We have generated preliminary data showing that retroviral elements actively transpose throughout the process of tumor growth and relapse in pediatric HGGs. We hypothesize that transposable elements have a crucial role in contributing to clonal and subclonal genomic evolution in this cancer.
We also hypothesize that transposition events underlie the biology of other pediatric brain cancers, including medulloblastomas and ependymomas. We expect that transposition events have outsized contributions in these childhood cancers compared to adult tumors. This is because pediatric tumors tend to have lower mutational loads than their adult counterparts, and we therefore propose that epigenetic and chromatin changes nucleated by transposition events are important to drive these childhood malignancies.
What are the goals of this project?
The goals of this project are to identify somatic transposition events, by comparing WGS data for matched germline-tumor pairs, to identify active transposition events during tumor evolution, by comparing genomic data at diagnosis and relapse (for the subset of patients with profiled diagnostic-relapse pairs). and to determine how transposition events may alter epigenetic and transcriptional programs that favor tumor growth. This aim will rely on RNA-seq data and will identify (i) effects of transposition events on differential regulation of gene transcription, (ii) coding gene-retroviral element transcript hybrids and (iii) cancer-specific patterns of transposition events.
What is the impact of this project?
Because genetic events in the coding space do not fully explain the spectrum of malignant properties in pediatric tumors, our studies could deliver important new insight into the factors that drive or contribute tumor initiation, growth and relapse.
The Children's Brain Tumor Network contributed to this project by providing access to the Pediatric Brain Tumor Atlas.
Medulloblastomas comprises the vast majority of pediatric embryonal tumors and by definition arise in the posterior fossa, where they constitute approximately 40% of all posterior fossa tumors. Other forms of embryonal tumors each make up 2% or less of all childhood brain tumors.The clinic
Ependymomas arise from ependymal cells that line the ventricles and passageways in the brain and the center of the spinal cord. Ependymal cells produce cerebrospinal fluid (CSF). These tumors are classified as supratentorial or infratentorial. In children, most ependymomas are infratentorial tumo