Project 465503

PFA ependymoma is an incurable brain tumor affecting mostly infants and young children. Unlike other tumor types, PFA has few mutations in genes, and only rarely the same gene is mutated in more than one patient. The vast majority of PFAs lack recurrent mutations or mutations in genes known to be involved in cancer, and this has complicated the search for a target for therapeutic intervention. To understand the mechanisms that sustain PFA growth, we used new approaches that allowed us to look beyond genes. Specifically, we looked at how the DNA is organized in PFA cells; in other words, we looked at the structure of the DNA in this tumor type, and compared it to a large collection of other childhood brain tumor types and non-tumor cell types. We found that PFA cells organize their DNA in a unique fashion. Even more importantly, we discovered new DNA structures that are only found in PFAs and, most importantly, occur in every sample we studied. Whereas recurrent gene mutations are very rare in this malignancy, we found a DNA structure that is universally present in every PFA and is unique to this cancer. In this application, we propose experiments that will elucidate the function of these new DNA structures. We will use genomic approaches and functional studies with patient-derived models to understand how the DNA structures we discovered promote the growth and aggressiveness of PFA cells. We hypothesize that by finding ways to unravel these structures, we will be able to stop the growth of this lethal childhood brain cancer.