Discovering Infection-mediated Pathways of Glioma Etiology and Prognosis by Leveraging Multiplex Serology and Immunogenomics

项目摘要 胶质瘤占所有恶性脑肿瘤的80%，并且具有极差的预后，5年 生存率5.1%。胶质瘤的病因学仍然知之甚少，很少有确定的可改变的危险因素。 多项研究表明，感染与胶质瘤的发生有关，但其潜在机制尚不清楚。 和假定的致病病原体仍不清楚。除了风险，还有越来越多的证据表明， 研究新疗法的研究表明，对感染的免疫反应可能是预后性的， 神经胶质瘤患者。以前的流行病学研究已经调查了有限数量的病原体， 仅允许检测的血清学测定。我们试图进行一项大型血清学研究， 使用提供定量测量的分析， 抗体反应。我们的研究将包括1000例神经胶质瘤病例对照对， 流行病学数据。在目标1中，我们将评估每种感染对胶质瘤风险和生存率的影响 并检查合并感染的分组模式。在目标2中，我们将采用创新的长读段测序， 技术详细说明人类白细胞抗原（HLA）I类和II类基因的所有多态性，在同一组 科目HLA区域的遗传变异在调节对病毒攻击的免疫应答中起着关键作用 并且以前与神经胶质瘤的风险和进展有关。我们将研究一系列功能性HLA 与胶质瘤相关的多态性，包括抗原呈递经典等位基因和氨基酸残基 风险与生存在目标3中，我们将整合血清学和HLA测序数据， 感染的免疫应答机制和对胶质瘤终点的后续影响。这将使我们能够 开发用于预测胶质瘤风险和存活的综合免疫基因组学模型。总的来说， 一项拟议的研究将提供新的、高质量的数据，这将大大促进我们对胶质瘤的理解 发病机制，以及预防和改善胶质瘤患者预后的信息途径。

PROJECT SUMMARY Gliomas account for 80% of all malignant brain tumors and have an extremely poor prognosis, with a 5-year survival of 5.1%. The etiology of glioma remains poorly understood, with few established modifiable risk factors. Multiple studies have implicated infections in the development of glioma, however the underlying mechanisms and putative causal pathogens remain unclear. In addition to risk, there is also accumulating evidence from studies investigating novel therapeutics suggesting that immune response to infection may be prognostic in glioma patients. Previous epidemiologic studies have investigated a limited number of pathogens using serological assays that only allowed detection. We seek to conduct a large serologic study measuring 41 antigens from all 12 infections previously associated with glioma using assays that provide quantitative measures of antibody response. Our study will include 1000 glioma case-control pairs with extensive clinical and epidemiologic data. In Aim 1 we will estimate the effect of each individual infection on glioma risk and survival and also examine grouped patterns of co-infections. In Aim 2, we will employ innovative long read sequencing technology to detail all polymorphisms in human leukocyte antigen (HLA) class I and II genes in the same set of subjects. Genetic variation in the HLA region plays a pivotal role in regulating immune response to viral challenge and has been previously linked to glioma risk and progression. We will investigate a range of functional HLA polymorphisms, including antigen-presenting classical alleles and amino acid residues, with respect to glioma risk and survival. In Aim 3, we will integrate serological and HLA sequencing data to delineate host genetic mechanisms of immune response to infection and subsequent effects on glioma endpoints. This will allow us to develop comprehensive immunogenomic models for predicting glioma risk and survival. Taken together, the proposed study will contribute new, high-quality data that will significantly advance our understanding of glioma pathogenesis, as well as inform avenues for prevention and improvement of outcomes in glioma patients.