The Landscape of Structural Variants Within Pediatric High Grade Glioma

Abstract

Pediatric high grade glioma is class of aggressive pediatric brain tumors with no current effective means of treatment. Unlike other pediatric tumors that often are characterized by specific, high frequency driver alterations in an otherwise stable genomic background, previous genomic studies have shown pediatric high grade glioma to have a complex and heterogeneous genomic profile, with high rates of structural rearrangement and somatic point mutations, in addition to alteration in chromatin modifying genes that suggest profound importance of somatic epigenetic changes. To further elucidate the spectrum of somatic events that lead to this devastating disease, we present a complete genomic characterization of the largest cohort of pediatric high grade gliomas, including the largest cohort of Diffuse Intrinsic Pontine Gliomas (DIPG), subjected to Whole genome sequencing (WGS) to date. In addition to confirming previous findings, our numerical power and deep sequencing approach has allows us to present the first comprehensive landscape of structural rearrangements in this disease. This includes elucidating new significantly mutated genes, as well as highlights new recurrent structural rearrangements involving the MYC and MYCN loci, as well as ID2, which is a key downstream effector of MYC signaling.