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.

通过染色体重排（chromosomal rearrangements）形成的致癌融合基因（oncogenic fusion），是儿童癌症的标志性特征：其可界定癌症亚型、预测临床结局、在治疗过程中持续存在，且可作为理想的治疗靶点。然而，目前对致癌融合基因形成的病因学机制仍缺乏清晰认知。本研究基于5190名儿童癌症患者的肿瘤转录组测序数据，对致癌融合基因开展全面分析，鉴定出多种调控其形成的关键因素。通过数学建模，本研究发现致癌融合基因所承受的差异化选择压力与临床结局之间存在显著关联。我们还发现了一类具有类似启动子劫持（promoter-hijacking）特征的致癌融合基因亚型，这类亚型有望为治疗靶点开发提供全新策略。此外，我们在部分致癌融合基因中发现了广泛存在的可变剪接（alternative splicing）现象。尤为引人注目的是，我们在部分致癌融合基因中鉴定出全新的剪接位点，并证实这些剪接位点可为基于病因学的基因组编辑提供全新的治疗易感靶点。本研究揭示了儿童癌症中致癌融合基因形成的通用机制原理，并展现出深远的临床意义，涵盖基于病因学的风险分层（risk stratification）策略以及基于基因组编辑的治疗手段。