Characterization of ELP1 as a novel SHH medulloblastoma predisposition gene

ELP1 作为新型 SHH 髓母细胞瘤易感基因的表征

• 批准号: 10270674
• 负责人: Paul Northcott
• 金额: $ 45.06万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10270674
• 关键词: Affect; Age; Anticodon; Biochemical; Biogenesis; Biological; Blood Vessels; Brain; CRISPR/Cas technology; Cells; Cellular Morphology; Cerebellum; Chemicals; Child; Childhood; Childhood Brain Neoplasm; Childhood Malignant Brain Tumor; Clinical; Code; Codon Nucleotides; Complex; Consensus; Cytoplasmic Granules; Defect; Development; Disease; Embryo; Exhibits; Family; Functional disorder; Future; Genes; Genetic; Genetic Predisposition to Disease; Genetically Engineered Mouse; Genomics; Histopathology; Image; Immunofluorescence Immunologic; Immunohistochemistry; Impairment; In Vitro; Knock-out; Link; Loss of Heterozygosity; Maintenance; Malignant - descriptor; Modeling; Modification; Molecular; Mus; Mutation; Neoplasms; Oncogenes; Outcome; PPM1D gene; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Physiological; Pre-Clinical Model; Protein Complex Subunit; Proteins; Proteome; Reagent; Research; Research Personnel; Role; SHH gene; Scientist; Secondary to; Series; Signal Transduction; Subgroup; Surveys; Survivors; Susceptibility Gene; TP53 gene; Testing; Transfer RNA; Transgenic Mice; Transgenic Organisms; Translational Regulation; Translations; Transplantation; Treatment outcome; Tumor Suppressor Proteins; Uridine; Variant; aggressive therapy; base; biological heterogeneity; cancer predisposition; cancer risk; demographics; effective therapy; human disease; improved; improved outcome; interest; loss of function; loss of function mutation; medulloblastoma; multiple omics; mutant; nerve stem cell; neurodevelopment; novel; patient derived xenograft model; programs; protein folding; proteostasis; response; risk variant; scaffold; sex; side effect; tumor; tumorigenesis

PROJECT SUMMARY Medulloblastoma (MB) is among the most common malignant childhood brain tumors. Although aggressive treatments have improved outcomes, too many affected children still die of their disease, and survivors often suffer from severe long-term side effects of therapy. Extensive molecular and biological heterogeneity underlying MB has been described, culminating in the recognition of consensus molecular subgroups – WNT, SHH, Group 3, and Group 4 – each of which is associated with divergent genomic landscapes, patient demographics, and clinical outcomes. Although somatically altered genes and biological pathways are well annotated, comprehensive understanding of genetic predisposition to MB has lagged behind. We recently investigated germline loss-of-function (LoF) across all protein-coding genes in a series of >1,000 MB patients. This unbiased approach uncovered highly significant deleterious germline variants in ELP1 that were specific to childhood SHH-MB patients and twice as common as pathogenic variants affecting known MB-associated genes. ELP1 encodes a scaffolding subunit of Elongator, a multi-subunit protein complex (ELP1-6) that chemically modifies wobble U34 uridines in the anticodon loop of tRNAs to enable efficient translational elongation and maintenance of physiological protein folding dynamics. ELP1-associated tumors exhibited frequent co-occurrence of somatic PTCH1 mutations and amplifications of PPM1D and MDM4, suggesting germline ELP1 LoF variants cooperate with constitutive activation of SHH and/or TP53 signaling to promote MB development. ELP1-associated SHH-MBs were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis. Based on these findings, we hypothesize that ELP1 is a novel cancer predisposition gene and aim to functionally elucidate the developmental, biochemical, and molecular mechanisms by which pathogenic ELP1 LoF promotes SHH-MB. To test this hypothesis, we propose to (i) evaluate the requirement for Elp1 during cerebellar development; (ii) validate the tumor suppressive role of Elp1 in SHH-MB; and (iii) determine the impact of MB-associated Elp1 LoF on translation and the proteome. These studies will be conducted in a series of novel Elp1+/- transgenic mice, primary cells derived from the developing mouse cerebellum, and genetically faithful SHH-MB patient-derived xenografts. Successful execution of this research program will effectively link germline ELP1 LoF to the biochemical and molecular mechanisms governing SHH-MB pathogenesis. Outcomes of the proposed research will be of broad interest, extending to scientists and clinicians with an interest in cancer predisposition, as well as basic researchers studying the fundamentals of translational regulation and protein homeostasis and their role in human disease.

项目摘要 髓母细胞瘤（MB）是最常见的儿童脑肿瘤之一。虽然 积极的治疗改善了结果，太多受影响的儿童仍然死于疾病，并且 幸存者经常遭受严重的长期治疗副作用。广泛的分子和生物学 已经描述了MB的异质性，最终取决于识别共识分子 亚组 - Wnt，SHH，第3组和第4组 - 每个组与不同的基因组有关 景观，患者人口统计和临床结果。 生物学途径是很好的注释，对MB的遗传易感性的全面理解 落后了。我们最近研究了所有蛋白质编码的种系功能丧失（LOF） 一系列> 1,000名MB患者的基因。这种公正的方法发现了非常重要的有害 ELP1中的种系变体，特有针对儿童SHH-MB患者的生殖线变体，是常见的两倍 影响已知MB相关基因的致病变异。 ELP1编码一个脚手架的亚基 延伸器，一种多生产蛋白络合物（ELP1-6），可以化学修饰Wobble U34尿苷中的尿苷 TRNA的反登陆循环可以有效地翻译和维持生理 蛋白质折叠动力学。 ELP1相关的肿瘤经常暴露于体细胞PTCH1 PPM1D和MDM4的突变和扩增，表明种系ELP1 LOF变体合作 随着SHH和/或TP53信号的构型激活，以促进MB发育。 ELP1相关 SHH-MB的特征是不稳定的伸长仪复合物，依赖延伸器的tRNA的丧失 修改，依赖密码子的翻译重编程以及展开蛋白的诱导 反应，与蛋白质稳态的丧失一致。基于这些发现，我们假设 ELP1是一种新型的癌症易感基因，旨在在功能上阐明发育性， 致病性ELP1 LOF促进SHH-MB的生化和分子机制。测试这个 假设，我们建议（i）评估小脑发育过程中对ELP1的要求； （ii） 验证ELP1在SHH-MB中的肿瘤抑制作用； （iii）确定与MB相关的影响 ELP1 LOF在翻译和蛋白质组上。这些研究将在一系列新型ELP1 +/-中进行。 转基因小鼠，源自发育中的小鼠小脑的原代细胞和遗传忠实 SHH-MB患者衍生的Xenographictic。该研究计划的成功执行将有效链接 生殖线ELP1 lof用于管理SHH-MB发病机理的生化和分子机制。 拟议研究的结果将引起广泛关注，将科学家和临床医生与 对癌症倾向的兴趣，以及研究的基础研究人员 翻译调节和蛋白质稳态及其在人类疾病中的作用。