Exploiting the immune response to detect pathogen-induced cancers

 描述(申请人提供)：癌症是一种遗传性疾病，由遗传和环境因素相互作用引起。了解这种复杂的相互作用以及各个因素对个体患者癌症的影响程度，将影响风险评估、预防和治疗。微生物作为癌症的环境贡献者的作用已经得到了很好的证明，全世界20%的癌症都是由微生物引起的。结直肠癌(CRC)发生在暴露于微生物浓度最高的组织中，其肿瘤发生的表面位置表明，某些CRC可能是这种暴露造成的。尽管努力了解病原体在结直肠癌中的作用，但由于缺乏研究感染史的综合工具，探索一直受到限制。下一代测序(NGS)极大地促进了我们对结直肠癌患者微生物组变化的了解。我们提出了一项免疫蛋白质组学研究，以补充现有的NGS研究，并假设对微生物抗原的体液免疫反应的蛋白质组规模的综合研究将产生具有临床实用价值的特异性抗体生物标记物。我们的首要目标是找出能及早发现病原体相关癌症的抗体标记物或找出罹患癌症的高危人群。我们将使用三种不同的资源来选择候选病原体，包括：可用的文献、我们自己对NGS数据的分析以及我们的大量微生物基因集合。我们将利用我们创新的蛋白质微阵列平台，即核酸可编程蛋白质阵列(NAPPA)(22，23)，通过对大量癌症患者中数千种微生物蛋白质的血清图谱来识别癌症中的抗体标记物。蛋白质微阵列提供了一个多路、高通量的平台，用于并行分析宿主对数千种蛋白质的抗体免疫反应。尽管利用抗体反应来检测病原体相关癌症的潜力很大，但蛋白质微阵列从未被应用于这一目的。我们的NAPPA克服了传统高密度蛋白质阵列在成本和可编程性方面的一些挑战，并在发现阶段实现了蛋白质组水平的定量抗体分析。顶级候选抗体标志物将通过使用更接近临床的ELISA免疫分析的独立样本集进一步盲目验证，以确保严格性。癌症的特异性也将通过分析非恶性炎症性肠病(IBD)患者中有效抗体的表现来评估。我们的研究团队由疾病蛋白质组学专家、统计学家、微生物学家和胃肠道肿瘤学家组成。在诊断时收集的具有详细临床信息的高质量样本可用于本研究。因此，我们可以确保技术卓越，以解决对患者管理具有潜在影响的临床重要问题。提高对感染性病原体和癌症之间联系的了解可能有助于识别癌症诊断、管理风险和开发疫苗和预防策略。

 DESCRIPTION (provided by applicant): Cancer is a genetic disease caused by an interaction between genetic and environmental factors. Understanding this complex interaction and the degree to which factors contribute to cancer in individual patients will impact risk assessment, prevention and treatment. The role of microbes as environmental contributors to cancer has been well documented, causing >20% of cancers worldwide. Colorectal cancer (CRC) occurs at the tissue exposed to the highest concentration of microorganisms, and the surface location of its tumorigenesis implies that some CRC may result from this exposure. Despite efforts to understand the role of pathogens in CRC, exploration has been limited because comprehensive tools to study infection history are lacking. Next-gen sequencing (NGS) has greatly advanced our knowledge of microbiome changes in CRC patients. We are proposing an immunoproteomics study that complements existing NGS studies and hypothesize that a proteome-scale, comprehensive study of the humoral immune response against microbial antigens will yield specific antibody biomarkers with clinical utilities. Our overarching goal is t identify antibody markers that detect pathogen-associated cancer early or identify subjects at high risk of developing cancer. We will select candidate pathogens using three different resources including: the available literature, our own analysis of NGS data, and our large collection of microbial genes. We will identify antibody markers in cancers by profiling serum against thousands of microbial proteins in a large number of cancer patients using our innovative protein microarray platform, namely Nucleic Acid Programmable Protein Array (NAPPA) (22,23). Protein microarrays provide a multiplexed, high-throughput platform to profile host antibody immune responses against thousands of proteins in parallel. Despite the strong potential of harnessing antibody responses to detect pathogen-associated cancers, protein microarrays have never been applied to this purpose. Our NAPPA overcomes some challenges associated with conventional high-density protein arrays in terms of cost and programmability and enables quantitative antibody profiling at the proteome level in the discovery phase. Top candidate antibody markers will be further verified blindly with an independent sample set using the closer-to-clinic ELISA immunoassay to ensure rigor. Cancer specificity will also be assessed by assaying the performance of validated antibodies in non-malignant inflammatory bowel disease (IBD) patients. Our research team comprises experts on disease proteomics, statisticians, microbiologists and GI oncologists. High quality samples collected at diagnosis with detailed clinical information are available for this study. Thus, we can ensure technical excellence to solve clinically important questions with potential impact on patient management. Improved knowledge of the link between infectious agents and cancers may help identify cancer diagnostics, manage risks and develop vaccine and prevention strategies.