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DMD genomic deletions characterize a subset of progressive/higher-grade meningiomas with poor outcome

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Abstract

Progressive meningiomas that have failed surgery and radiation have a poor prognosis and no standard therapy. While meningiomas are more common in females overall, progressive meningiomas are enriched in males. We performed a comprehensive molecular characterization of 169 meningiomas from 53 patients with progressive/high-grade tumors, including matched primary and recurrent samples. Exome sequencing in an initial cohort (n = 24) detected frequent alterations in genes residing on the X chromosome, with somatic intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene as the most common alteration (n = 5, 20.8%), along with alterations of other known X-linked cancer-related genes KDM6A (n =2, 8.3%), DDX3X, RBM10 and STAG2 (n = 1, 4.1% each). DMD inactivation (by genomic deletion or loss of protein expression) was ultimately detected in 17/53 progressive meningioma patients (32%). Importantly, patients with tumors harboring DMD inactivation had a shorter overall survival (OS) than their wild-type counterparts [5.1 years (95% CI 1.3–9.0) vs. median not reached (95% CI 2.9–not reached, p = 0.006)]. Given the known poor prognostic association of TERT alterations in these tumors, we also assessed for these events, and found seven patients with TERT promoter mutations and three with TERT rearrangements in this cohort (n = 10, 18.8%), including a recurrent novel RETREG1–TERT rearrangement that was present in two patients. In a multivariate model, DMD inactivation (p = 0.033, HR = 2.6, 95% CI 1.0–6.6) and TERT alterations (p = 0.005, HR = 3.8, 95% CI 1.5–9.9) were mutually independent in predicting unfavorable outcomes. Thus, DMD alterations identify a subset of progressive/high-grade meningiomas with worse outcomes.

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Acknowledgements

This work is supported by US National Institutes of Health (NIH) 1R21NS099844 (to Drs. D. Cahill and P. Brastianos); the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Projektnummer: 401837860 and the Max Kade Foundation (to Dr. T. Juratli); the Meningioma Mommas (to Dr. H. Wakimoto); the Burroughs Wellcome Fund Career Award (to Dr. D. Cahill.); the Brain Science Foundation, the American Brain Tumor Association, and the Damon Runyon Research Foundation (to Dr. P. Brastianos).

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Author notes

  1. Tareq A. Juratli and Devin McCabe have equally contributed to this paper.

  2. Scott L. Carter, Daniel P. Cahill and Priscilla K. Brastianos are senior authors.

Authors and Affiliations

  1. Translational Neuro-Oncology Laboratory, Department of Neurosurgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA

    Tareq A. Juratli, Erik A. Williams, Shilpa S. Tummala, Alexandria L. Fink, Ganesh M. Shankar, Tristan Penson, Shingo Fujio, Julie J. Miller, Fred G. Barker II, Hiroaki Wakimoto & Daniel P. Cahill

  2. Stephen E. and Catherine Pappas Center for Neuro-Oncology, Divisions of Hematology/Oncology and Neuro-Oncology, Departments of Medicine and Neurology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA

    Tareq A. Juratli, Naema Nayyar, Ivanna V. Bihun, Alexander B. Kaplan, Benjamin M. Kuter, Mia S. Bertalan & Priscilla K. Brastianos

  3. Department of Neurosurgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    Tareq A. Juratli, Silke Hennig & Gabriele Schackert

  4. Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston, MA, 02215, USA

    Devin McCabe, Matthew Lastrapes & Scott L. Carter

  5. Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA, 02142, USA

    Devin McCabe, Matthew Lastrapes & Scott L. Carter

  6. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    Erik A. Williams, Aymen Baig, Maria Martinez-Lage, Martin K. Selig, Julie M. Batten, Anat O. Stemmer-Rachamimov, Miguel N. Rivera & A. John Iafrate

  7. Ignyta, Inc, San Diego, CA, USA

    Ian M. Silverman, Heather A. Ely & Jason Christiansen

  8. Institute of Neuroradiology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    Dirk Daubner

  9. Institute of Pathology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    Matthias Meinhardt & Gustavo B. Baretton

  10. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    Sandro Santagata

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Corresponding author

Correspondence to Priscilla K. Brastianos.

