Letter | Published:

Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas

Nature Genetics volume 45, pages 295298 (2013) | Download Citation

Abstract

One-third of all primary central nervous system tumors in adults are meningiomas1. Rarely, meningiomas occur at multiple sites, usually occurring in individuals with type 2 neurofibromatosis (NF2). We sequenced the exomes of three unrelated individuals with familial multiple spinal meningiomas without NF2 mutations. We identified two individuals with heterozygous loss-of-function mutations in the SWI/SNF chromatin-remodeling complex subunit gene SMARCE1. Sequencing of SMARCE1 in six further individuals with spinal meningiomas identified two additional heterozygous loss-of-function mutations. Tumors from individuals with SMARCE1 mutations were of clear-cell histological subtype, and all had loss of SMARCE1 protein, consistent with a tumor suppressor mechanism. Our findings identify multiple-spinal-meningioma disease as a new discrete entity and establish a key role for the SWI/SNF complex in the pathogenesis of both meningiomas and tumors with clear-cell histology.

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Acknowledgements

We thank the families for their contributions to this study. We also thank N. Bowers and A. Wallace for NF2 mutation screening and T. Gledhill for immunohistochemistry images. M.J.S. is supported by a Young Investigator Award (2011-01-006) from the Children's Tumor Foundation. We also acknowledge support from the Association for International Cancer Research (12-0275) and the Manchester Biomedical Research Centre. D.G.E. is a National Institute for Health Research (NIHR) Senior Clinical Investigator. Finally, we thank the NHLBI GO Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the Women's Health Initiative (WHI) Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).

Author information

Author notes

    • William G Newman
    •  & D Gareth Evans

    These authors contributed equally to this work.

Affiliations

  1. Genetic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St. Mary's Hospital, University of Manchester, Manchester, UK.

    • Miriam J Smith
    • , James O'Sullivan
    • , Sanjeev S Bhaskar
    • , Kristen D Hadfield
    • , William G Newman
    •  & D Gareth Evans
  2. South East Scotland Genetic Service, Western General Hospital, Edinburgh, UK.

    • Gemma Poke
  3. Department of Neurosurgery, Beaumont Hospital, Dublin, Ireland.

    • John Caird
    •  & Daniel Rawluk
  4. Department of Clinical Genetics, West Midlands Regional Genetics Unit, Birmingham, UK.

    • Saba Sharif
  5. Faculty of Medicine, University of Southampton, Southampton University Hospital National Health Service (NHS) Trust, Southampton, UK.

    • Diana Eccles
  6. Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetic and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Edinburgh, UK.

    • David Fitzpatrick
  7. Department of Cellular Pathology, Salford Royal Hospitals NHS Foundation Trust, Salford, UK.

    • Daniel du Plessis
  8. Greater Manchester Neurosciences Centre, Salford Royal Hospitals NHS Foundation Trust, Salford, UK.

    • Daniel du Plessis

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Contributions

M.J.S., W.G.N. and D.G.E. designed the study and wrote the manuscript. J.O. and S.S.B. performed exome sequencing and bioinformatics analysis. M.J.S. and K.D.H. performed Sanger sequencing. D.G.E., G.P., D.F., S.S., D.R., D.E. and J.C. provided detailed clinical information and samples for analysis. D.d.P. performed histopathological review and immunohistochemistry studies. All authors reviewed the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to William G Newman or D Gareth Evans.

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DOI

https://doi.org/10.1038/ng.2552

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