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: 8542607
• 负责人: Martha L SLATTERY
• 金额: $ 142.61万
• 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/8542607
• 关键词: Address; 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）是一类小的调节性RNA，可介导特定靶标mRNA的转录后沉默。我们的总体假设是miRNA表达是肿瘤分子表型独有的。诊断时的miRNA表达水平可以预测生存。 miRNA的表达与炎症相关的遗传和生活方式因子（CRC）至关重要。这项研究采取了两种规律的方法来解决我们的假设。虽然我们建议验证先前鉴定的与CRC相关的miRNA（通过差异表达或突变评估），但我们将通过发现可能是特定分子表型所独有的新和重要关联来添加到现场，以质量为息肉，以癌症进展，以及生存。我们将使用从肿瘤中得出的数据并在诊断时配对正常组织的数据来分析866人miRNA的表达：1660人入射结肠癌； 840人发生直肠癌；和我们的结肠和直肠病例的350个息肉报告了先前的息肉； 5％的肿瘤将进行分析以进行质量控制。我们的总评估将是5475个样本。我们将扩展对先前鉴定的突变的miRNA和差异表达的miRNA的验证，以确定这些改变是否与特定的肿瘤分子表型，炎症相关因素，临床因素和存活率相关。重要的miRNA将使用基于Taqman的测定法进行验证。将使用几种统计方法的最近扩展（包括ANOVA，Logistic回归和COX比例危害模型）的近期扩展基于个体和miRNA组的差分表达来测试关联。我们的样本量允许培训和验证组件，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将为筛查和治疗的目标提供新的见解，以及在致癌过程中充当“驱动器”与“乘客”的差异miRNA。通过测序与肿瘤表型，临床和生存数据结合进行的测序测试，将进一步验证这些miRNA的重要性，并提供有关miRNA功能的CRC分子途径的见解。我们丰富的生活方式，遗传，临床和预后数据集以及2500 CRC和配对正常组织的肿瘤分子表型使我们能够检查与大量基于人群的病例中与miRNA相关的因素。这些分析中鉴定出的miRNA将阐明在CRC病因中重要的途径，并将洞悉筛查和治疗的潜在目标。