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


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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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.

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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.

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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 (2021).

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  • Pilocytic astrocytoma
  • Pediatric brain tumor
  • Neurofibromatosis
  • Methylation
  • FGFR1