Glioblastoma is one of the most challenging forms of cancer to treat. Here we describe a computational platform that integrates the analysis of copy number variations and somatic mutations and unravels the landscape of in-frame gene fusions in glioblastoma. We found mutations with loss of heterozygosity in LZTR1, encoding an adaptor of CUL3-containing E3 ligase complexes. Mutations and deletions disrupt LZTR1 function, which restrains the self renewal and growth of glioma spheres that retain stem cell features. Loss-of-function mutations in CTNND2 target a neural-specific gene and are associated with the transformation of glioma cells along the very aggressive mesenchymal phenotype. We also report recurrent translocations that fuse the coding sequence of EGFR to several partners, with EGFR-SEPT14 being the most frequent functional gene fusion in human glioblastoma. EGFR-SEPT14 fusions activate STAT3 signaling and confer mitogen independence and sensitivity to EGFR inhibition. These results provide insights into the pathogenesis of glioblastoma and highlight new targets for therapeutic intervention.
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This work was supported by National Cancer Institute grants R01CA101644 and R01CA131126 (A.L.) and R01CA085628 and R01CA127643 (A.I.), the Stewart Foundation (R.R.), the Partnership for Cure (R.R.), US National Institutes of Health (NIH) grant NIH 1 P50 MH094267-01 (R.R.), the Lymphoma Research Foundation (R.R.), NIH 1 U54 CA121852-05 (R.R.), NIH 1R01CA164152-01 (R.R.), the Leukemia and Lymphoma Society (R.R.), the Canadian Cancer Society (G.G.P.), the Cancer Research Society (G.G.P.), the National Institute of Neurological Disorders and Stroke R01NS061776 (A.I.) and a grant from The Chemotherapy Foundation (A.I.). G.F. was supported by grants from the Associazione Italiana per la Ricerca sul Cancro and from the Italian Ministry of Health. V.F., P.Z., C.D. and F.N. are supported by fellowships from the Italian Ministry of Welfare/Provincia di Benevento and the Federazione Italiana Associazioni Genitori Oncoematologia Pedriatica (FIAGOP) (C.D.). We thank J. Parkinson for helpful discussions on the phylogeny of LZTR1 genes, L. Bertin for help with protein blots, J. Kroll (Tumor Biology Center, Freiburg) for the LZTR1 plasmids and M. Pagano (New York University) for CUL3 expression plasmids.
The authors declare no competing financial interests.
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Frattini, V., Trifonov, V., Chan, J. et al. The integrated landscape of driver genomic alterations in glioblastoma. Nat Genet 45, 1141–1149 (2013) doi:10.1038/ng.2734
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