LAUSR

In recent years, next-generation sequencing has uncovered the spectrum of driver genes and molecular processes contributing to most cancer entities, including pediatric cancer. This holds true for medulloblastoma (MB), the most common malignant childhood brain tumor. A multitude of genomic studies conducted on large patient cohorts have culminated in the recognition of at least four molecular and clinically distinct MB subgroups: WNT, SHH, Group 3, and Group 4. Moreover, comprehensive sequencing efforts have reported the prevalence and subgroup distribution of somatically altered genes in MB, informing tumor biology and suggesting rational candidates for molecularly targeted therapy. In contrast to WNT and SHH subgroup MB, which are typically characterized by mutations/copy-number alterations leading to aberrant signaling of the WNT and SHH pathways, respectively, Groups 3 and 4 harbor a paucity of recurrently mutated genes and exhibit remarkable heterogeneity in their molecular landscapes. Looking beyond somatic gene-level mutations and focusing our analyses on recurrent structural variants (SVs) in Group 3 and Group 4, we recently discovered a series of atypical SVs converging on chr9q34 that coincided with aberrant induction of GFI1B expression, a transcription factor normally active in the hematopoietic system. Meticulous mapping of SV breakpoints and subsequent integration with DNA methylation and histone ChIP-seq datasets implicated misappropriation of highly active enhancers secondary to the observed SV, a mechanism we termed “enhancer hijacking.” In light of this surprising discovery, we have now extended our analyses, including the development of new computational pipelines, to systematically explore the extent of enhancer hijacking in MB and other pediatric brain tumors. Emerging results from these efforts will be presented, including strategies being employed to validate aberrant enhancer-promoter interactions in MBs with presumed enhancer hijacking, as well as functional approaches we are using to engineer these alterations in relevant cellular systems. Citation Format: Paul A. Northcott. Subgroup-specific enhancer hijacking in medulloblastoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA03.