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

项目总结 髓母细胞瘤是儿童最常见的恶性脑肿瘤。尽管咄咄逼人 治疗改善了结果，许多MB患者仍然死于他们的疾病，幸存者遭受痛苦 严重的长期治疗副作用。因此，更有效和毒性更低的治疗方法是 迫切需要。基因组学已经确定甲基溴不是一个单一的实体，而更准确地说是一个 被指定为亚组的生物学和临床上不同的疾病集合：WNT，SHH，第3组， 与WNT和SHH亚基MBS相比，基团3和基团4的分子基础， 对甲基溴最常见和最具攻击性的形式仍然只有部分了解。我们最近 发现了一系列重复出现的结构基因组改变，这些改变通常发生在高活性的远端 在编码GFI1和GFI1B的基因附近的增强子，导致深刻的GFI1/GFI1B过度表达。 受影响的第3组和第4组MBS的表达。这种基因的非凡而复杂的性质- 通过导致滥用增强子活性的结构变化缓解表观遗传相互作用 以及癌基因的解除管制，促使我们将这种现象命名为增强子劫持。集约化 测序工作已经确定，第3组和第4组MBS显示出缺乏重复基因- 水平突变，但往往隐藏着广泛的结构变化，其意义未知。鉴于这些， 结果，我们假设增强子劫持在第三组和第三组的病因中起着重要作用 旨在系统地确定这些事件并机械地描述这些事件的第四组和战略 将促进我们对这些定义不清的亚群的理解。为了检验这一假设，我们建议 (1)系统地调查甲基溴亚组中增强子劫持的范围和流行率；(2) 阐明导致甲基溴的显著增强子劫持事件的机制基础，包括 三维基因组组织的作用；和(Iii)功能概括的MB相关增强子 在相关的蜂窝环境中劫持。这些研究的结果将不仅仅是糟糕的 了解MB亚群，并致力于对决定 癌基因在癌症中的解除调控，并提供了对非编码基因组如何 变异会导致恶变。

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.