Clinical Utility of Salivary ExRNA Biomarkers for Gastric Cancer Detection

描述（由申请人提供）： 细胞外RNA（exRNA）作为内分泌信号在细胞通讯、生物标志物开发、治疗应用和系统生理学中是新兴的范例。这个UH 2/UH 3项目是为了测试唾液细胞外RNA（exRNA）可以用于人类疾病的临床检测的假设。我们的实验室首先报道了无细胞唾液中转录组和microRNA谱的存在，随后报道了其科学表征和临床效用，包括分子肿瘤学应用的生物标志物开发。最近，我们在无细胞唾液中进行了RNA测序，并报道了唾液中的三种主要类型的RNA（mRNA、miRNA和snoRNA）。该UH 2/UH 3申请旨在通过进行生物标志物开发研究以明确验证用于检测胃癌的唾液exRNA生物标志物来测试唾液exRNA可以开发用于检测胃癌的假设。我们之所以选择胃癌作为人类疾病适应症，是因为我们与三星医疗中心正在进行富有成效的合作，我们已经从500名胃癌患者和2250名非胃癌对照中获得了唾液。这将允许exRNA生物标志物发现的UH 2阶段立即开始。将在UH 3阶段采购额外的临床样本，每年375例病例和375例非胃癌匹配对照，持续两年。这些用于发现和验证的临床样本将允许我们明确验证唾液exRNA是否可用于在定义的临床环境中检测胃癌（使用背景）。 项目UH 2阶段有四个具体目标。目的1是从100例胃癌和100例非胃癌对照中随机选择唾液用于目的2，目的2是进行全面的RNA测序以在核苷酸水平上全面地分析唾液exRNA。目的3是对分析的唾液mRNA、miRNA和snoRNA进行数据和统计分析，以选择前20个唾液ex-mRNA、ex-miRNA和ex-snoRNA。目的4是验证原始发现群组中的候选exRNA生物标志物。只有经过验证的候选唾液exRNA将进入UH 3期。 在UH 3阶段，目标5是从另外750名胃癌患者和750名非胃癌对照中招募和获取唾液。目标6将使用来自目标4的500个胃癌唾液和500个匹配的对照受试者来单独验证经验证的候选唾液exRNA生物标志物，并使用逻辑回归分析配置一组具有最高性能的经验证的exRNA生物标志物。将在Aim 7中使用来自250例胃癌和250例非胃癌对照的独立队列的唾液对该小组进行验证。 该UH 2/UH 3申请的目的是通过发现和明确验证用于检测人类疾病状况的唾液exRNA生物标志物来证明唾液exRNA的临床效用。

DESCRIPTION (provided by applicant): Extracellular RNA (exRNA) is an emerging paradigm as endocrine signals in cellular communication, biomarker development, therapeutic applications and systemic physiology. This UH2/UH3 project is to test the hypothesis that salivary extracellular RNA (exRNA) can be developed for the clinical detection of human diseases. Our laboratory first reported the existence of a transcriptome and microRNA profile in cell free saliva followed by its scientific characterizations and clinical utilities including biomarker development for molecular oncology applications. Most recently we have performed RNA-sequencing in cell free saliva and reported three major types of RNA in saliva (mRNA, miRNA and snoRNA). This UH2/UH3 application is to test the hypothesis that salivary exRNA can be developed to detect gastric cancer by performing a biomarker development study to definitively validate salivary exRNA biomarkers for the detection of gastric cancer. We are selecting gastric cancer to be the human disease indication because of an ongoing productive collaboration with the Samsung Medical Center where we have already procured saliva from 500 gastric cancer patients and 2250 non-gastric cancer controls. This will permit the UH2 phase for exRNA biomarker discovery to begin immediately. Additional clinical samples will be procured in the UH3 phase, 375 cases and 375 non-gastric cancer match controls each year for two years. These clinical samples for discovery and validation will allow us to definitively validate if salivary exRNA can be used to detect gastrc cancer in a defined clinical setting (Context of Use). There are four Specific Aims in the UH2 phase of the project. Aim 1 is to randomly select saliva from 100 gastric cancer and 100 non-gastric cancer controls to be used in Aim 2 which is to perform comprehensive RNA-sequencing to comprehensively profile salivary exRNA to the nucleotide level. Aim 3 is to perform data and statistical analysis of the profiled salivary mRNA, miRNA, and snoRNA to select the top 20 salivary ex- mRNA, ex-miRNA and ex-snoRNA. Aim 4 is to verify the candidate exRNA biomarkers in the original discovery cohort. Only verified candidate salivary exRNA will be advanced to the UH3 phase. In the UH3 phase, Aim 5 is to enroll and procure saliva from an additional 750 gastric cancer patients and 750 non-gastric cancer controls. Aim 6 will use 500 of the gastric cancer saliva and 500 matched control subjects from Aim 4 to individually validate the verified candidate salivary exRNA biomarkers and configure a panel of validate exRNA biomarkers with highest performance using logistic regression analysis. The panel will be validated in Aim 7 using saliva from an independent cohort of 250 gastric cancer and 250 non-gastric cancer controls. The goals of this UH2/UH3 application are to demonstrate the clinical utility of salivary exRNA by the discovering and definitively validating salivary exRNA biomarkers for the detection of a human disease condition.