubMed
23.
Jiang Y, Qiu Y, Minn AJ, Zhang NR (2016) Assessing intratumor heterogeneity and tracking longitudinal and spatial clonal evolutionary history by next-generation sequencing. Proc Natl Acad Sci USA 113:E5528–5537PubMedPubMedCentral
24.
Jones DT, Hutter B, Jager N et al (2013) Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 45:927–932PubMedPubMedCentral
25.
Juratli TA, McCabe D, Nayyar N et al (2018) DMD genomic deletions characterize a subset of progressive/higher-grade meningiomas with poor outcome. Acta Neuropathol 136:779–792PubMed
26.
Juratli TA, Thiede C, Koerner MVA et al (2017) Intratumoral heterogeneity and TERT promoter mutations in progressive/higher-grade meningiomas. Oncotarget 8:109228–109237PubMedPubMedCentral
27.
Khan A, Zhang X (2016) dbSUPER: a database of super-enhancers in mouse and human genome. Nucleic Acids Res 44:D164–171PubMed
28.
Kishida Y, Natsume A, Kondo Y et al (2012) Epigenetic subclassification of meningiomas based on genome-wide DNA methylation analyses. Carcinogenesis 33:436–441PubMed
29.
Kovac M, Blattmann C, Ribi S et al (2015) Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. Nat Commun 6:8940PubMed
30.
Kulakovskiy IV, Vorontsov IE, Yevshin IS et al (2018) HOCOMOCO: towards a complete collection of transcription factor binding models for human and mouse via large-scale ChIP-Seq analysis. Nucleic Acids Res 46:D252–D259PubMed
31.
Laurendeau I, Ferrer M, Garrido D et al (2010) Gene expression profiling of the hedgehog signaling pathway in human meningiomas. Mol Med 16:262–270PubMedPubMedCentral
32.
33.
Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550PubMedPubMedCentral
34.
Loven J, Hoke HA, Lin CY et al (2013) Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153:320–334PubMedPubMedCentral
35.
Mahaney BL, Meek K, Lees-Miller SP (2009) Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining. Biochem J 417:639–650PubMed
36.
McLean CY, Bristor D, Hiller M et al (2010) GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol 28:495–501PubMedPubMedCentral
37.
Oh JE, Ohta T, Satomi K et al (2015) Alterations in the NF2/LATS1/LATS2/YAP pathway in Schwannomas. J Neuropathol Exp Neurol 74:952–959PubMed
38.
Olar A, Wani KM, Wilson CD et al (2017) Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma. Acta Neuropathol 133:431–444PubMedPubMedCentral
39.
Popova T, Manie E, Rieunier G et al (2012) Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res 72:5454–5462PubMed
40.
Rehrauer H, Wu L, Blum W et al (2018) How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing, and somatic mutations. Oncogene 37:2645–2659PubMedPubMedCentral
41.
Reuss DE, Piro RM, Jones DT et al (2013) Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations. Acta Neuropathol 125:351–358PubMed
42.
Ross-Innes CS, Stark R, Teschendorff AE et al (2012) Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature 481:389–393PubMedPubMedCentral
43.
Rubio-Perez C, Tamborero D, Schroeder MP, Antolín AA, Deu-Pons J, Perez-Llamas C et al (2015) In silico prescription of anticancer drugs to cohorts of 28 tumor types reveals novel targeting opportunities. Cancer Cell 27(3):382–96PubMed
44.
Sahm F, Schrimpf D, Olar A et al (2016) TERT promoter mutations and risk of recurrence in meningioma. J Natl Cancer Inst 108:djv377
45.
Sahm F, Schrimpf D, Stichel D et al (2017) DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol 18:682–694PubMed
46.
Sahm F, Toprak UH, Hubschmann D et al (2017) Meningiomas induced by low-dose radiation carry structural variants of NF2 and a distinct mutational signature. Acta Neuropathol 134:155–158PubMed
47.
Smith MJ, O’Sullivan J, Bhaskar SS et al (2013) Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas. Nat Genet 45:295–298PubMed
48.
Spiegl-Kreinecker S, Lotsch D, Neumayer K et al (2018) TERT promoter mutations are associated with poor prognosis and cell immortalization in meningioma. Neuro Oncol 20:1584–1593PubMedPubMedCentral
49.
Sturm D, Orr BA, Toprak UH et al (2016) New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 164:1060–1072PubMedPubMedCentral
50.
Telli ML, Timms KM, Reid J et al (2016) Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin Cancer Res 22:3764–3773PubMedPubMedCentral
51.
Vasudevan HN, Braunstein SE, Phillips JJ et al (2018) Comprehensive molecular profiling identifies FOXM1 as a key transcription factor for meningioma proliferation. Cell Rep 22:3672–3683PubMedPubMedCentral
52.
Whyte WA, Orlando DA, Hnisz D et al (2013) Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153:307–319PubMedPubMedCentral
53.
Metadata
Title
Mutational patterns and regulatory networks in epigenetic subgroups of meningioma
Authors
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 Sahm
Publication date
01-08-2019
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 2/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-019-02008-w

Other articles of this Issue 2/2019

Acta Neuropathologica 2/2019 Go to the issue

Review

Evaluation of CD33 as a genetic risk factor for Alzheimer’s disease

Editorial

Novel Alzheimer’s disease risk genes: exhaustive investigation is paramount

Original Paper

Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease

Review

The role of ABCA7 in Alzheimer’s disease: evidence from genomics, transcriptomics and methylomics

Original Paper

RhoA regulates translation of the Nogo-A decoy SPARC in white matter-invading glioblastomas

Review

SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data