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Expanded analysis of high-grade astrocytoma with piloid features identifies an epigenetically and clinically distinct subtype associated with neurofibromatosis type 1

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Abstract

High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with CDKN2A/B homozygous deletion and/or ATRX mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (n = 144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence CDKN2A/B homozygous deletion, and/or ATRX mutations/loss in this tumor type, along with a subset showing NF1 alterations. Five of 93 (5.4%) cases sequenced harbored TP53 mutations and RNA fusion analysis identified a single tumor containing an NTRK2 gene fusion, neither of which have been previously reported in HGAP. Clustering analysis revealed the presence of three distinct HGAP subtypes (or groups = g) based on whole-genome DNA methylation patterns, which we provisionally designated as gNF1 (n = 18), g1 (n = 72), and g2 (n = 54) (median ages 43.5 years, 47 years, and 32 years, respectively). Subtype gNF1 is notable for enrichment with patients with Neurofibromatosis Type 1 (33.3%, p = 0.0008), confinement to the posterior fossa, hypermethylation in the NF1 enhancer region, a trend towards decreased progression-free survival (p = 0.0579), RNA processing pathway dysregulation, and elevated non-neoplastic glia and neuron cell content (p < 0.0001 and p < 0.0001, respectively). Overall, our expanded cohort broadens the genetic, epigenetic, and clinical phenotype of HGAP and provides evidence for distinct epigenetic subtypes in this tumor type.

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Acknowledgements

This work utilized the computational resources of the NIH HPC Biowulf cluster.

Funding

This work was supported by the Intramural Research Program at the Center for Cancer Research, National Cancer Institute and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health.

Author information

Author notes

  1. Patrick J. Cimino and Courtney Ketchum have contributed equally.

Authors and Affiliations

  1. Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Dr., Room 3D20, Bethesda, MD, 20892, USA

    Patrick J. Cimino

  2. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Dr., Room 2S235, Bethesda, MD, 20892, USA

    Courtney Ketchum, Rust Turakulov, Omkar Singh, Zied Abdullaev, Martha Quezado, Drew Pratt & Kenneth Aldape

  3. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Caterina Giannini

  4. Department of Pathology, University of Chicago, Chicago, IL, USA

    Peter Pytel

  5. Department of Pathology, Duke University, Durham, NC, USA

    Giselle Yvette Lopez

  6. Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    Howard Colman

  7. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    MacLean P. Nasrallah

  8. Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Mariarita Santi

  9. Laboratorio Bacchi, São Paulo, Brazil

    Igor Lima Fernandes

  10. Department of Pathology, Stanford University, Stanford, CA, USA

    Jeff Nirschl

  11. Department of Pathology and Immunology, Washington University, St. Louis, MO, USA

    Sonika Dahiya

  12. Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA

    Stewart Neill

  13. Department of Pathology, University of California San Francisco, San Francisco, CA, USA

    David Solomon

  14. Charite, Universitatsmedizin Berlin, Berlin, Germany

    Eilis Perez & David Capper

  15. Department of Pathology, Inova Fairfax Hospital, Fairfax, VA, USA

    Haresh Mani

  16. Department of Pathology, Mercy General Hospital, Sacramento, CA, USA

    Dario Caccamo

  17. Department of Neurology, Center for Neurosciences, Tucson, AZ, USA

    Matthew Ball

  18. Department of Pathology, Tucson Medical Center, Tucson, AZ, USA

    Michael Badruddoja

  19. Department of Pathology, University of Alabama, Birmingham, AL, USA

    Rati Chkheidze

  20. Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI, USA

    Sandra Camelo-Piragua

  21. Department of Pathology, Beaumont Hospital, Royal Oak, MI, USA

    Joseph Fullmer

  22. Department of Pathology, Boston Children’s Hospital, Boston, MA, USA

    Sanda Alexandrescu

  23. Department of Pathology, Cleveland Clinic, Cleveland, OH, USA

    Gabrielle Yeaney

  24. Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA

    Charles Eberhart

  25. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    Maria Martinez-Lage

  26. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    Jie Chen

  27. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Leor Zach

  28. Department of Pathology, University of Colorado Hospital, Aurora, CO, USA

    B. K. Kleinschmidt-DeMasters

  29. Department of Pathology, University of Iowa Hospitals, Iowa City, IA, USA

    Marco Hefti

  30. Department of Pathology, University of Virginia Health System, Charlottesville, VA, USA

    Maria-Beatriz Lopes

  31. Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA, USA

    Nicholas Nuechterlein

  32. Department of Pathology, Northwestern Memorial Hospital, Chicago, IL, USA

    Craig Horbinski

  33. Department of Pathology, University of California Los Angeles Medical Center, Los Angeles, CA, USA

    Fausto J. Rodriguez

Authors
  1. Patrick J. Cimino
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  2. Courtney Ketchum
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  38. Martha Quezado
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  39. Drew Pratt
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  40. Kenneth Aldape
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Cimino, P.J., Ketchum, C., Turakulov, R. et al. Expanded analysis of high-grade astrocytoma with piloid features identifies an epigenetically and clinically distinct subtype associated with neurofibromatosis type 1. Acta Neuropathol 145, 71–82 (2023). https://doi.org/10.1007/s00401-022-02513-5

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