miRNA and colorectal cancer: associations with tumor phenotype and survival

描述(由申请人提供)：microRNAs(MiRNA)是一类小的调节RNA，介导特定靶标mRNAs的转录后沉默。我们的总体假设是miRNA的表达是肿瘤分子表型所特有的；在诊断时miRNA的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素对结直肠癌(CRC)至关重要。这项研究采取了双管齐下的方法来解决我们的假设。虽然我们建议验证之前发现的与结直肠癌相关的miRNAs(通过差异表达或通过突变评估)，但我们将通过发现可能与特定分子表型、息肉与癌症进展和生存相关的新的重要关联来增加这一领域。我们将使用来自肿瘤的数据和诊断时配对的正常组织来分析866个人类miRNAs的表达：1660名结肠癌患者；840名直肠癌患者；350例结直肠息肉病例；5%的肿瘤将被分析以进行质量控制。我们将对5475个样品进行总评估。我们将延长先前发现的突变miRNAs和差异表达miRNAs的有效性，以确定这些变化是否与特定的肿瘤分子表型、炎症相关因素、临床因素和生存期有关。重要的miRNAs将使用基于TaqMan的分析进行验证。将使用最近扩展的几种统计方法，包括方差分析、Logistic回归和COX比例风险模型，基于miRNAs个体和组的差异表达来测试关联性。我们的样本量同时考虑了培训和验证部分，并提供了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miRNAs将为筛查和治疗的靶点提供新的见解，并提供在致癌过程中起“司机”和“乘客”作用的不同miRNAs。通过测序结合肿瘤表型、临床和生存数据对突变的miRNAs进行检测，将进一步验证这些miRNAs的重要性，并提供有关miRNAs功能的CRC分子途径的洞察力。我们对2500例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miRNAs相关的因素。这些分析中确定的miRNAs将阐明在结直肠癌病因中重要的途径，并将为筛查和治疗的潜在靶点提供洞察力。

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.