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Integrated molecular and clinical analysis of low-grade gliomas in children with neurofibromatosis type 1 (NF1)

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Abstract

Low-grade gliomas (LGGs) are the most common childhood brain tumor in the general population and in individuals with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Surgical biopsy is rarely performed prior to treatment in the setting of NF1, resulting in a paucity of tumor genomic information. To define the molecular landscape of NF1-associated LGGs (NF1-LGG), we integrated clinical data, histological diagnoses, and multi-level genetic/genomic analyses on 70 individuals from 25 centers worldwide. Whereas, most tumors harbored bi-allelic NF1 inactivation as the only genetic abnormality, 11% had additional mutations. Moreover, tumors classified as non-pilocytic astrocytoma based on DNA methylation analysis were significantly more likely to harbor these additional mutations. The most common secondary alteration was FGFR1 mutation, which conferred an additional growth advantage in multiple complementary experimental murine Nf1 models. Taken together, this comprehensive characterization has important implications for the management of children with NF1-LGG, distinct from their sporadic counterparts.

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Acknowledgements

Research support for this study was provided by a Children’s Tumor Foundation Synodos Low Grade Glioma Grant (2015-18-004 to Michael Fisher, David Gutmann, Stefan Pfister, Joanna Phillips, Angela Waanders). We thank Vidya Browder, Salvo La Rosa and Annette Bakker of the Children’s Tumor Foundation for coordinating the efforts of the Synodos Low Grade Glioma and providing input. We thank SAGE Bionetworks for creating the database and housing the data for this study. This research was conducted using samples made available by The Children’s Brain Tumor Network (formerly the Children’s Brain Tumor Tissue Consortium). Additional support for other biorepositories were made possible by the UCSF Brain Tumor SPORE Biorepository NIH/NCI P50CA097257, St. Louis Children’s Hospital Foundation and Children’s Surgical Sciences Institute, and the Morgan Adams Foundation. We thank Jaishri Blakeley (Johns Hopkins University), David Ellison (St. Jude Children’s Research Hospital), Mathias Karajannis (Memorial Sloan Kettering Cancer Center), Laura Klesse (University of Texas Southwestern Medical Center), Jeff Knipstein (Children’s Hospital of Wisconsin), Nathan Robison (Children’s Hospital Los Angeles), Fausto Rodriguez (Johns Hopkins University), Anat Stemmer-Rachamimov (Massachussets General Hospital), Uri Tabori (Hospital for Sick Children, Toronto), and Lauren Weintraub (Albany Medical Center) for providing specimens that were not used as part of this manuscript. We thank Thomas de Raedt, Till Milde, and Olaf Witt for helpful input.

Author information

Author notes

  1. Angela J. Waanders

    Present address: Division of Hematology/Oncology, Lurie Children’s Hospital of Chicago, Chicago, IL, USA

  2. Sara Gosline

    Present address: Pacific Northwest National Laboratory, Seattle, WA, USA

  3. Mark W. Kieran

    Present address: Bristol Myers Squibb, Lawrenceville, NJ, USA

  4. Zhihong Wang

    Present address: Division of Hematology and Oncology, Children’s Hospital of Richmond, Richmond, VA, USA

  5. Maryam Fouladi

    Present address: Division of Hematology and Oncology, Nationwide Children’s Hospital, Columbus, OH, USA

  6. Luca Massimi

    Present address: Pediatric Neurosurgery, A. Gemelli Hospital, Rome, Italy

  7. Michael J. Fisher and David T. W. Jones are co-first authors.

  8. Stefan M. Pfister and David H. Gutmann are co-last authors.

Authors and Affiliations

  1. Division of Oncology, The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, USA

    Michael J. Fisher, Angela J. Waanders & Stephen J. Markham

  2. Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

    David T. W. Jones, Pengbo Beck, Natalie Jäger, Andrea Wittmann, Alexander C. Sommerkamp & Stefan M. Pfister

  3. Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany

    David T. W. Jones, Pengbo Beck, Natalie Jäger, Alexander C. Sommerkamp & Stefan M. Pfister

  4. Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, USA

    Yimei Li

  5. Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, MO, 63110, USA

    Xiaofan Guo & David H. Gutmann

  6. Division of Neurosurgery, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Poonam S. Sonawane & Adam C. Resnick

  7. Departments of Pathology, University of California, San Francisco, CA, USA

    Joanna J. Phillips

  8. Departments of Neurology, University of California, San Francisco, CA, USA

    William A. Weiss

  9. Sage Bionetworks, Seattle, WA, USA

    Sara Gosline, Jineta Banerjee & Justin Guinney

  10. Faculty of Medicine, University Augsburg, Augsburg, Germany

    Astrid Gnekow & Daniela Kandels

  11. University of Colorado, Denver, CO, USA

    Nicholas K. Foreman

  12. Department of Neuropathology, Heidelberg University, Heidelberg, Germany

    Andrey Korshunov & Felix Sahm

  13. Department of Neuropathology, NN Burdenko Neurosurgical Research Centre, Moscow, Russia

    Marina Ryzhova

  14. Fondazione Policlinico A. Gemelli, IRCCS, Rome, Italy

    Luca Massimi

  15. Department of Neurosurgery, UF Health Shands Hospital, Gainesville, FL, USA

    Sri Gururangan

  16. Department of Pediatrics, Dana-Farber Cancer Institute, Boston, MA, USA

    Mark W. Kieran

  17. Division of Hematology/Oncology, Children’s Hospital of Michigan, Detroit, MI, USA

    Zhihong Wang

  18. Division of Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Maryam Fouladi

  19. Division of Hematology/Oncology, University of Iowa Stead Family Children’s Hospital, Iowa City, IA, USA

    Mariko Sato

  20. Lund University Cancer Center, Lund University, Lund, Sweden

    Ingrid Øra

  21. Karolinska University Hospital, Stockholm, Sweden

    Stefan Holm

  22. Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany

    Stefan M. Pfister

Authors
  1. Michael J. Fisher
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  2. David T. W. Jones
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  33. David H. Gutmann
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Contributions

MJF and DHG conceptualized and designed the study and analyzed the clinical data. SMP and DTWJ performed the molecular analyses and provided input into study design and overall analyses. XG and PSS performed the in vitro and in vivo mouse model experiments. YL performed the statistical analyses. AJW, JJP, WAW, ACR, and SG are funded members of the Synodos LGG Team, were involved in data and sample acquisition, and provided input into study design and analysis. AG, DK, NKF, AK, MR, LM, SG, MWK, ZW, MF, MS, IO, and SH provided clinical samples and data. SJM created the majority of the tables. All authors had final approval of manuscript.

Corresponding authors

Correspondence to Michael J. Fisher or David H. Gutmann.

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Fisher, M.J., Jones, D.T.W., Li, Y. et al. Integrated molecular and clinical analysis of low-grade gliomas in children with neurofibromatosis type 1 (NF1). Acta Neuropathol 141, 605–617 (2021). https://doi.org/10.1007/s00401-021-02276-5

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  • DOI: https://doi.org/10.1007/s00401-021-02276-5

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