Splicing-sensitive fusion transcripts associated with key tumor characteristics occur at high frequency in neuroblastoma

Abstract

The paucity of recurrent mutations has hampered efforts to understand the pathogenesis of neuroblastoma. Through analysis of RNA-sequenced neuroblastoma, we identified >900 primarily intrachromosomal fusion transcripts generated by genes in close proximity. Fusions were enriched in chromosomal regions gained or lost in neuroblastoma and included well-known neuroblastoma oncogenes. The majority of fusions contained canonical splicing sites and a subset exhibited increased sensitivity to spliceosome inhibition. As a proof-of-principle that a gene product with altered properties can be produced by these fusions, we characterized the ZNF451-BAG2 fusion which generates a truncated BAG2-protein capable of inhibiting retinoic acid-induced differentiation. Our findings elucidate a mechanism through which altered gene products, relevant for neuroblastoma pathogenesis and representing possible novel drug targets, can be generated.