Splicing is an alternate oncogenic pathway activation mechanism in glioma

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 Brudno, Arun Ramani, Vidya Gopalakrishnan and Cynthia Hawkins ()
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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
Oren Becher: Ann & Robert H. Lurie Children’s Hospital of Chicago
Michael Brudno: University of Toronto
Arun Ramani: The Hospital for Sick Children
Vidya Gopalakrishnan: The University of Texas MD Anderson Cancer Center
Cynthia Hawkins: The Hospital for Sick Children

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28253-4

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DOI: 10.1038/s41467-022-28253-4

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