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Splicing is an alternate oncogenic pathway activation mechanism in glioma

Author

Listed:
  • Robert Siddaway

    (The Hospital for Sick Children)

  • Scott Milos

    (The Hospital for Sick Children)

  • Arun Kumaran Anguraj Vadivel

    (The Hospital for Sick Children)

  • Tara H. W. Dobson

    (The University of Texas MD Anderson Cancer Center)

  • Jyothishmathi Swaminathan

    (The University of Texas MD Anderson Cancer Center)

  • Scott Ryall

    (The Hospital for Sick Children)

  • Sanja Pajovic

    (The Hospital for Sick Children)

  • Palak G. Patel

    (The Hospital for Sick Children)

  • Javad Nazarian

    (Children’s National Medical Center, George Washington University
    University Children’s Hospital)

  • Oren Becher

    (Ann & Robert H. Lurie Children’s Hospital of Chicago)

  • Michael Brudno

    (University of Toronto
    The Hospital for Sick Children
    University Health Network)

  • Arun Ramani

    (The Hospital for Sick Children)

  • Vidya Gopalakrishnan

    (The University of Texas MD Anderson Cancer Center)

  • Cynthia Hawkins

    (The Hospital for Sick Children
    University of Toronto
    The Hospital for Sick Children)

Abstract

High-grade diffuse glioma (HGG) is the leading cause of brain tumour death. While the genetic drivers of HGG have been well described, targeting these has thus far had little impact on survival suggesting other mechanisms are at play. Here we interrogate the alternative splicing landscape of pediatric and adult HGG through multi-omic analyses, uncovering an increased splicing burden compared with normal brain. The rate of recurrent alternative splicing in cancer drivers exceeds their mutation rate, a pattern that is recapitulated in pan-cancer analyses, and is associated with worse prognosis in HGG. We investigate potential oncogenicity by interrogating cancer pathways affected by alternative splicing in HGG; spliced cancer drivers include members of the RAS/MAPK pathway. RAS suppressor neurofibromin 1 is differentially spliced to a less active isoform in >80% of HGG downstream from REST upregulation, activating the RAS/MAPK pathway and reducing glioblastoma patient survival. Overall, our results identify non-mutagenic mechanisms by which cancers activate oncogenic pathways which need to accounted for in personalized medicine approaches.

Suggested Citation

  • Robert Siddaway & Scott Milos & Arun Kumaran Anguraj Vadivel & Tara H. W. Dobson & Jyothishmathi Swaminathan & Scott Ryall & Sanja Pajovic & Palak G. Patel & Javad Nazarian & Oren Becher & Michael Bru, 2022. "Splicing is an alternate oncogenic pathway activation mechanism in glioma," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28253-4
    DOI: 10.1038/s41467-022-28253-4
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    Citations

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    Cited by:

    1. Adrian B. Levine & Liana Nobre & Anirban Das & Scott Milos & Vanessa Bianchi & Monique Johnson & Nicholas R. Fernandez & Lucie Stengs & Scott Ryall & Michelle Ku & Mansuba Rana & Benjamin Laxer & Java, 2024. "Immuno-oncologic profiling of pediatric brain tumors reveals major clinical significance of the tumor immune microenvironment," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Maciej Bak & Erik Nimwegen & Ian U. Kouzel & Tamer Gur & Ralf Schmidt & Mihaela Zavolan & Andreas J. Gruber, 2024. "MAPP unravels frequent co-regulation of splicing and polyadenylation by RNA-binding proteins and their dysregulation in cancer," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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