Decoding splicing dysregulation in pediatric CNS tumors through multi-omic integration
Childhood brain tumors remain the deadliest form of childhood cancer, claiming more young lives each year than any other disease. Over the past decade, advances in DNA sequencing have identified many of the genetic mutations, fusions, and chromosomal changes that initiate these tumors. These discoveries have transformed diagnosis and led to new molecular classifications. Yet, despite these breakthroughs, many tumors still lack clear genetic drivers or fail to respond to targeted therapies, suggesting that the answers lie beyond DNA alone. One critical and often overlooked layer of regulation lies in RNA splicing: the process that edits and joins RNA segments for protein synthesis. When splicing goes wrong, it can generate abnormal RNA and protein products that alter cell growth, signaling, and immune recognition. The brain is especially prone to splicing complexity, producing the highest isoform diversity of any human tissue. In this context, splicing errors can easily masquerade as normal variation, making interpretation extremely difficult. Modern RNA-sequencing can detect hundreds of thousands of splicing events per tumor, but determining which are biologically meaningful remains a major barrier. By investigating how splicing becomes dysregulated and uncovering the molecular forces that drive it, we can better understand the biology of pediatric brain tumors and tap into the vast number of splicing events that may offer therapeutic opportunities
Project Goals
Using a large, harmonized dataset of more than 2,000 pediatric brain tumors, this project will systematically map splicing disruption across tumor types and determine the drivers of these changes. By integrating RNA sequencing with whole-genome, whole-exome, and methylation data, we will identify genetic mutations and epigenetic changes that alter RNA splicing. We will quantify the overall level of splicing disruption per patient, assess its association with age, tumor subtype, and survival, and examine whether changes in RNA-binding proteins or the spliceosome contribute to this disruption. These analyses will reveal whether extensive splicing dysregulation marks aggressive disease or defines specific biological subgroups. Ultimately, this work will create the most comprehensive picture to date of how splicing is controlled—and miscontrolled—in childhood brain tumors. It will uncover molecular mechanisms that generate novel RNA isoforms, some of which may encode tumor specific antigens or vulnerable targets for RNA-based therapies. By pinpointing the biological consequences of splicing dysregulation, this project will map the key splicing events that can be harnessed for diagnosis and therapy, guiding future efforts to turn RNA vulnerabilities into effective treatments. The diversity of RNA changes within each patient provides a rich set of molecular targets that are currently untapped yet could meaningfully improve outcomes for children with brain cancers.
