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.

项目摘要/摘要 脑肿瘤是最常见的实体瘤，是儿童中第二常见的恶性肿瘤。几乎 每年在15岁以下的美国儿童中诊断出2,000个小儿神经胶质瘤（PG），其中只有一半 生存到成年。 80％的幸存者经历了与治疗有关的威胁生命状况，包括 中风和第二个恶性肿瘤。尽管有明确的证据表明PG风险是基础的遗传成分，但几乎没有 关于影响这种致命脑肿瘤的可遗传因素。如前所述，成人神经胶质瘤 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 生物学途径是疾病发病机理的基础。以前寻求识别遗传风险的研究 PG的因素受样本量较小的限制。这种障碍使研究不足 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专注于常见的遗传变异，这可能只是一个成分 PG风险的遗传起源。罕见和常见遗传变异的假设 在此提案中将正式测试有助于PG风险和特定亚型的风险。为此， 已经开发了嵌套在加利福尼亚出生队列（CBC）内的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稀有遗传变异的全基因组分析 来自1988年至2013年期间诊断为PG的2,920名加利福尼亚儿童的血迹和1：1匹配 控件。首先，来自300名恶性星形细胞瘤和100个对照儿童的DNA将接受全外观 测序（WES）确定造成疾病风险的稀有变体（次要等位基因频率<1％）。基因 与CBC和公共控制相比，在受影响儿童中显示出罕见变体的大量富集 在另外675例恶性星形细胞瘤病例和 875名来自CBC的儿童。接下来，有20,000个有前途的低频变体（MAF 1-5％） WES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 常见变体。来自所有2,920个CBC病例儿童和2,920 CBC对照儿童的DNA样本将接受 全基因组基因分型进行经验丰富的全基因组关联研究（EEGWAS）。这 EEGWAS分析可以识别PG风险的低频和常见变体，并且在统计上是 用于合并和亚型分层的分析。大约1,500个变体 EEGWAS将在1,210个案件中尝试复制，并从三个合作的儿童中进行1,850名对照儿童 机构。通过利用遗传疾病分支中的独特和成熟资源 加利福尼亚公共卫生部，这种基于注册表的方法将产生前所未有的大型 样本量。识别PG风险潜在的稀有变体和常见变体可能会暴露出新的 知识导致对儿童，青少年和面对这种诊断的年轻人的护理改善。