Alternative splicing in pediatric central nervous system tumors highlights oncofetal candidate CLK1 exon 4

作者：Ammar S. Naqvi, Patricia A. Sullivan, Ryan J. Corbett, Priyanka Sehgal, Karina L. Conkrite, Komal S. Rathi, Brian Ennis, Katharina E. Hayer, Bo Zhang, Miguel Brown, Daniel P. Miller, Alex Sickler, Adam Kraya, Kaleem L. Coleman, Joseph M. Dybas, Zhuangzhuang Geng, Christopher Blackden, Shehbeel Arif, Antonia Chroni, Aditya Lahiri, Madison Hollawell, Phillip B. Storm, Dalia Haydar, Jessica Foster, Mateusz Koptyra, Peter J. Madsen, Sharon J. Diskin, Andrei Thomas‐Tikhonenko, Adam Resnick, Jo Lynne Rokita · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.08.03.606419 · 被引用次数：5 · 研究领域：RNA Research and Splicing、RNA modifications and cancer、Genomics and Chromatin Dynamics

Abstract Background Pediatric brain tumors are the leading cause of disease-related mortality in children, yet many aggressive tumors lack effective therapies. RNA splicing is a hallmark of cancer, but it has not yet been systematically studied in pediatric brain tumors. Methods We analyzed 729 pediatric brain tumors spanning histologies and molecular subtypes to quantify differential tumor splicing. We developed the Splicing Burden Index (SBI) to enable cross-sample comparisons and performed hierarchical clustering of highly variable splice events to define splicing-informed tumor groups. These were integrated with clinical outcomes, pathway activity, and proteogenomic data. Recurrent splice events were prioritized for predicted functional impact, and in vitro perturbation studies were performed targeting the splicing kinase CDC-like kinase 1 (CLK1) . Results SBI revealed substantial inter- and intra-histology heterogeneity. Clusters were enriched for histologies and molecular subtypes, several of which were independently associated with survival beyond histology and clinical covariates. Spliceosome pathway activity varied across clusters and was associated with worse survival, yet was not correlated with SBI, indicating distinct dimensions of splicing dysregulation. Functional prioritization identified a recurrent in CLK1 exon 4, required for canonical kinase activity. CLK1 exon 4 inclusion followed an oncofetal pattern and showed context-dependent associations with outcome...