Copy number variations (CNVs) in neuroblastoma

神经母细胞瘤中的拷贝数变异 (CNV)

• 批准号: 8548915
• 负责人: Sharon Diskin
• 金额: $ 22.85万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-21 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8548915
• 关键词: Affect; Automobile Driving; Biological; Biology; Biometry; Blood; Cancer Biology; Categories; Cephalic; Child; Child health care; Childhood Solid Neoplasm; Chromosomes; Code; Constitutional; Copy Number Polymorphism; Critical Pathways; DNA Methylation; DNA copy number; Data; Data Set; Developmental Gene; Disease; Environment; Etiology; Event; Funding; Gene Expression; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Transcription; Genome; Genomics; Goals; Human Development; Inherited; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Malignant neoplasm of testis; Manuscripts; Medicine; Mentors; Messenger RNA; Methods; Methylation; MicroRNAs; Molecular; Molecular Diagnostic Testing; Mutation; Neoplasms; Nerve Tissue; Neuroblastoma; Pathway interactions; Patients; Pattern; Pediatric Hospitals; Pennsylvania; Phase; Phenotype; Philadelphia; Play; Population; Predisposition; Preparation; Primary Neoplasm; Proteins; Research; Research Training; Resources; Risk; Role; Sampling; Series; Single Nucleotide Polymorphism; Specimen; Survival Rate; Sympathetic Nervous System; Techniques; Testing; Training Programs; Translational Research; Tumor Tissue; Universities; Variant; base; cancer genetics; case control; disease phenotype; genome sequencing; genome wide association study; genome-wide; high risk; insight; mRNA Expression; malignant breast neoplasm; malignant phenotype; neurodevelopment; protein expression; tumor; tumorigenesis

Project Title: Copy number variations (CNVs) in neuroblastoma Project Summary: Neuroblastoma remains one of the most deadly cancers in children with an overall survival rate for high-risk disease less than 40% despite intensive multi-modal therapy. A deeper understanding of the genetics and biology driving neuroblastoma tumorigenesis may reveal important genes and/or pathways to be targeted therapeutically and will pave the way for molecular diagnostic testing and personalized medicine. We hypothesize that both common and rare copy number variations (CNVs) also influence the genesis of neuroblastoma and that they mark critical genomic regions where somatic alterations and/or mutations occur in primary tumors. This proposal seeks to identify genes important to initiation and progression of neuroblastoma by achieving the following specific aims 1) Identify common constitutional CNVs associated with neuroblastoma through a CNV-based GWAS of 5,000 neuroblastoma cases and 10,000 healthy children as controls. 2) Identify rare constitutional CNVs affecting genes enriched in relevant functional categories and/or pathways associated with neuroblastoma, also utilizing data generated as part of our GWAS effort. 3) Characterize and determine biological relevance of genes influenced by neuroblastoma-associated CNVs. Here, a two-pronged approach is proposed a) a detailed integrative molecular characterization using matched germline and tumor specimens (germline/tumor whole genome sequencing, DNA copy number, DNA methylation, and mRNA/miRNA expression) of all genes directly influenced by neuroblastoma-associated CNVs. b) confirm biological relevance of NBPF23 and NME7, two genes we have demonstrated to be influenced by neuroblastoma-associated CNVs, using molecular biological techniques applied to both developing sympathetic nervous tissue and a large set of annotated tumor tissues. The discoveries generated from this effort will provide substantial insight into both genetic predisposition as well as malignant progression of this important childhood cancer, and will provide the first functional characterization of genes influenced by CNV in neuroblastoma. Discoveries from this study are likely to have broader implications to cancer biology and cancer predisposition. This proposal lays out a 5-year research plan. The first 2-years include a detailed research and training program that will prepare the PI for transition to the independent phase starting year 3 with the goal of obtaining R01 funding prior to year 5. Her mentors and advisors are leaders in the fields of neuroblastoma research, biostatistics, cancer genetics/genomics, and translational research. She will take advantage of the extensive resources of her environment, both at the Children's Hospital of Philadelphia, and the University of Pennsylvania.

项目名称：神经母细胞瘤中的副本编号变化（CNV） 项目摘要： 神经母细胞瘤仍然是高风险总体生存率的儿童中最致命的癌症之一 尽管进行了强化多模式疗法，疾病小于40％。对遗传学和 驱动神经母细胞瘤肿瘤发生的生物学可能揭示了重要的基因和/或途径。 治疗，将为分子诊断测试和个性化医学铺平道路。我们 假设常见和稀有拷贝数变化（CNV）也影响 神经母细胞瘤，并标志着体细胞改变和/或突变的关键基因组区域 发生在原发性肿瘤中。该提案旨在确定对开始和发展重要的基因 神经母细胞瘤通过实现以下特定目的1）确定相关的常见宪法CNV 通过5,000例神经母细胞瘤病例和10,000名健康儿童的神经母细胞瘤通过神经母细胞瘤 作为控件。 2）确定罕见的宪法CNV，影响富含相关功能类别的基因 和/或与神经母细胞瘤相关的途径，还利用了作为GWAS工作的一部分生成的数据。 3） 表征并确定受神经母细胞瘤相关的CNV影响的基因的生物学相关性。 在这里，提出了两种条件的方法a）使用匹配的详细的集成分子表征 种系和肿瘤标本（种系/肿瘤全基因组测序，DNA拷贝数，DNA 直接受神经母细胞瘤相关影响的所有基因的甲基化和mRNA/miRNA表达） CNV。 b）确认NBPF23和NME7的生物学相关性，我们证明是两个基因 受神经母细胞瘤相关的CNV的影响，使用分子生物学技术 产生交感神经组织和大量注释的肿瘤组织。发现的发现 从这项工作中，将为遗传易感性和恶性进展提供实质性的洞察力 在这种重要的儿童癌症中，将提供受影响的基因的第一个功能表征 神经母细胞瘤中的CNV。这项研究的发现可能对癌症生物学具有更广泛的影响 和癌症易感性。 该提案制定了一项为期5年的研究计划。前两年包括详细的研究和培训 计划将准备PI开始过渡到独立阶段的第3年，目标 在第五年之前获得R01资金。她的导师和顾问是神经母细胞瘤领域的领导者 研究，生物统计学，癌症遗传学/基因组学和转化研究。她将利用 她的环境的广泛资源，包括费城儿童医院和大学 宾夕法尼亚州。