Development of microRNA Biomarkers For Noninvasive Detection of Colorectal Cancer

开发用于无创检测结直肠癌的 microRNA 生物标志物

• 批准号: 8818968
• 负责人: Ajay Goel
• 金额: $ 36.04万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8818968
• 关键词: Bioinformatics; Biological Assay; Biological Markers; Blood; Blood Tests; Body Fluids; Cancer Etiology; Cessation of life; Characteristics; Clinical; Collection; Colon; Colonoscopy; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Discrimination; Disease; Early Diagnosis; Evaluation; Excision; Failure; Feces; Gene Expression Regulation; Genome; Goals; Healthcare; Individual; Intervention; Lesion; Link; Malignant Neoplasms; Maps; Messenger RNA; MicroRNAs; Modality; Mucous Membrane; Patients; Performance; Play; Population; Premalignant; Prevention; Resistance; Risk; Risk Assessment; Role; Sampling; Savings; Second Primary Cancers; Sensitivity and Specificity; Sequence Analysis; Serum; Specimen; Technology; Testing; Therapeutic; Tissues; Untranslated RNA; Validation; base; carcinogenesis; clinical practice; clinically relevant; cohort; colorectal cancer prevention; colorectal cancer screening; cost; design; diagnostic accuracy; genome-wide; high risk; improved; innovation; mortality; neoplastic; next generation sequencing; novel; novel strategies; prognostic; public health relevance; screening; success

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is a potentially preventable disease; however, it still ranks as the third most common cancer and second leading cause of cancer-related deaths in the U.S., with an estimated 50,000 deaths annually. Early detection of clinically relevant colorectal neoplasia (CRN), i.e. CRC and advanced CRAs (A-CRA), is the best way to improve survival. However, available screening modalities to diagnose these lesions are impractical due to invasiveness and cost (i.e., colonoscopy) or insufficient diagnostic accuracy (i.e., fecal-based blood tests). A better approach to screening and surveillance, preferably through noninvasive biomarkers that can facilitate earlier diagnosis of CRC would be highly desirable. MicroRNAs (miRNAs), small non-coding RNAs involved in gene regulation and cancer development, are more robust and stable than larger RNAs, being resistant to degradation in tissues, blood, stool, and other body fluids. Previous studies have achieved limited success in developing definitive sets of miRNA biomarkers for CRC screening due non-comprehensive approaches, and a failure to include all CRNs as meaningful targets for clinical discovery. Also, cohorts used in serum-based studies have been insufficiently powered and lacked independent validation sets. In this proposal, innovative strategies that include Next Generation Sequencing (NGS)-based miRNA-Seq will be applied to permit genome-wide miRNA mapping using tissues and matching sera from patients with CRN, and compared with tissues and sera from individuals without CRN. A novel and powerful new approach is being proposed to identify novel miRNA biomarkers with the highest sensitivity and specificity, which will be validated using large, well-characterized sample sets through the following Specific Aims. Aim 1: Candidate miRNA biomarkers will be discovered using genome-wide NGS approaches in matched tissue and serum specimens from patients with CRN and individuals with a normal colon. Aim 2: Candidate non-invasive miRNA biomarkers will be developed that distinguish patients with CRN vs. those without CRN, and validated using quantitative PCR assays. Aim 3: Clinical validation of prioritized non-invasive miRNA biomarkers identified in Aim 2b will be performed in asymptomatic average risk individuals. The innovation of this project is based upon the first use of a novel, NGS-based miRNA-Seq platform for the biomarker discovery of genome-wide profiling of all miRNAs and iso-miRNAs that are linked to colorectal neoplasia, and validating these using a large, well-characterized cohort of patients with CRN and controls. The long-term goal and potential impact of this project is to develop a sensitive, specific, non-invasive and inexpensive diagnostic test for early colorectal neoplasia.

描述（由申请人提供）：结直肠癌（CRC）是一种潜在可预防的疾病；然而，它仍然是美国第三大常见癌症和癌症相关死亡的第二大原因，估计每年有 50,000 人死亡。早期发现临床相关结直肠肿瘤 (CRN)，即 CRC 和晚期 CRA (A-CRA)，是提高生存率的最佳方法。然而，由于侵入性和成本（即结肠镜检查）或诊断准确性不足（即基于粪便的血液测试），诊断这些病变的可用筛查方式是不切实际的。非常需要一种更好的筛查和监测方法，最好是通过无创生物标志物来促进结直肠癌的早期诊断。 MicroRNA (miRNA) 是参与基因调控和癌症发展的小型非编码 RNA，比较大的 RNA 更强大、更稳定，能够抵抗组织、血液、粪便和其他体液中的降解。先前的研究由于方法不全面，在开发用于 CRC 筛查的明确 miRNA 生物标志物方面取得了有限的成功，并且未能将所有 CRN 作为临床发现的有意义的靶标。此外，基于血清的研究中使用的队列动力不足且缺乏独立的验证集。在该提案中，将应用包括基于下一代测序（NGS）的 miRNA-Seq 在内的创新策略，以允许使用 CRN 患者的组织和匹配血清进行全基因组 miRNA 作图，并与没有 CRN 的个体的组织和血清进行比较。正在提出一种新颖而强大的新方法来识别具有最高灵敏度和特异性的新型 miRNA 生物标志物，该方法将通过以下具体目标使用大量、特征良好的样本集进行验证。目标 1：将使用全基因组 NGS 方法在 CRN 患者和正常结肠个体的匹配组织和血清标本中发现候选 miRNA 生物标志物。目标 2：将开发候选非侵入性 miRNA 生物标志物，以区分 CRN 患者与无 CRN 患者，并使用定量 PCR 测定进行验证。目标 3：目标 2b 中确定的优先非侵入性 miRNA 生物标志物的临床验证将在无症状的平均风险个体中进行。该项目的创新基于首次使用基于 NGS 的新型 miRNA-Seq 平台，用于发现与结直肠肿瘤相关的所有 miRNA 和 iso-miRNA 的全基因组分析的生物标志物，并使用大型、特征明确的 CRN 患者和对照队列。该项目的长期目标和潜在影响是开发一种敏感、特异、非侵入性且廉价的早期结直肠肿瘤诊断测试。