Dissecting the Spectrum, Prevalence, and Molecular Mechanisms of Enhancer Hijacking in Medulloblastoma

点击翻译按钮获取中文摘要

PROJECT SUMMARY Medulloblastoma (MB) is the most common malignant brain tumor in children. Although aggressive treatments have improved outcomes, many MB patients still die of their disease, and survivors suffer severe long-term side effects from therapy. Thus, more effective and less toxic treatments are desperately needed. Genomics has established that MB is not a single entity, but more accurately a collection of biologically and clinically distinct diseases designated as subgroups: WNT, SHH, Group 3, and Group 4. In contrast to WNT and SHH subgroup MBs, the molecular basis of Group 3 and Group 4, the most common and aggressive forms of MB, remains only partially understood. We recently discovered a series of recurrent structural genomic alterations that relocate normally distal highly active enhancers proximal to the genes encoding GFI1 and GFI1B, resulting in profound GFI1/GFI1B over- expression in affected Group 3 and Group 4 MBs. The remarkable but complex nature of this genetic- epigenetic interplay mitigated by structural alterations leading to misappropriation of enhancer activity and oncogene deregulation, prompted us to designate this phenomenon `enhancer hijacking'. Intensive sequencing efforts have determined that Group 3 and Group 4 MBs exhibit a paucity of recurrent gene- level mutations, yet often harbor extensive structural alterations of unknown significance. In light of these findings, we hypothesize that enhancer hijacking plays a prominent role in the etiology of Group 3 and Group 4 and strategies aimed to systematically identify and mechanistically characterize these events will advance our understanding of these poorly defined subgroups. To test this hypothesis, we propose to: (i) systematically investigate the spectrum and prevalence of enhancer hijacking in MB subgroups; (ii) elucidate the mechanistic basis of prominent enhancer hijacking events contributing to MB, including the role of 3-dimensional genome organization; and (iii) functionally recapitulate MB-associated enhancer hijacking in relevant cellular contexts. The results from these studies will extend beyond poorly understood MB subgroups and aim to yield essential insights into the molecular mechanisms governing oncogene deregulation in cancer and provide a deeper understanding into how noncoding genomic variation contributes to malignancy.