The integrated landscape of driver genomic alterations in glioblastoma by Frattini Veronique, Trifonov Vladimir, Chan Joseph Minhow, Castano Angelica, Lia Marie, Abate Francesco, Keir Stephen T, Ji Alan X, Zoppoli Pietro, Niola Francesco, Danussi Carla, Dolgalev Igor, Porrati Paola, Pellegatta Serena, Heguy Adriana, Gupta Gaurav, Pisapia David J, Canoll Peter, Bruce Jeffrey N, McLendon Roger E, Yan Hai, Aldape Ken, Finocchiaro Gaetano, Mikkelsen Tom, Privé Gilbert G, Bigner Darell D, Lasorella Anna, Rabadan Raul, Iavarone Antonio in Nature genetics (2013). PubMed

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.

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