miRNA and colorectal cancer: associations with tumor phenotype and survival

描述（由申请人提供）：MicroRNA（miRNA）是一类介导特定靶mRNA转录后沉默的小调控RNA。我们的总体假设是，miRNA表达是肿瘤分子表型所特有的;诊断时的miRNA表达水平可预测生存率; miRNA表达与结直肠癌（CRC）关键的炎症相关遗传和生活方式因素相关。这项研究采取了双管齐下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），但我们将通过发现新的重要关联来增加该领域，这些关联可能是特定分子表型、息肉到癌症进展和生存所独有的。我们将使用来自诊断时肿瘤和配对正常组织的数据分析866种人类miRNA的表达，这些数据来自：1660例结肠癌患者; 840例直肠癌患者;以及来自我们的结肠和直肠病例的350例息肉，这些病例报告了先前的息肉;将分析5%的肿瘤用于质量控制。我们将对5475个样本进行总评估。我们将扩展先前鉴定的突变miRNAs和差异表达miRNAs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、临床因素和生存相关。重要的miRNA将使用基于TaqMan的测定进行验证。将使用最近扩展的几种统计方法，包括ANOVA、逻辑回归和考克斯比例风险模型，基于单个和组miRNA的差异表达来测试关联性。我们的样本量允许训练和验证组件，并提供足够的统计能力来满足研究目标。在息肉和后续肿瘤中差异表达的miRNA将为筛选和治疗靶点以及在致癌过程中充当“驾驶员”与“乘客”的差异miRNA提供新的见解。结合肿瘤表型、临床和生存数据对测序鉴定的突变miRNA进行测试将进一步验证这些miRNA的重要性，并提供关于miRNA在哪种CRC分子途径中起作用的见解。我们对2500例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。在这些分析中鉴定的miRNAs将阐明CRC病因学中的重要途径，并将为筛选和治疗提供潜在靶点。

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.