The integrated landscape of driver genomic alterations in glioblastoma. Academic Article uri icon

Overview

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.

publication date

  • August 5, 2013

Research

keywords

  • Brain Neoplasms
  • Genomics
  • Glioblastoma

Identity

PubMed Central ID

  • PMC3799953

Scopus Document Identifier

  • 84884996623

Digital Object Identifier (DOI)

  • 10.1038/ng.2734

PubMed ID

  • 23917401

Additional Document Info

volume

  • 45

issue

  • 10