Lay Summary Brain tumors are the leading cause of cancer-related death in children, and many pediatric brain tumors remain difficult to treat. While most research has focused on genetic mutations, another important layer of regulation—how genes are “spliced” to make different versions of RNA and proteins—has been less well studied in childhood brain cancers. In this study, we analyzed RNA data from 729 pediatric brain tumors to understand how RNA splicing differs across tumor types. We found that tumors could be grouped into distinct categories based on their splicing patterns, and that these patterns were linked to differences in tumor behavior and patient outcomes. Some tumors showed widespread splicing changes that affected important cancer-related pathways. We also identified a splicing change in a gene called CLK1 that is common in pediatric brain tumors and normally seen during early brain development. Changing how CLK1 is spliced reduced tumor cell growth and disrupted cancer-related pathways in a representative patient-derived model. Importantly, drugs that target this pathway are already being tested in adults with cancer. Together, these findings show that RNA splicing plays a major role in pediatric brain tumor biology and may represent a new way to classify tumors and develop targeted treatments for children with brain cancer.
Naqvi et al. (Mon,) studied this question.