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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 detection of 272 oncogenic fusion gene pairs by using tumor transcriptome sequencing data from 5190 childhood cancer patients. We identify diverse factors, including translation frame, protein domain, splicing, and gene length, that shape the formation of oncogenic fusions. Our mathematical modeling reveals a strong link between differential selection pressure and clinical outcome in CBFB-MYH11. We discover 4 oncogenic fusions, including RUNX1-RUNX1T1, TCF3-PBX1, CBFA2T3-GLIS2, and KMT2A-AFDN, with promoter-hijacking-like features that may offer alternative strategies for therapeutic targeting. We uncover extensive alternative splicing in oncogenic fusions including KMT2A-MLLT3, KMT2A-MLLT10, C11orf95-RELA, NUP98-NSD1, KMT2A-AFDN and ETV6-RUNX1. We discover neo splice sites in 18 oncogenic fusion gene pairs and demonstrate that such splice sites confer 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 etiology-based risk stratification and genome-editing-based therapeutics.

ObjectiveMoral injury is a nascent construct intended to capture reactions to events that violate deeply held beliefs and moral values. Although a model of moral injury has been proposed, many of the theoretical propositions of this model have yet to be systematically studied.MethodWe conducted semistructured interviews with eight veterans who reported experiencing morally injurious events during war zone deployments.ResultsUsing narrative thematic analysis, five main themes and associated subthemes emerged from the data. The main themes capture the timing of the event, contextual factors that affected the decision-making process during the morally injurious event, reactions to the moral injurious event, search for purpose and meaning, and opening up.ConclusionThe findings from the present study supported an existing model of moral injury, while extending it in several important ways. Preliminary clinical recommendations and directions for future research are discussed based on the study findings. These include directly exploring the context surrounding the morally injurious event, examining the veterans' moral appraisals, and helping them assume appropriate responsibility for their actions to reduce excessive self-blame. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

ObjectiveMoral injury is a nascent construct intended to capture reactions to events that violate deeply held beliefs and moral values. Although a model of moral injury has been proposed, many of the theoretical propositions of this model have yet to be systematically studied.MethodWe conducted semistructured interviews with eight veterans who reported experiencing morally injurious events during war zone deployments.ResultsUsing narrative thematic analysis, five main themes and associated subthemes emerged from the data. The main themes capture the timing of the event, contextual factors that affected the decision-making process during the morally injurious event, reactions to the moral injurious event, search for purpose and meaning, and opening up.ConclusionThe findings from the present study supported an existing model of moral injury, while extending it in several important ways. Preliminary clinical recommendations and directions for future research are discussed based on the study findings. These include directly exploring the context surrounding the morally injurious event, examining the veterans' moral appraisals, and helping them assume appropriate responsibility for their actions to reduce excessive self-blame. (PsycINFO Database Record (c) 2019 APA, all rights reserved).