The Genetic Basis of Neuroblastoma Tumorigenesis

神经母细胞瘤肿瘤发生的遗传基础

• 批准号: 7461269
• 负责人: JOHN M MARIS
• 金额: $ 67.56万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7461269
• 关键词: Adult; African American; Alleles; Biological Assay; Biological Markers; Biology; Cancer Etiology; Cancer Patient; Candidate Disease Gene; Caucasians; Caucasoid Race; Characteristics; Child; Childhood; Children' s Oncology Group; Clinical; Complex; Constitutional; Country; Custom; DNA; DNA Resequencing; Data; Databases; Development; Diagnostic; Disease; Disease Outcome; Dose; Evaluation; Event; Family; Gene Frequency; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Genetic Recombination; Genomics; Genotype; Geographic Locations; Graph; HRAS gene; Hand; Haplotypes; Human; Human Genome; Institution; Lead; Linkage Disequilibrium Mapping; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Modeling; Molecular; Mutate; Neuroblastoma; Numbers; PTEN gene; Patients; Penetrance; Population; Population Control; Principal Component Analysis; Public Health; Purpose; Qualifying; RB1 gene; Reagent; Research; Research Design; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Staging; Stratification; Surveys; Susceptibility Gene; Syndrome; TP53 gene; TSC1 gene; TSC2 gene; Technology; Testing; Thinking; Time; Translating; Translational Research; Tumor Biology; Validation; Variant; WT1 gene; base; c-Ha-ras p21; cancer genomics; case control; cohort; density; design; genome wide association study; insight; interest; mortality; mutant; next generation; prognostic; response; sample collection; tumor; tumor initiation; tumorigenesis

DESCRIPTION (provided by applicant): Neuroblastoma is a common and lethal pediatric malignancy, but the genetic events that initiate tumorigenesis are largely unknown. We hypothesize that neuroblastoma is a complex disease that results from the interaction of mutant alleles with relatively low to moderate effect on tumor initiation. We now plan to discover neuroblastoma susceptibility genes by performing a definitive whole genome association study in ~5000 neuroblastoma patients from the Children's Oncology Group using a high-density single nucleotide polymorphism (SNP)-based replicative study design. We will compare our cases to two control sets: both pediatric non-cancer patients accessioned from our institution, and adult control subjects matched by region across the country. We propose four Specific Aims: First, we will perform a whole genome scan for association of neuroblastoma with SNPs and SNP haplotypes in 2000 neuroblastoma cases and an equal number of matched controls (both children and adults in parallel analyses). Over 550K SNPs will be surveyed, and we anticipate identifying 25,000-50,000 candidate SNPs for further evaluation. Second, we will identify true disease-associated SNP alleles using a customized genotyping platform enriched for haplotype analyses in an independent set of 2000 cases and again two large control sets. By leveraging the HapMap project and controlling for population substructure, we anticipate that this Aim will identify 10-20 genomic regions as candidates for association with neuroblastoma. Third, we will validate at least 5-10 disease-associated regions in a final independent sample set of 675 cases and two sets of ~675 controls. We will again use a gene-centric haplotyping approach to determine true disease associated variants and candidate genes. Finally, we will definitively identify neuroblastoma predisposition genes through direct resequencing of candidate regions in a carefully selected set of 100 neuroblastoma cases and 100 controls, each equally proportioned between the presence or absence of the SNP/haplotype variant associated with neuroblastoma. Our large panel of tumor reagents and genomics databases will be leveraged to assist in region prioritization and identification of candidate genes for further analysis. The successful completion of this project will provide insight into the underlying genetic etiology of neuroblastoma tumorigenesis. We ultimately plan to translate the discovered neuroblastoma predisposition genes into a prognostic biomarkers and/or a target for new treatment approaches. In addition, the data generated here will rapidly be made available to any academically qualified petitioner interested in associating the SNP genotypes with the robust phenotypic information that we have captured including clinical characteristics, tumor biology, response to therapy and disease outcome. Finally, this project should also help catalyze the field of childhood cancer applied genomics research, and if past lessons from other childhood cancers are repeated, it will identify genes that are fundamentally important in human cancer in general. PUBLIC HEALTH RELEVANCE: Neuroblastoma is a common and lethal childhood cancer for which the genetic basis is poorly understood. Our genome-wide association study is designed to discover the most common variations in the human genome that lead to the development of neuroblastoma. These insights will lead to new molecular diagnostic assays and/or new treatments for this frequently devastating malignancy of young children.

描述（由申请人提供）：神经母细胞瘤是一种常见且致命的小儿恶性肿瘤，但是启动肿瘤发生的遗传事件在很大程度上是未知的。我们假设神经母细胞瘤是一种复杂的疾病，它是由于突变等位基因对肿瘤起始作用相对较低至中等作用的相互作用而引起的。现在，我们计划通过使用高密度的单核苷酸多态性（SNP）基于复制性研究设计设计，通过对来自儿童肿瘤学组的约5000例神经母细胞瘤患者进行确定的整个基因组关联研究来发现神经母细胞瘤易感基因。我们将将案件与两组控制组进行比较：两名从我们机构加入的儿科非癌症患者以及全国各地与地区相匹配的成人对照对象。我们提出了四个具体目标：首先，我们将在2000年神经母细胞瘤病例和相等数量的匹配对照组（在平行分析中的儿童和成年人）中进行整体基因组扫描，以实现神经母细胞瘤与SNP和SNP和SNP单倍型的关联。将对超过55万的SNP进行调查，我们预计将确定25,000-50,000名候选SNP进行进一步评估。其次，我们将使用自定义的基因分型平台来鉴定真正的相关SNP等位基因，该平台富含在2000年的独立病例中进行单倍型分析，并再次是两个大型控制集。通过利用HAPMAP项目并控制人口子结构，我们预计该目标将确定10-20个基因组区域是与神经母细胞瘤相关的候选者。第三，我们将在最终的675例病例和两组〜675个对照组中验证至少5-10个与疾病相关的区域。我们将再次使用以基因为中心的单倍型方法来确定与真正疾病相关的变异和候选基因。最后，我们将通过在精心挑选的100例神经母细胞瘤病例和100个对照组中直接重新定制候选区域，从而确定鉴定神经母细胞瘤倾向基因，每种神经母细胞基因在与神经母细胞瘤相关的SNP/单倍型变体之间的存在或不存在之间相同。我们的大型肿瘤试剂和基因组数据库面板将被利用，以帮助区域优先级和鉴定候选基因以进行进一步分析。该项目的成功完成将洞悉神经母细胞瘤肿瘤发生的潜在遗传病因。我们最终计划将发现的神经母细胞瘤倾向基因转化为预后的生物标志物和/或新治疗方法的靶标。此外，此处生成的数据将迅速提供给有兴趣将SNP基因型与我们捕获的可靠表型信息相关联的任何学术资格的请愿人，包括临床特征，肿瘤生物学，对治疗和疾病结果。最后，该项目还应有助于催化儿童癌症应用基因组学研究的领域，如果重复其他儿童癌症的过去课程，它将确定一般来说在人类癌症中至关重要的基因。公共卫生相关性：神经母细胞瘤是一种常见且致命的儿童癌症，遗传基础知之甚少。我们全基因组的关联研究旨在发现导致神经母细胞瘤发展的人类基因组中最常见的变异。这些见解将导致新的分子诊断测定法和/或新的治疗方法，以实现这种经常破坏性的幼儿恶性肿瘤。