Abstract
Mutations in genes such as LZTR1 and CTNND2 and recurrent EGFR translocations drive glioblastoma.
Major finding: Mutations in genes such as LZTR1 and CTNND2 and recurrent EGFR translocations drive glioblastoma.
Approach: Driver mutations were nominated via integration of somatic mutations and copy number variations.
Impact: EGFR inhibitors may suppress the growth of human glioblastomas harboring EGFR fusions.
The identification of driver mutations essential for tumor initiation and progression has been hampered by the abundance of passenger mutations in tumors. Although somatic mutations in genes including EGF receptor (EGFR) have been implicated in the pathogenesis of glioblastoma multiforme (GBM), treatment of these tumors remains challenging, underscoring the need to characterize additional therapeutic targets. To address these issues, Frattini and colleagues integrated whole-exome sequencing and copy number variation (CNV) analysis of a panel of human GBM tumors and nominated driver genes targeted by both recurrent somatic mutations and focal CNVs. This approach identified known GBM driver genes as well as 18 new candidate driver genes. Among the top-scoring genes, leucine-zipper-like transcription regulator 1 (LZTR1) was concomitantly mutated and deleted in GBM, suggesting that LZTR1 is a tumor suppressor inactivated by loss of heterozygosity. Mutations in LZTR1 impaired its interaction with the ubiquitin ligase cullin 3 and enhanced the growth of GBM-derived glioma spheres, supporting a role for LZTR1 in limiting GBM stem cell self-renewal. In contrast, mutations and deletions of catenin, delta 2 (CTNND2), which encodes a protein required for neural development, were associated with the mesenchymal GBM subtype and poor outcome. Expression of wild-type CTNND2 diminished glioma sphere formation and xenograft growth, downregulated mesenchymal markers, and induced a neuronal phenotype, suggesting that CTNND2 inactivation drives mesenchymal transformation. Furthermore, RNA sequencing identified recurrent translocations involving EGFR in primary GBM tumors, in particular fusions of the region encoding the EGFR tyrosine kinase domain with the septin 14 gene, which stimulated mitogen-independent glioma cell growth and self-renewal, constitutive activation of downstream STAT3 signaling, and enhanced sensitivity to EGFR inhibitors. These findings establish the landscape of genomic alterations in GBM and suggest a personalized therapeutic strategy for patients with GBM who harbor EGFR fusions.
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