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

剖析髓母细胞瘤中增强子劫持的谱系、患病率和分子机制

• 批准号: 9789850
• 负责人: Paul Northcott
• 金额: $ 35.77万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789850
• 关键词: 3-Dimensional; Accounting; Affect; Automobile Driving; Biological; Biological Models; Brain; CRISPR/Cas technology; Cancer Biology; Cancer Etiology; Childhood; Childhood Brain Neoplasm; Childhood Malignant Brain Tumor; Clinical; Code; Collection; Complex; DNA Sequence Alteration; Data Set; Development; Diagnosis; Disease; Distal; Engineering; Enhancers; Epigenetic Process; Etiology; Event; Exhibits; GFI1 gene; GFI1B gene; Gene Activation; Generations; Genes; Genetic; Genetic Transcription; Genome; Genome engineering; Genomics; Goals; Higher Order Chromatin Structure; In Vitro; Investigation; Lead; Light; Link; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Methods; Modeling; Molecular; Mutation; Nature; Oncogene Activation; Oncogene Deregulation; Oncogenes; Pathogenesis; Patient-Focused Outcomes; Patients; Pediatric Neoplasm; Play; Pre-Clinical Model; Prevalence; Process; Proteins; Recurrence; Research Design; Role; SHH gene; Sampling; Secondary to; Seminal; Series; Stem cells; Structural defect; Structure; Subgroup; Survivors; Technology; Testing; Treatment outcome; Tumor Biology; Untranslated RNA; Up-Regulation; Variant; Xenograft procedure; cancer genome; cell type; childhood cancer mortality; chromosome conformation capture; cohort; effective therapy; epigenomics; genomic data; genomic variation; improved; improved outcome; in vivo; insight; medulloblastoma; medulloblastoma cell line; molecular phenotype; novel; overexpression; promoter; side effect; structural genomics; three dimensional structure; transcriptomics; tumor; tumorigenesis; variant of unknown significance

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.

项目摘要 髓母细胞瘤（MB）是儿童最常见的恶性脑肿瘤。虽然是积极进取的 治疗的预后改善，许多MB患者仍然死于疾病，幸存者遭受 治疗严重的长期副作用。因此，更有效和毒性治疗更为有效 迫切需要。基因组学确定MB不是一个实体，而是更准确地 收集的生物学和临床上不同疾病被指定为亚组：Wnt，SHH，第3组， 和第4组。与Wnt和SHH亚组MB相比，第3组和第4组的分子基础 MB的最常见和侵略性形式仍然仅被部分理解。我们最近 发现了一系列复发性的结构基因组改变，这些改变正常远端高度活跃 附近编码GFI1和GFI1B的基因的增强剂，导致GFI1/GFI1B过度深度 在受影响的第3组和4 MBS中的表达。这种遗传的显着但复杂的性质 结构改变减轻了表观遗传相互作用，导致盗用增强剂活性 和癌基因放松管制，促使我们指定了这种现象“劫持”。密集的 测序工作已经确定第3组和第4组MB表现出很少的复发基因 水平突变，但通常具有未知意义的广泛结构变化。鉴于这些 调查结果，我们假设劫持增强剂在第3组的病因中起着重要的作用 第4组和旨在系统地识别和机理表征这些事件的策略 将促进我们对这些定义较差的亚组的理解。为了检验这一假设，我们提出了 至：（i）系统地研究MB亚组中增强子劫持的频谱和患病率； （ii） 阐明突出的增强子劫持事件的机械基础，这些事件有助于MB，包括 三维基因组组织的作用； （iii）在功能上概括了与MB相关的增强子 在相关的蜂窝情况下进行劫持。这些研究的结果将超出较差 理解MB亚组，并旨在产生有关分子机制的基本见解 癌症中的癌基因失控，并更深入地了解非编码基因组如何 变异导致恶性肿瘤。