Clinical Utility of Salivary ExRNA Biomarkers for Gastric Cancer Detection

唾液 ExRNA 生物标志物在胃癌检测中的临床应用

• 批准号: 8581852
• 负责人: David T Wong
• 金额: $ 50万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581852
• 关键词: Biological Markers; Blinded; Cancer Control; Cancer Detection; Cancer Patient; Cells; Clinical; Collaborations; Communication; Complex; Data; Data Analyses; Detection; Development; Diagnosis; Endocrine; Enrollment; Evaluation; Gene Expression Profile; Goals; Human; Individual; Laboratories; Logistic Regressions; Macromolecular Complexes; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Medical center; MicroRNAs; Modeling; Nucleotides; Odds Ratio; Performance; Phase; Physiology; Preparation; Procedures; RNA; RNA Sequences; Randomized; Regression Analysis; Reporting; Resources; Saliva; Salivary; Sampling; Series; Signal Transduction; Sjogren' s Syndrome; Small Nucleolar RNA; Statistical Data Interpretation; Testing; Validation; base; biobank; cDNA Library; cohort; design; extracellular; human disease; malignant breast neoplasm; malignant mouth neoplasm; malignant stomach neoplasm; molecular oncology; prospective; public health relevance; sample collection; therapeutic development; transcriptome sequencing

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.

描述（由申请人提供）： 细胞外 RNA (exRNA) 是细胞通讯、生物标志物开发、治疗应用和系统生理学中内分泌信号的新兴范例。该UH2/UH3项目旨在检验唾液细胞外RNA（exRNA）可用于人类疾病的临床检测这一假设。我们的实验室首先报告了无细胞唾液中转录组和 microRNA 谱的存在，随后报道了其科学特征和临床实用性，包括用于分子肿瘤学应用的生物标志物开发。最近，我们对无细胞唾液进行了 RNA 测序，报告了唾液中三种主要类型的 RNA（mRNA、miRNA 和 snoRNA）。该 UH2/UH3 应用旨在测试以下假设：通过进行生物标志物开发研究，可开发唾液 exRNA 来检测胃癌，以明确验证用于检测胃癌的唾液 exRNA 生物标志物。我们选择胃癌作为人类疾病适应症，是因为与三星医疗中心正在进行富有成效的合作，我们已经从该中心采集了 500 名胃癌患者和 2250 名非胃癌对照者的唾液。这将使 exRNA 生物标志物发现的 UH2 阶段立即开始。 UH3 阶段将每年采购 375 例病例和 375 例非胃癌对照样本，持续两年。这些用于发现和验证的临床样本将使我们能够明确验证唾液 exRNA 是否可用于在特定的临床环境（使用背景）中检测胃癌。 该项目的 UH2 阶段有四个具体目标。目标 1 是从 100 个胃癌和 100 个非胃癌对照中随机选择唾液用于目标 2，即进行全面的 RNA 测序，以在核苷酸水平上全面分析唾液 exRNA。目标 3 是对唾液 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。目标 4 是验证原始发现队列中的候选 exRNA 生物标志物。只有经过验证的候选唾液 exRNA 才会进入 UH3 阶段。 在 UH3 阶段，目标 5 是招募并获取另外 750 名胃癌患者和 750 名非胃癌对照者的唾液。目标 6 将使用目标 4 中的 500 份胃癌唾液和 500 名匹配的对照受试者来单独验证经过验证的候选唾液 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验证 exRNA 生物标志物。该小组将在目标 7 中使用来自 250 名胃癌和 250 名非胃癌对照的独立队列的唾液进行验证。 该 UH2/UH3 应用的目标是通过发现并明确验证唾液 exRNA 生物标志物用于检测人类疾病状况，证明唾液 exRNA 的临床实用性。