miRNA and colorectal cancer: associations with tumor phenotype and survival

描述（由申请人提供）：MicroRNAs （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表达水平预测生存；miRNA表达与炎症相关的遗传和生活方式因素有关，是结直肠癌的关键因素。这项研究采用了两种方法来解决我们的假设。虽然我们建议验证先前已鉴定的与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与特定分子表型、息肉、癌症进展和生存相关的新的重要关联来增加该领域。我们将使用来自肿瘤和配对正常组织的数据分析866个人类mirna的表达，这些数据来自1660名结肠癌患者；840人患直肠癌；350个结肠和直肠息肉患者报告之前有息肉；5%的肿瘤，将进行分析以进行质量控制。我们总共评估5475个样品。我们将扩展先前鉴定的突变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的检测方法进行验证。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，基于个体和群体mirna的差异表达来检验相关性。我们的样本量允许训练和验证成分，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作为“驱动者”和“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，对测序中发现的突变mirna进行测试，将进一步验证这些mirna的重要性，并提供mirna发挥作用的CRC分子途径的见解。我们丰富的数据集包括2500个结直肠癌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，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。在这些分析中发现的mirna将阐明在CRC病因学中重要的途径，并将为筛查和治疗的潜在靶点提供见解。

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. PUBLIC HEALTH RELEVANCE: Our rich dataset of lifestyle, genetic, clinical and prognosis, and tumor molecular phenotype on 2500 CRC (colorectal cancer) and paired normal tissue allows us to examine factors that are associated with miRNA expression and mutation in a large sample of population-based cases. Having data available on polyps from those cases who developed cancer, will help us determine "drivers" vs. "passengers" in the carcinogenic process. 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.