Genetic Susceptibility to Pediatric Glioma inIndividuals and Diverse populations

项目摘要/摘要 脑瘤是儿童最常见的实体肿瘤，也是儿童第二常见的恶性肿瘤。差一点 美国15岁以下儿童每年诊断出2000例儿童胶质瘤(PG)，其中只有一半 活到成年。80%的幸存者经历了与治疗相关的危及生命的情况，包括 中风和第二种恶性肿瘤。尽管有明确的证据表明PG风险背后有遗传成分，但几乎没有 已知影响这种致命脑瘤的遗传因素。正如之前对成人神经胶质瘤所展示的那样， 识别可靠和有效的遗传风险因素可以改善风险分层，并揭示 生物途径是疾病发病的基础。先前寻求识别遗传风险的研究 影响PG的因素受样本量较小的限制。这一障碍使研究不足以 以高通量方式鉴定真实的遗传关联。此外，技术上的 局限性迫使以前的研究集中在常见的基因变异上，这可能只是其中一个组成部分 前列腺癌风险的遗传来源。假设罕见和常见的遗传变异 对PG风险的贡献，以及特定亚型的风险，将在本提案中进行正式测试。要实现这一点，需要一个 已开展以人群为基础的病例对照研究，嵌套在加州出生队列(CBC)中。 将利用现有的存档新生儿对常见和罕见的遗传变异进行全基因组分析 1988年至2013年期间，2920名加州儿童被诊断为PG，血迹1：1匹配 控制。首先，来自300名恶性星形细胞瘤儿童和100名对照儿童的DNA将进行全外显子组分析 测序(WES)以确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，在受影响的儿童中显示出罕见变异的显著丰富 外显子组将通过靶向测序在另外675例恶性星形细胞瘤病例中得到验证。 875名来自CBC的对照儿童。接下来，20,000个有希望的低频变体(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 常见的变种。所有2920名CBC病例儿童和2920名CBC对照儿童的DNA样本将接受 全基因组基因分型，以执行经验丰富的全基因组关联研究(EeGWAS)。这个 EeGwas分析可以识别导致PG风险的低频率和常见变异，并且具有统计学意义 支持混合分析和子类型分层分析。大约1,500个变异体是由 EeGwas将在来自三个合作伙伴的1210名病例和1850名对照儿童中进行尝试复制 机构。利用世界卫生组织遗传病科独特和成熟的资源 加州公共卫生部，这种基于注册的方法将产生前所未有的 样本大小。识别PG风险的罕见和常见变异可能会暴露出新的 知识有助于改善对面临这种诊断的儿童、青少年和年轻人的护理。

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.