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

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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Anastasaki C, Morris SM, Gao F, Gutmann DH (2017) Children with 5′-end NF1 gene mutations are more likely to have glioma. Neurol Genet 3:192

    Article  Google Scholar 

  2. 2.

    Bandopadhayay P, Ramkissoon LA, Jain P, Bergthold G, Wala J, Zeid R et al (2016) MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet 48:273–282

    CAS  Article  Google Scholar 

  3. 3.

    Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D et al (2018) DNA methylation-based classification of central nervous system tumours. Nature 555:469–474

    CAS  Article  Google Scholar 

  4. 4.

    Chen YH, McGowan LD, Cimino PJ, Dahiya S, Leonard JR, Lee DY et al (2015) Mouse low-grade gliomas contain cancer stem cells with unique molecular and functional properties. Cell Rep 10:1899–1912

    CAS  Article  Google Scholar 

  5. 5.

    Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S et al (2013) STAR: ultrafast universal RNA-seq aligner. Bioinform (Oxf, Engl) 29:15–21

    CAS  Article  Google Scholar 

  6. 6.

    Fontebasso AM, Shirinian M, Khuong-Quang DA, Bechet D, Gayden T, Kool M et al (2015) Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age. Oncotarget 6:31844–31856

    Article  Google Scholar 

  7. 7.

    Griffith JL, Morris SM, Mahdi J, Goyal MS, Hershey T, Gutmann DH (2018) Increased prevalence of brain tumors classified as T2 hyperintensities in neurofibromatosis 1. Neurol Clin Pract 8:283–291

    Article  Google Scholar 

  8. 8.

    Gröbner SN, Worst BC, Weischenfeldt J, Buchalter I, Kleinheinz K, Rudneva VA et al (2018) The landscape of genomic alterations across childhood cancers. Nature 555:321–327

    Article  Google Scholar 

  9. 9.

    Guillamo JS, Creange A, Kalifa C, Grill J, Rodriguez D, Doz F et al (2003) Prognostic factors of CNS tumours in neurofibromatosis 1 (NF1): a retrospective study of 104 patients. Brain 126:152–160

    Article  Google Scholar 

  10. 10.

    Gutmann DH, McLellan MD, Hussain I, Wallis JW, Fulton LL, Fulton RS et al (2013) Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma. Genome Res 23:431–439

    CAS  Article  Google Scholar 

  11. 11.

    Jones DT, Jager N, Kool M, Zichner T, Hutter B, Sultan M et al (2012) Dissecting the genomic complexity underlying medulloblastoma. Nature 488:100–105

    CAS  Article  Google Scholar 

  12. 12.

    Jones DT, Hutter B, Jager N, Korshunov A, Kool M, Warnatz HJ et al (2013) Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 45:927–932

    CAS  Article  Google Scholar 

  13. 13.

    Lake JA, Donson AM, Prince E, Davies KD, Nellan A, Green AL et al (2020) Targeted fusion analysis can aid in the classification and treatment of pediatric glioma, ependymoma, and glioneuronal tumors. Pediatr Blood Cancer 67:e28028

    CAS  Article  Google Scholar 

  14. 14.

    Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, 1000 Genome Project Data Processing Subgroup (2009) The sequence alignment/map format and SAMtools. Bioinform (Oxf, Engl) 25:2078–2079

    Article  Google Scholar 

  15. 15.

    Liao Y, Smyth GK, Shi W (2014) Feature Counts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinform (Oxf, Engl) 30:923–930

    CAS  Article  Google Scholar 

  16. 16.

    Mahdi J, Shah AC, Sato A, Morris SM, McKinstry RC, Listernick R et al (2017) A multi-institutional study of brainstem gliomas in children with neurofibromatosis type 1. Neurology 88:1584–1589

    Article  Google Scholar 

  17. 17.