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Conflict of interest

I.M.S. and H.A.E. are employees in Ignyta, and Inc. J.C. is an employee and owns stocks in Ignyta, Inc. All other authors have no conflicts of interest to report with regard to this manuscript.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Online Resource 1:

Detailed method and materials description: Whole-exome sequencing, copy number analysis, RNA sequencing, Multiplex Ligation-dependent Probe Amplification (MLPA), Western blotting, Electron Microscopy and Immunofluorescence (PDF 540 kb)

Online Resource 2: Supplementary Table

 1: patients’ and tumor characteristics (XLSX 19 kb)

Online Resource 3:

Supplementary Fig. 1 | Copy number variations in progressive/high-grade meningiomas Deletions are depicted in blue, whereas amplifications are shown in red. Supplementary Fig. 2 | An overview of DMD deletions across multiple GISTIC analyses performed on the entire dataset (all_cancers) DMD is significantly focally deleted in 13 of 33 independent cancer types analyzed in the dataset. Among these, it is located within a focal peak region of deletion in 10 cancer types. For reference, 11.221% of all genes are significantly focally deleted in at least 13 cancer types and 5.877% of all genes are present in focal deletion peaks in at least 10 cancer types. The q-value calculated of focal DMD deletions in our cohort is 10−9.(http://portals.broadinstitute.org/tcga/gistic/browseGisticByGene). Supplementary Fig. 3 | Myogenic transcriptomic signature in higher-grade/progressive meningiomas RNA expression data was analyzed using the GTEx portal (https://www.gtexportal.org/home/) to identify genes that are predominantly expressed in the mesodermal tissue (skeletal or heart muscles). The expression of these genes was compared between samples with and without DMD inactivation. Of the seven mesodermal genes with detectable expression in at least three samples, a markedly higher expression level of these genes was observed in meningioma samples with DMD deletions.The seven genes shown in the heat map are:- ATPase Sarcoplasmic/Endoplasmic Reticulum Ca2 + Transporting 1 (ATP2A1): encodes one of the SERCA Ca(2 +)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of muscle cells.- Desmin (DES): encodes a muscle-specific class III intermediate filament.- Enolase 3 (ENO3): encodes an isoenzyme in skeletal muscle cells that may play a role in muscle development and regeneration.- Myosin light chain, phosphorylatable, fast skeletal muscle (MYLPF).- Titin-cap(TCAP): encodes a protein found in striated and cardiac muscle that binds to the titin Z1–Z2 domains and is a substrate of titin kinase, interactions thought to be critical to sarcomere assembly. Mutations in this gene are associated with limb-girdle muscular dystrophy type 2G- Tropomyosin (TPM2): encodes beta-tropomyosin, a member of the actin filament-binding protein family, and mainly expressed in slow, type 1 muscle fibers.- Troponin T1 (TNNT1): encodes a protein that is a subunit of troponin, which is a regulatory complex located on the thin filament of the sarcomere. Supplementary Fig. 4 | DMD inactivation in the malignant IOMM-Lee meningioma cell line(a) Immunohistochemistry with DYS1 demonstrates loss of dystrophin expression in IOMM-Lee cells implanted into the mouse brain. (b) Immunofluorescence using DMD ab15227 (Abcam) revealed the cytoplasmic loss of expression in the IOMM-Lee cell line when compared with the Ben-Men-1 (BM1) cell line. (c) Screenshot of DMD mRNA expression in three anaplastic meningioma cell lines (IOMM-Lee, CH157 and F5) as shown by the CCLE dataset. A significant reduction of DMD mRNA expression is seen in the IOMM-Lee cell line (RPKM 0.000712), whereas CH157 and F5 cell lines showed a higher expression (RPKM 0.404 and 0.510, respectively). https://portals.broadinstitute.org/ccle/data Supplementary Fig. 5 | Additional Western blotting, RT-PCR and electron microscopic data(a) Representative Western blotting using DYS1 (reacts with the rod domain of dystrophin) shows loss of dystrophin 427 kDa expression in two patient samples with DMD deletion (MGH001 and MGH025) and in the malignant IOMM-Lee meningioma cell line. (b) An example for a reverse transcriptase PCR demonstrating loss of DMD mRNA expression of exons 10–15 and 63–68 in case MGH031 (DMD-deleted sample), compared to samples of patients with intact DMD. (c) Representative electron microscopic imaging demonstrates the DMD-inactivated IOMM-Lee cell line displayed predominantly rounded cell morphology with an apparently lower density of cytoskeleton filaments compared with the human arachnoid cells (AC007-hTERT). (PDF 6619 kb)

Online Resource 4: Supplementary Table

 2: Sheet 1: List of all synonymous and non-synonymous mutations identified using the criteria for somatic mutation calling Sheet 2: List of genes residing in late-replicating common fragile sites that were assessed for deletions in the current study Sheet 3: List of genes larger than 1 Mb evaluated for alterations in the current study (XLSX 498 kb)

Online Resource 5: Supplementary Table

 3: Sheet 1: TERT fusion data Sheet 2: List of used RT-PCR primers in the study Sheet 3: List of used RT-PCR primers to validate the TERT fusions (XLSX 14 kb)

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Juratli, T.A., McCabe, D., Nayyar, N. et al. DMD genomic deletions characterize a subset of progressive/higher-grade meningiomas with poor outcome. Acta Neuropathol 136, 779–792 (2018). https://doi.org/10.1007/s00401-018-1899-7

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