Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication. Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication

Oncogenic fusions formed through chromosomal rearrangements are hallmarks of childhood cancer that define cancer subtype, predict outcome, persist through treatment, and can be ideal therapeutic targets. However, mechanistic understanding of the etiology of oncogenic fusions remains elusive. Here we report a comprehensive analysis of oncogenic fusions by using tumor transcriptome sequencing data from 5,190 childhood cancer patients. We identified diverse factors that shape the formation of oncogenic fusions. Our mathematical modeling revealed a strong link between differential selection pressure on oncogenic fusions and clinical outcome. We discovered subset of oncogenic fusions with promoter-hijacking-like features that may offer novel strategies for therapeutic targeting. We uncovered extensive alternative splicing in a subset of oncogenic fusions. Strikingly, we discovered novel splice sites in some oncogenic fusions and demonstrated that these splice sites confer novel therapeutic vulnerability for etiology-based genome editing. Our study reveals general principles on the etiology of oncogenic fusions in childhood cancer and suggests profound clinical implications including novel etiology-based risk stratification and genome-editing-based therapeutics.