miRNA and colorectal cancer: associations with tumor phenotype and survival

miRNA 和结直肠癌：与肿瘤表型和生存的关联

• 批准号: 8686601
• 负责人: Martha L SLATTERY
• 金额: $ 137.14万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-08 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686601
• 关键词: Address; Analysis of Variance; Aspirin; Biological Assay; Clinical; Colon; Colon Carcinoma; Colonic Neoplasms; Colonic Polyps; Colorectal Cancer; Cox Proportional Hazards Models; Data; Data Set; Diagnosis; Disease; Etiology; Family; Genes; Genetic; Genetic Variation; Goals; Human; IL6 gene; IL8 gene; Individual; Inflammation; KRAS2 gene; Lead; Life Style; Link; Logistic Regressions; Malignant Neoplasms; Mediating; Messenger RNA; MicroRNAs; Molecular; Mutate; Mutation; Non-Steroidal Anti-Inflammatory Agents; Normal tissue morphology; Obesity; PTEN gene; Pathway interactions; Phenotype; Polyps; Population; Prevention Research; Process; Quality Control; Rectal Cancer; Rectal Polyp; Rectal Tumors; Reporting; Sample Size; Sampling; Signal Pathway; Signaling Pathway Gene; Staging; Statistical Methods; TNF gene; TP53 gene; Testing; Time; Tissues; Training; Tumor-Derived; Validation; base; cancer prevention; cancer risk; clinical phenotype; deep sequencing; follow-up; genetic variant; insight; lifestyle factors; meetings; molecular phenotype; outcome forecast; population based; rectal; screening; tumor; tumor progression

DESCRIPTION (provided by applicant): MicroRNAs (miRNA) are a class of small regulatory RNAs that mediate post-transcriptional silencing of specific target mRNAs. Our overall hypotheses are that miRNA expression is unique to tumor molecular phenotype; that miRNA expression levels at time of diagnosis predicts survival; and that miRNA expression is associated with inflammation-related genetic and lifestyle factors key to colorectal cancer (CRC). This study takes a two pronged approach to addressing our hypotheses. While we propose to validate previously identified miRNAs that have been identified as associated with CRC (either by differential expression or from assessment of mutations), we will add to the field through discovery of new and important associations that may be unique to specific molecular phenotypes, to polyp to cancer progression, and to survival. We will analyze the expression of 866 human miRNAs using data derived from tumor and paired normal tissue at time of diagnosis from: 1660 people with incident colon cancer; 840 people with incident rectal cancer; and 350 polyps from our colon and rectal cases who reported a prior polyp; 5% of tumors, will be analyzed for quality control. Our total assessment will be on 5475 samples. We will extend the validation of previously identified mutated miRNAs and differentially expressed miRNAs to determine if these alterations are associated with specific tumor molecular phenotype, inflammation-related factors, clinical factors and survival. Important miRNAs will be validated using TaqMan-based assays. Associations will be tested based on differential expression for both individual and groups of miRNAs using recent extensions of several statistical methods including ANOVA, logistic regression, and Cox proportional hazards models. Our sample size allows for both a training and validation component, and provides sufficient statistical power to meet the study goals. MiRNAs that are differentially expressed in polyps and in subsequent tumors will provide new insights into targets for screening and treatment and differential miRNAs that function as the "driver" vs. the "passenger" in the carcinogenic process. Testing of mutated miRNAs identified from sequencing in conjunction with tumor phenotype, clinical, and survival data will further validate the importance of these miRNAs, and provide insight as to which CRC molecular pathway the miRNAs function. Our rich dataset of lifestyle, genetic, clinical and prognosis, and tumor molecular phenotype on 2500 CRC and paired normal tissue allows us to examine factors that are associated with miRNAs in a large set of population-based cases. The miRNAs identified in these analyses will elucidate pathways important in the etiology of CRC and will provide insight into potential targets for screening and treatment.

描述（由申请人提供）：MicroRNA (miRNA) 是一类小调节 RNA，可介导特定靶标 mRNA 的转录后沉默。我们的总体假设是 miRNA 表达对于肿瘤分子表型来说是独特的；诊断时的 miRNA 表达水平可预测生存率； miRNA 的表达与炎症相关的遗传和生活方式因素有关，这些因素是结直肠癌 (CRC) 的关键。这项研究采用了双管齐下的方法来解决我们的假设。虽然我们建议验证之前确定的与 CRC 相关的 miRNA（通过差异表达或突变评估），但我们将通过发现新的重要关联来拓展该领域，这些关联可能是特定分子表型、息肉与癌症进展和生存所特有的。我们将使用来自肿瘤和诊断时配对正常组织的数据来分析 866 种人类 miRNA 的表达： 1660 名结肠癌患者； 840 人患有直肠癌；以及来自我们的结肠和直肠病例的 350 例息肉，这些病例报告既往患有息肉；将分析 5% 的肿瘤以进行质量控制。我们的总体评估将针对 5475 个样本。我们将扩大对先前鉴定的突变 miRNA 和差异表达 miRNA 的验证，以确定这些改变是否与特定肿瘤分子表型、炎症相关因素、临床因素和生存相关。重要的 miRNA 将使用基于 TaqMan 的检测进行验证。将使用最近扩展的几种统计方法（包括方差分析、逻辑回归和 Cox 比例风险模型），根据个体和 miRNA 组的差异表达来测试关联性。我们的样本量允许训练和验证部分，并提供足够的统计能力来满足研究目标。在息肉和随后的肿瘤中差异表达的 miRNA 将为筛选和治疗靶点以及在致癌过程中充当“驱动程序”与“乘客”的差异 miRNA 提供新的见解。对测序鉴定出的突变 miRNA 结合肿瘤表型、临床和生存数据进行测试将进一步验证这些 miRNA 的重要性，并提供有关 miRNA 发挥功能的 CRC 分子途径的见解。我们关于 2500 个 CRC 和配对正常组织的生活方式、遗传、临床和预后以及肿瘤分子表型的丰富数据集使我们能够在大量基于人群的病例中检查与 miRNA 相关的因素。这些分析中鉴定出的 miRNA 将阐明 CRC 病因学中的重要途径，并为筛查和治疗的潜在靶点提供深入见解。