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NF1 patient missense variants predict a role for ATM in modifying neurofibroma initiation

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Abstract

In Neurofibromatosis type 1, NF1 gene mutations in Schwann cells (SC) drive benign plexiform neurofibroma (PNF), and no additional SC changes explain patient-to-patient variability in tumor number. Evidence from twin studies suggests that variable expressivity might be caused by unidentified modifier genes. Whole exome sequencing of SC and fibroblast DNA from the same resected PNFs confirmed biallelic SC NF1 mutations; non-NF1 somatic SC variants were variable and present at low read number. We identified frequent germline variants as possible neurofibroma modifier genes. Genes harboring variants were validated in two additional cohorts of NF1 patients and by variant burden test. Genes including CUBN, CELSR2, COL14A1, ATR and ATM also showed decreased gene expression in some neurofibromas. ATM-relevant DNA repair defects were also present in a subset of neurofibromas with ATM variants, and in some neurofibroma SC. Heterozygous ATM G2023R or homozygous S707P variants reduced ATM protein expression in heterologous cells. In mice, genetic Atm heterozygosity promoted Schwann cell precursor self-renewal and increased tumor formation in vivo, suggesting that ATM variants contribute to neurofibroma initiation. We identify germline variants, rare in the general population, overrepresented in NF1 patients with neurofibromas. ATM and other identified genes are candidate modifiers of PNF pathogenesis.

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Acknowledgements

This work was funded by NIH-R37-NS083580 (NINDS Javits Neuroscience Investigator Award to NR) and an Innovation Award from Cincinnati Children’s Hospital. We thank Dr. Carlos Prada for review of the manuscript, Sage Bioinformatics (Sara J.C. Gosline) for access to the dermal neurofibroma dataset prior to publication, A. Pemov and D. Stewart (NCI) for assistance with data transfer, and Doug Marchuk (Duke) for suggesting use of the Burden test. We thank the CHTN Midwestern Division for some samples used in this study. All procedures involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Author notes

  1. Yanan Yu and Kwangmin Choi contributed equally.

Authors and Affiliations

  1. Department of Experimental Hematology and Cancer Biology, Cincinati Children’s Hospital Medical Center and Department of Pediatrics, University of Cincinanti School of Medicine, Cincinnati, OH, USA

    Yanan Yu, Kwangmin Choi, Jianqiang Wu, Paul R. Andreassen, Jose A. Cancelas & Nancy Ratner

  2. Division of Biomedical Informatics, Cincinnati Children’s Hospital, Cincinnati, OH, USA

    Phillip J. Dexheimer

  3. Division of Human Genetics, Cincinnati Children’s Hospital Medical Center and the Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, USA

    Mehdi Keddache & Lisa J. Martin

  4. Department of Human Genetics, KU Leuven, Leuven, Belgium

    Hilde Brems & Eric Legius

  5. Department of Neurological Surgery, Mayo Clinic, Rochester, MN, USA

    Robert J. Spinner

  6. Hoxworth Blood Center, University of Cincinnati, Cincinnati, OH, USA

    Jose A. Cancelas

  7. Department of Molecular Genetics and Microbiology, UF Genetics Institute, UF Health Cancer Center, University of Florida, Gainesville, FL, USA

    Margaret R. Wallace

  8. Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA

    Kristine S. Vogel

  9. Graduate Program in Cancer and Cell Biology, University of Cincinnati, Cincinnati, OH, USA

    Yanan Yu

Authors
  1. Yanan Yu
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  2. Kwangmin Choi
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  3. Jianqiang Wu
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  4. Paul R. Andreassen
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  5. Phillip J. Dexheimer
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  6. Mehdi Keddache
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  7. Hilde Brems
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  8. Robert J. Spinner
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  9. Jose A. Cancelas
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  10. Lisa J. Martin
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  11. Margaret R. Wallace
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  12. Eric Legius
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  13. Kristine S. Vogel
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  14. Nancy Ratner
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Contributions

NR, KC and YY designed the study and prepared the manuscript. RJS provided surgical specimens. MW provided tissue sections and DNA. EL and HB provided cells. JW and JAC sorted cells. MK and PD performed WES. KC performed variant calling and downstream bioinformatics analyses. YY and KC filtered predicted variants. YY verified candidates with IGV, Sanger sequencing, and functional analysis of ATM in NF1. KV performed 53BP1 focus and DNA comet assays. LJM analyzed population distribution.

Corresponding author

Correspondence to Nancy Ratner.

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Yu, Y., Choi, K., Wu, J. et al. NF1 patient missense variants predict a role for ATM in modifying neurofibroma initiation. Acta Neuropathol 139, 157–174 (2020). https://doi.org/10.1007/s00401-019-02086-w

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  • DOI: https://doi.org/10.1007/s00401-019-02086-w

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