Abstract
The widespread application of high-throughput sequencing methods is resulting in the identification of a rapidly growing number of novel gene fusions caused by tumour-specific chromosomal rearrangements, whose oncogenic potential remains unknown. Here we describe a strategy that builds upon recent advances in genome editing and combines ex vivo and in vivo chromosomal engineering to rapidly and effectively interrogate the oncogenic potential of genomic rearrangements identified in human brain cancers. We show that one such rearrangement, an microdeletion resulting in a fusion between Brevican (BCAN) and Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1), is a potent oncogenic driver of high-grade gliomas and confers sensitivity to the experimental TRK inhibitor entrectinib. This work demonstrates that BCAN-NTRK1 is a bona fide human glioma driver and describes a general strategy to define the oncogenic potential of novel glioma-associated genomic rearrangements and to generate accurate preclinical models of this lethal human cancer.
Highlights
The widespread application of high-throughput sequencing methods is resulting in the identification of a rapidly growing number of novel gene fusions caused by tumour-specific chromosomal rearrangements, whose oncogenic potential remains unknown
We describe a strategy that builds upon recent advances in genome editing and combines ex vivo and in vivo chromosomal engineering to rapidly and effectively interrogate the oncogenic potential of genomic rearrangements identified in human brain cancers
We show that one such rearrangement, an microdeletion resulting in a fusion between Brevican (BCAN) and Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1), is a potent oncogenic driver of high-grade gliomas and confers sensitivity to the experimental TRK inhibitor entrectinib
Summary
The widespread application of high-throughput sequencing methods is resulting in the identification of a rapidly growing number of novel gene fusions caused by tumour-specific chromosomal rearrangements, whose oncogenic potential remains unknown. Ongoing large-scale sequencing efforts provide an unprecedented picture of the genetic complexity of human cancers Deciphering this wealth of data and separating true driver mutations from benign passengers is essential to better understand cancer pathogenesis and develop more effective targeted therapies. The generation of new mouse models via conventional gene targeting methods is time-consuming and costly, and cannot be scaled up to investigate the functional relevance of the myriad recurrent cancer-associated mutations that have been—and are being—identified in patient samples. Among these mutations, chromosomal rearrangements are of particular interest as they can result in the generation of therapeutically actionable gene fusions[1,2,3]. We previously demonstrated that infecting the lungs of adult mice with recombinant adenoviral vectors expressing Cas[9] and two guide RNAs targeting the relevant intronic regions on Chromosome 17 is sufficient to generate the Eml4-Alk chromosomal inversion and promote the formation of lung adenocarcinomas that closely recapitulate the histological and biological features of human EML4-ALK-driven lung cancers[10]
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