Copy number variations (CNVs) in neuroblastoma

神经母细胞瘤中的拷贝数变异 (CNV)

• 批准号: 7958934
• 负责人: Sharon Diskin
• 金额: $ 17.08万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958934
• 关键词: Affect; Automobile Driving; Biological; Biology; Biometry; Blood; Breast; Cancer Biology; Categories; Cephalic; Child; Child health care; Childhood; 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 phenotype; neurodevelopment; protein expression; public health relevance; tumor; tumorigenesis

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Neuroblastoma is the most common extra-cranial solid tumor of childhood and is often lethal. Understanding the genetic events, such as copy number variation (CNV), that drive neuroblastoma tumorigenesis will have considerable relevance to the health of children with this disease as these events may identify molecular pathways critical to the malignant phenotype and thus exploitable therapeutically. Furthermore and as demonstrated in the past, the genes involved in predisposition to neuroblastoma may provide substantial insight into normal human development and cancer biology in general.

描述（由申请人提供）：神经母细胞瘤仍然是高危疾病总体存活率最致命的癌症之一，尽管进行了强化多模式疗法，却小于40％。对驱动神经母细胞瘤肿瘤发生的遗传学和生物学的更深入了解可能会揭示重要的基因和/或途径，以靶向治疗，并为分子诊断测试和个性化医学铺平道路。我们假设常见和罕见的拷贝数变化（CNV）也会影响神经母细胞瘤的起源，并且它们标志着在原发性肿瘤中发生体细胞改变和/或突变的关键基因组区域。该提案旨在通过实现以下特定目的来鉴定对神经母细胞瘤起始和进展至关重要的基因1）通过基于CNV的GWA鉴定与神经母细胞瘤相关的常见宪法CNV，该基因通过基于CNV的GWA，5,000例神经母细胞瘤病例和10,000名健康儿童作为对照。 2）确定罕见的宪法CNV，影响与神经母细胞瘤相关的相关功能类别和/或途径的基因，也利用了作为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，提出了两种宽松的方法a）使用直接受神经母细胞瘤相关CNV影响的所有基因的匹配种系和肿瘤标本（种系/肿瘤全基因组测序，DNA拷贝数，DNA甲基化和mRNA/miRNA表达）的详细整合分子表征。 B）证实了NBPF23和NME7的生物学相关性，我们已经证明，我们证明了使用神经母细胞瘤相关的CNV影响的两个基因，该基因使用用于发展的交感神经组织和大量注释的肿瘤组织的分子生物学技术。从这项工作中产生的发现将为这种重要的儿童癌症的遗传易感性以及恶性进展提供大量见解，并将提供神经母细胞瘤中CNV影响的基因的第一个功能表征。这项研究的发现可能对癌症生物学和癌症易感性具有更广泛的影响。 该提案制定了一项为期5年的研究计划。前两年包括一项详细的研究和培训计划，该计划将准备PI从第3年开始过渡到独立阶段，目的是在第五年之前获得R01资金。她的导师和顾问是神经母细胞瘤研究，生物统计学，生物统计学，癌症遗传学/基因组学和转化研究领域的领导者。她将利用费城儿童医院和宾夕法尼亚大学的环境中广泛的环境资源。 公共卫生相关性：神经母细胞瘤是最常见的儿童颅外实体瘤，通常是致命的。了解驱动神经母细胞瘤肿瘤发生的遗传事件，例如拷贝数变化（CNV），将与这种疾病儿童的健康有很大的相关性，因为这些事件可能会确定对恶性表型至关重要的分子途径，从而可以利用治疗。此外，正如过去所证明的那样，与神经母细胞瘤易感的基因可能会对正常的人类发育和癌症生物学提供实质性的见解。