The integrated landscape of driver genomic alterations in glioblastoma

Veronique Frattini, Vladimir Trifonov, Joseph Minhow Chan, Angelica Castano, Marie Lia, Francesco Abate, Stephen T. Keir, Alan X. Ji, Pietro Zoppoli, Francesco Niola, Carla Danussi, Igor Dolgalev, Paola Porrati, Serena Pellegatta, Adriana Heguy, Gaurav Gupta, David J. Pisapia, Peter Canoll, Jeffrey N. Bruce, Roger E. McLendonHai Yan, Ken Aldape, Gaetano Finocchiaro, Tom Mikkelsen, Gilbert G. Privé, Darell D. Bigner, Anna Lasorella, Raul Rabadan, Antonio Iavarone

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1141-1149
Number of pages9
JournalNature Genetics
Volume45
Issue number10
DOIs
Publication statusPublished - Oct 2013

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ASJC Scopus subject areas

  • Genetics

Cite this

Frattini, V., Trifonov, V., Chan, J. M., Castano, A., Lia, M., Abate, F., Keir, S. T., Ji, A. X., Zoppoli, P., Niola, F., Danussi, C., Dolgalev, I., Porrati, P., Pellegatta, S., Heguy, A., Gupta, G., Pisapia, D. J., Canoll, P., Bruce, J. N., ... Iavarone, A. (2013). The integrated landscape of driver genomic alterations in glioblastoma. Nature Genetics, 45(10), 1141-1149. https://doi.org/10.1038/ng.2734