    Mahdi J, Goyal MS, Griffith J, Morris SM, Gutmann DH (2020) Nonoptic pathway tumors in children with neurofibromatosis type 1. Neurology 95:e1052–e1059

    CAS  Article  Google Scholar 

  18. 18.

    Neurofibromatosis Conference statement (1988) National institutes of health consensus development conference. Arch Neurol 45:575–578

    Article  Google Scholar 

  19. 19.

    Packer RJ, Iavarone A, Jones DTW, Blakeley JO, Bouffet E, Fisher MJ et al (2020) Implications of new understandings of gliomas in children and adults with NF1: report of a consensus conference. Neuro Oncol 2:773–784

    Article  Google Scholar 

  20. 20.

    Pan Y, Xiong M, Chen R, Ma Y, Corman C, Maricos M et al (2018) Athymic mice reveal a requirement for T-cell-microglia interactions in establishing a microenvironment supportive of Nf1 low-grade glioma growth. Genes Dev 32:491–496

    CAS  Article  Google Scholar 

  21. 21.

    Qaddoumi I, Orisme W, Wen J, Santiago T, Gupta K, Dalton JD et al (2016) Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol 131:833–845

    CAS  Article  Google Scholar 

  22. 22.

    Reinhardt A, Stichel D, Schrimpf D, Sahm F, Korshunov A, Reuss DE et al (2018) Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations. Acta Neuropathol 136:273–291

    CAS  Article  Google Scholar 

  23. 23.

    Rimmer A, Phan H, Mathieson I, Iqbal Z, Twigg SRF, WGS500 Consortium et al (2014) Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications. Nat Genet 46:912–918

    CAS  Article  Google Scholar 

  24. 24.

    Sahm F, Schrimpf D, Jones DT, Meyer J, Kratz A, Reuss D et al (2016) Next-generation sequencing in routine brain tumor diagnostics enables an integrated diagnosis and identifies actionable targets. Acta Neuropathol 131:903–910

    CAS  Article  Google Scholar 

  25. 25.

    Stein LD, Knoppers BM, Campbell P, Getz G, Korbel JO (2015) Data analysis: create a cloud commons. Nature 523:149–151

    CAS  Article  Google Scholar 

  26. 26.

    Usta D, Sigaud R, Buhl JL, Selt F, Marquardt V, Pauck D et al (2020) A cell-based MAPK reporter assay reveals synergistic MAPK pathway activity suppression by MAPK inhibitor combination in BRAF-driven pediatric low-grade glioma cells. Mol Cancer Ther 19:1736–1750

    CAS  Article  Google Scholar 

  27. 27.

    Wagle MC, Kirouac D, Klijn C, Liu B, Mahajan S, Juntila M et al (2018) A transcriptional MAPK pathway activity score (MPAS) is a clinically relevant biomarker in multiple cancer types. NPJ Precis Oncol 2:7

    Article  Google Scholar 

  28. 28.

    Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38:e164

    Article  Google Scholar 

  29. 29.

    Wefers AK, Stichel D, Schrimpf D, Coras R, Pages M, Tauziede-Espariat A et al (2020) Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course. Acta Neuropathol 139:193–209

    Article  Google Scholar 

  30. 30.

    Wong WH, Junck L, Druley TE, Gutmann DH (2019) NF1 glioblastoma clonal profiling reveals KMT2B mutations as potential somatic oncogenic events. Neurology 93:1067–1069

    Article  Google Scholar 

  31. 31.

    Worst BC, van Tilburg CM, Balasubramanian GP, Fiesel P, Witt R, Freitag A et al (2016) Next-generation personalised medicine for high-risk paediatric cancer patients—the INFORM pilot study. Eur J Cancer 65:91–101

    Article  Google Scholar 

  32. 32.

    Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W (2013) Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun 4:2612

    Article  Google Scholar 

Download references

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

Affiliations

Authors

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.

Ethics declarations

Conflict of interest

The authors have no relevant conflicts to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 213 KB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Keywords

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