HGG-39. ALTERNATIVE SPLICING OF NEUROFIBROMIN 1 IS ASSOCIATED WITH ELEVATED MAPK ACTIVITY AND POOR PROGNOSIS IN HIGH-GRADE GLIOMA. (1st June 2021)

• Record Type: Journal Article
• Authors: Siddaway, Robert; Milos, Scott; Vadivel, Arun; Dobson, Tara; Swaminathan, Jyothishmathi; Ryall, Scott; Pajovic, Sanja; Nazarian, Javad; Becher, Oren; Brudno, Michael; Ramani, Arun; Gopalakrishnan, Vidya; Hawkins, Cynthia
• Is Part Of: Neuro-oncology. Volume 23(2021)Supplement 1
• Page Start: i25
• Page End: i25
• Publication Date: 2021-06-01
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noab090.103
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Despite a good understanding of the coding mutations underlying high-grade gliomas (HGG), their prognosis remains poor. We sought to characterize their transcriptional alterations and how this contributes to pathogenesis. We analyzed a large cohort of pediatric HGG (pHGG) by DNA sequencing (n=79) and RNA-Seq (n=63 plus normal brain, n=20), finding spliceosome mutations that are associated with increased splicing burden. High levels of alternative splicing were found in known cancer driver genes, with enrichment for chromatin regulators (including the SWI/SNF and NuRD complexes) and the RAS/MAPK pathway, in particular neurofibromin 1 ( NF1 ). Both pediatric and adult HGG preferentially expressed NF1 -II, a less active RAS GTPase, resulting in increased RAS/MAPK activity resulting from inclusion of exon23a into the GAP-related domain of NF1. In IDH wild-type, adult HGG, NF1 -II was associated with reduced survival independently from RAS/MAPK pathway mutations. NF1 exon23a splicing was regulated by REST-mediated suppression of splicing factors controlling its inclusion. Together, our results identify a novel mechanism by which HGG can activate RAS/MAPK signaling and other oncogenic pathways to promote tumorigenesis independently from direct mutations.