Splicing is an alternate oncogenic pathway activation mechanism in glioma

Robert Siddaway, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
Scott Milos, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
Arun Kumaran Vadivel, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
Tara H. Dobson, Department of Pediatrics - Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Jyothishmathi Swaminathan, Department of Pediatrics - Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Scott Ryall, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
Sanja Pajovic, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
Palak G. Patel, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.
Javad Nazarian, Department of Integrative Systems Biology, Children's National Medical Center, George Washington University, Washington, DC, 20010, USA.
Oren Becher, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA.
Michael Brudno, Department of Computer Science, University of Toronto, Toronto, Canada.
Arun Ramani, Centre for Computational Medicine, The Hospital for Sick Children, Toronto, Canada.
Vidya Gopalakrishnan, Department of Pediatrics - Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Cynthia Hawkins, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada. cynthia.hawkins@sickkids.ca.

Document Type

Journal Article

Publication Date

1-31-2022

Journal

Nature communications

Volume

13

Issue

1

DOI

10.1038/s41467-022-28253-4

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.

Department

Pediatrics

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