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: 9295844
• 负责人: Ajay Goel
• 金额: $ 34.99万
• 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/9295844
• 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; Goals; Healthcare; Individual; Intervention; Lesion; Link; Malignant Neoplasms; Messenger RNA; MicroRNAs; Modality; Mucous Membrane; Patients; Performance; Play; Population; Premalignant; Prevention; Resistance; Risk; Risk Assessment; Role; Sampling; Savings; Sensitivity and Specificity; Serum; Specimen; Standardization; Technology; Testing; Therapeutic; Tissues; Untranslated RNA; Validation; base; biomarker discovery; biomarker panel; carcinogenesis; clinical practice; clinically relevant; cohort; colon cancer patients; colorectal cancer prevention; colorectal cancer screening; cost; design; diagnostic accuracy; early detection biomarkers; genome-wide; high risk; improved; innovation; microRNA biomarkers; mortality; neoplastic; next generation sequencing; novel; novel strategies; prognostic; public health relevance; screening; success; whole genome

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）是一种潜在的可预防疾病；但是，在美国，它仍然是癌症相关死亡的第三大癌症和第二大主要原因，估计每年有50,000例死亡。早期检测临床相关的结直肠肿瘤（CRN），即CRC和晚期CRA（A-CRA），是提高生存率的最佳方法。但是，由于侵入性和成本（即结肠镜检查）或诊断准确性不足（即基于粪便的血液检查），可用的筛查方式诊断这些病变是不切实际的。一种更好的筛查和监视方法，最好是通过非侵入性生物标志物可以促进更早的CRC诊断。 MicroRNA（miRNA），参与基因调节和癌症发育的小型非编码RNA，比较大的RNA更健壮和稳定，对组织，血液，粪便和其他体液的降解具有抵抗力。先前的研究在开发确定的miRNA生物标志物进行CRC筛查方面取得了有限的成功，因此由于非整理方法而无法将所有CRN纳入临床发现的有意义的目标。同样，基于血清的研究中使用的队列的功率不足，缺乏独立的验证集。在此提案中，将应用包括下一代测序（NGS）的miRNA-SEQ在内的创新策略，以允许使用组织的组织和匹配CRN患者的血清量的全基因组miRNA映射，并与无CRN个体的组织和血清进行比较。提出了一种新颖而强大的新方法，以识别具有最高敏感性和特异性的新型miRNA生物标志物，将使用以下特定目标使用大型，良好的样品集来验证。 AIM 1：将使用匹配组织中的全基因组NGS方法和CRN患者的血清标本中的候选miRNA生物标志物和正常患者的血清标本中发现。 AIM 2：将开发候选非侵入性miRNA生物标志物，以区分CRN与没有CRN的患者，并使用定量PCR分析进行了验证。目标3：在AIM 2B中确定的优先级非侵入性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。该项目的创新是基于新型基于NGS的miRNA-Seq平台的首次使用，以发现与大小写肿瘤相关的所有miRNA和ISO-MIRNA对全基因组分析的生物标志物，并使用CRN和对照组的大型，良好的率组成的大型，具有较大的，具有较大的，良好的cr和对照组群体来验证这些分析。该项目的长期目标和潜在影响是为早期结直肠肿瘤开发敏感，特异性，无创和廉价的诊断测试。