Genetic Susceptibility to Pediatric Glioma inIndividuals and Diverse populations

个体和不同人群对儿童胶质瘤的遗传易感性

基本信息

批准号：
9548184
负责人：
Kyle M Walsh
金额：
$ 101.39万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-09 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9548184
关键词：
Address Adolescent and Young Adult Adult Adult Glioma Affect Age Anaplastic astrocytoma Archives Biological Birth Blood Brain Neoplasms California Case-Control Studies Child Child Care Childhood Childhood Glioma Childhood Malignant Brain Tumor Cognitive Complex Control Groups Custom DNA Data Data Set Diagnosis Disease Endocrine Ependymoma Ethnic Origin Etiology Frequencies Future Gene Frequency Genes Genetic Genetic Diseases Genetic Predisposition to Disease Genetic Risk Genetic Variation Genome Genotype Glioblastoma Glioma Goals Heritability Individual Inherited Institution Knowledge Lead Life Experience Location Malignant Childhood Neoplasm Malignant Neoplasms Meta-Analysis Minor Morbidity - disease rate Mutation Neonatal Neuraxis Newborn Infant Operative Surgical Procedures Pathogenesis Pathway interactions Pilocytic Astrocytoma Play Population Population Heterogeneity Population Study Prevention therapy Privatization Public Health Recurrence Registries Renaissance Research Research Design Resected Resources Risk Risk Factors Risk stratification Role Sample Size Sampling Scientific Advances and Accomplishments Second Primary Cancers Second Primary Neoplasms Solid Neoplasm Specimen Stroke Survivors Sweden Telomere Maintenance Testing Texas Validation Variant Washington base cancer risk case control cohort design disability disorder risk epidemiology study exome exome sequencing experience genetic association genetic epidemiology genetic risk factor genetic variant genome wide association study genome-wide genome-wide analysis improved mortality novel pediatric patients population based public health relevance rare variant risk variant targeted sequencing tumor virtual

项目摘要

DESCRIPTION (provided by applicant): Brain tumors are the most common solid tumor and the second most common malignancy in children. Nearly 2,000 pediatric gliomas (PG) are diagnosed annually in U.S. children under the age of 15, only half of whom survive into adulthood. 80% of survivors experience life-threatening conditions related to treatment, including stroke and second malignancies. Despite clear evidence of a genetic component underlying PG risk, little is known about heritable factors affecting this deadly brain tumor. As previously demonstrated for adult glioma, identification of robust and validated genetic risk factors can lead to improved risk stratification and reveal the biologic pathways fundamental to the disease pathogenesis. Previous studies seeking to identify genetic risk factors for PG were limited by small sample size. This obstacle rendered studies inadequate for the identification of authentic genetic associations in high-throughput fashion. Furthermore, technological limitations have forced prior studies to focus on common genetic variation, which may be only one component of the genetic origins underlying PG risk. The hypothesis that both rare and common genetic variation contribute to PG risk, and risk of specific subtypes, will be formally tested in this proposal. To achieve this, a population-based case-control study, nested within the California Birth Cohort (CBC), has been developed. Genome-wide analysis of common and rare genetic variants will be conducted using existing archived neonatal bloodspots from 2,920 Californian children diagnosed with PG between 1988 and 2013, and 1:1 matched controls. First, DNA from 300 children with malignant astrocytoma and 100 controls will undergo whole-exome sequencing (WES) to identify rare variants contributing to disease risk (Minor Allele Frequency<1%). Genes displaying significant enrichment of rare variants in affected children compared to CBC and public control exomes will be validated by targeted sequencing in an additional 675 malignant astrocytoma case children and 875 control children from the CBC. Next, 20,000 promising low-frequency variants (MAF 1-5%) identified from the WES will be added as custom content to a genome-wide genotyping array, already containing 818,000 common variants. DNA samples from all 2,920 CBC case children and 2,920 CBC control children will undergo genome-wide genotyping to perform an empirically-enriched genome-wide association study (eeGWAS). The eeGWAS analysis can identify both low-frequency and common variants underlying PG risk, and is statistically powered for both pooled and subtype-stratified analyses. Approximately 1,500 variants identified by the eeGWAS will undergo attempted replication in 1,210 case and 1,850 control children from three collaborating institutions. By leveraging the unique and mature resources within the Genetic Diseases Branch of the California Department of Public Health, this registry-based approach will yield an unprecedentedly large sample size. The identification of both rare and common variants underlying PG risk can expose new knowledge leading to improved care of children, adolescents, and young adults facing this diagnosis.

描述（由适用提供）：脑肿瘤是最常见的实体瘤，也是儿童中第二常见的恶性肿瘤。每年在15岁以下的美国儿童中诊断出近2,000个小儿神经胶质瘤（PG），只有一半的儿童能够生存到成年。 80％的生存经历与治疗有关的威胁生命状况，包括中风和第二种恶性肿瘤。尽管有明确的证据表明PG风险是遗传成分，但对影响这种致命脑肿瘤的可遗传因素知之甚少。正如先前证明的成人神经胶质瘤所证明的那样，识别可靠和经过验证的遗传危险因素可以改善风险分层，并揭示疾病发病机理基础的生物学途径。先前旨在鉴定PG遗传危险因素的研究受到小样本量的限制。这种障碍使研究不足以以高通量方式识别真实的遗传关联。此外，技术局限性迫使先前的研究集中在常见的遗传变异上，这可能只是PG风险基础的遗传起源的一部分。在本提案中，将正式测试罕见和常见遗传变异的假设有助于PG风险和特定亚型的风险。为此，已经开发了一项基于人群的病例对照研究，该研究嵌套在加利福尼亚出生队列中（CBC）。在1988年至2013年期间，有2,920名被诊断为PG的加利福尼亚儿童以及1：1匹配的对照组，将对共同遗传变异的基因组全基因组分析进行。首先，来自300名恶性星形胶质细胞瘤和100个对照的儿童的DNA将接受全外活体测序（WES），以识别造成疾病风险的稀有变体（次要等位基因频率<1％）。与CBC和公共对照组件相比，在受影响儿童中显示出明显增强的稀有变异的基因将通过在另外675个恶性星形胶质细胞瘤病例儿童和CBC的875名对照儿童中进行靶向测序来验证。接下来，从WES确定的20,000个承诺低频变体（MAF 1-5％）将作为自定义内容添加到全基因组基因分型阵列中，已经包含818,000个常见变体。来自所有2,920例CBC病例儿童和2,920个CBC对照儿童的DNA样本将接受全基因组全基因组协会研究（EEGWAS）。 EEGWAS分析可以识别PG风险的基本低频和常见变体，并且在统计上均可用于合并和亚型分层分析。 EEGWAS确定的大约1,500种变体将在1,210例病例中进行尝试复制，并从三个合作机构中获得1,850名对照儿童。通过利用加利福尼亚公共卫生部遗传疾病分支机构内的独特和成熟资源，这种基于注册表的方法将产生前所未有的大型样本量。鉴定PG风险的稀有变体和常见变体可以暴露新知识，从而改善对这种诊断的儿童，青少年和年轻人的护理。