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: 9742734
• 负责人: Kyle M Walsh
• 金额: $ 96.38万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 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 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9742734
• 关键词: Genetic; Susceptibility; Pediatric; Glioma; inIndividuals

PROJECT SUMMARY/ABSTRACT 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.

项目总结/摘要 脑肿瘤是儿童最常见的实体瘤，也是第二常见的恶性肿瘤。近 在美国，每年有2,000例15岁以下儿童被诊断出患有小儿神经胶质瘤（PG），其中只有一半的人 活到成年。80%的幸存者经历与治疗相关的危及生命的状况，包括 中风和继发性恶性肿瘤。尽管有明确的证据表明遗传因素是PG风险的基础， 已知影响这种致命脑瘤的遗传因素。正如先前对成人神经胶质瘤所证明的， 确定可靠和有效的遗传风险因素可以改善风险分层，并揭示 疾病发病机理的基本生物学途径。以前的研究试图确定遗传风险 PG的因素受到样本量小的限制。这一障碍使研究不足以为 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集中在共同的遗传变异，这可能只是一个组成部分， 潜在PG风险的基因来源。这一假说认为罕见和常见的遗传变异 有助于PG风险和特定亚型的风险，将在本提案中进行正式测试。为了实现这一点，A 在加州出生队列（CBC）中进行了一项基于人群的病例对照研究。 将使用现有的存档新生儿进行常见和罕见遗传变异的全基因组分析。 1988年至2013年期间，2,920名加利福尼亚儿童被诊断患有PG， 对照首先，来自300名恶性星形细胞瘤儿童和100名对照儿童的DNA将进行全外显子组测序。 基因测序（WES）以鉴定导致疾病风险的罕见变异（次要等位基因频率<1%）。基因 与CBC和公共对照相比，受影响儿童中罕见变异的显著富集 外显子组将在另外675例恶性星形细胞瘤病例儿童中通过靶向测序进行验证， 来自CBC的875名对照儿童。接下来，20，000个有希望的低频变异（MAF 1-5%）从 WES将作为定制内容添加到全基因组基因分型阵列中，该阵列已经包含818，000个 常见变体所有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，以进行一项药物富集的全基因组关联研究（eeGWAS）。的 eeGWAS分析可以识别潜在PG风险的低频和常见变异，并且在统计学上是 合并和亚型分层分析的把握度。大约有1,500种变异被鉴定出来， eeGWAS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性复制 机构职能体系通过利用遗传病分支内独特且成熟的资源 加州公共卫生部，这种基于注册的方法将产生前所未有的大 样本量鉴定罕见和常见的PG风险变异可以暴露新的 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。