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

• 批准号: 9142298
• 负责人: Kyle M Walsh
• 金额: $ 98.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-09 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9142298
• 关键词: Address; Adolescent and Young Adult; Adult; Adult Glioma; Affect; Age; Ally; Anaplastic astrocytoma; Archives; Birth; Blood; Brain Neoplasms; California; Child; Child Care; Childhood; Childhood Glioma; Childhood Malignant Brain Tumor; Cognitive; Complex; Control Groups; Custom; DNA; Data; Data Set; Diagnosis; Disease; Endocrine; Ependymoma; Epidemiologic Studies; Ethnic Origin; Etiology; Frequencies; Future; Gene Frequency; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genome; Genotype; Glioblastoma; Glioma; Goals; Health; Hereditary Disease; Individual; Inherited; Institution; Knowledge; Lead; Life Experience; Location; Malignant Childhood Neoplasm; Malignant Neoplasms; Meta-Analysis; Minor; Morbidity - disease rate; Mutation; Neonatal; Nested Case-Control Study; Neuraxis; Newborn Infant; Pathogenesis; Pathway interactions; Pilocytic Astrocytoma; Play; Population; Population Heterogeneity; Prevention therapy; Public Health; Recurrence; Registries; Renaissance; Research; Research Design; Resected; Resources; Risk; Risk Factors; Role; Sample Size; Sampling; Scientific Advances and Accomplishments; Second Primary Cancers; Second Primary Neoplasms; Sequence Analysis; Solid Neoplasm; Specimen; Stratification; Stroke; Survivors; Sweden; Telomere Maintenance; Testing; Texas; Validation; Variant; Washington; base; cancer risk; case control; cohort; design; disability; disorder risk; 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; rare variant; risk variant; targeted sequencing; tumor

 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（由申请人提供）：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。美国 15 岁以下儿童每年诊断出近 2,000 例儿童神经胶质瘤 (PG)，其中只有一半能存活到成年。 80% 的幸存者经历与治疗相关的危及生命的病症，包括中风和第二恶性肿瘤。尽管有明确的证据表明 PG 风险存在遗传因素，但人们对影响这种致命脑肿瘤的遗传因素知之甚少。正如之前针对成人神经胶质瘤所证明的那样，识别可靠且经过验证的遗传风险因素可以改善风险分层并揭示疾病发病机制的基本生物学途径。先前旨在确定 PG 遗传风险因素的研究因样本量较小而受到限制。这一障碍使得研究不足以以高通量方式鉴定真实的遗传关联。此外，技术限制迫使先前的研究重点关注常见的遗传变异，这可能只是潜在 PG 风险遗传起源的一个组成部分。罕见和常见遗传变异都会导致 PG 风险和特定亚型风险的假设将在本提案中得到正式检验。为了实现这一目标，一项基于人群的病例对照研究已经在加州出生队列 (CBC) 内开展。将使用 1988 年至 2013 年间诊断为 PG 的 2,920 名加州儿童的现有存档新生儿血斑和 1:1 匹配的对照对常见和罕见遗传变异进行全基因组分析。首先，来自 300 名恶性星形细胞瘤儿童和 100 名对照儿童的 DNA 将接受全外显子组测序 (WES)，以识别导致疾病风险的罕见变异（次要等位基因频率<1%）。与 CBC 和公共对照外显子组相比，受影响儿童中罕见变异显着富集的基因将通过靶向测序在来自 CBC 的另外 675 名恶性星形细胞瘤病例儿童和 875 名对照儿童中进行验证。接下来，从 WES 中识别出的 20,000 个有希望的低频变异 (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，该阵列已包含 818,000 个常见变异。来自所有 2,920 名 CBC 病例儿童和 2,920 名 CBC 对照儿童的 DNA 样本将接受全基因组基因分型，以进行经验丰富的全基因组关联研究 (eeGWAS)。 eeGWAS 分析可以识别 PG 风险的低频变异和常见变异，并且对于汇总分析和亚型分层分析具有统计功效。 eeGWAS 识别出的大约 1,500 个变异将在来自三个合作机构的 1,210 名病例和 1,850 名对照儿童中进行尝试复制。通过利用加州公共卫生部遗传疾病部门独特且成熟的资源，这种基于登记的方法将产生前所未有的大样本量。鉴定潜在 PG 风险的罕见和常见变异可以揭示新知识，从而改善对面临这种诊断的儿童、青少年和年轻人的护理。