Role of MicroRNA in Bladder Cancer Risk and Outcome: A Genome-Wide analysis

该项目建立在美国最大的膀胱癌（BC）病例对照研究的基础上，具有广泛的流行病学和临床数据以及丰富的生物标本（DNA，组织和血清/血浆）。我们提出了一个系统的研究微小RNA（miRNA）在BC病因，预后和BCG反应，包括生殖系SNP基因分型，体细胞miRNA分析，循环miRNA的检测。我们的具体目标是：1）使用两阶段设计来鉴定miRNA通路中的新的生殖系易感基因座，其易患BC风险。我们将在1000例病例和1000例对照中筛选约8000个SNP，然后在另外1000例病例和对照中验证前384个SNP。2)使用与目的1相似的两阶段设计，鉴定miRNA途径中预测非肌层浸润性BC（NMIBC）复发和进展的新生殖系易感基因座。在筛选阶段，我们将使用来自我们正在进行的病例对照研究的1，200名NMIBC患者。我们还将对接受BCG治疗的患者进行分层分析，因为BCG是高危NMIBC的普遍膀胱内治疗。在验证阶段，我们将使用300名参加BCG治疗临床试验的患者。3)鉴定体细胞miRNA表达作为BCG应答的预测因子。我们将在接受BCG治疗的患者中确定50个复发的BC肿瘤组织和50个未复发的BC肿瘤组织中的总体miRNA表达谱，以鉴定预测复发的体细胞miRNA签名，然后在另外75对组织中验证签名。我们还将从Aim 2验证的SNP与从该目的验证的miRNA的表达相关联。4)确定循环miRNA作为接受BCG治疗的NMIBC患者复发和进展的预测因子。与目标3类似，我们将使用两阶段设计来鉴定和验证BCG治疗背景下复发和进展的miRNA特征。将在100名BCG治疗的NMIBC复发患者和100名未复发患者的血清中进行筛选，并在50名BCG治疗的NMIBC进展患者和50名未进展患者的血清中进行筛选，并将使用入组BCG临床试验的300名患者进行验证。

The project builds upon the largest case control study of bladder cancer (BC) in U.S. with extensive epidemiologic and clinical data and rich biospecimens (DNA, tissue, and serum/plasma). We propose a systematic study of microRNAs (miRNAs) in BC etiology, prognosis, and BCG response, including germline SNP genotyping, somafic miRNA profiling, and detection of circulating miRNA. Our specific aims are: 1) To identify novel germline susceptibility loci in miRNA pathway that predispose to BC risk using a two-stage design. We will screen -8000 SNPs in 1000 cases and 1000 controls and then validate top 384 SNPs in an additional 1000 cases and controls. 2) To identify novel germline susceptibility loci in miRNA pathway that predict non-muscle invasive BC (NMIBC) recurrence and progression using a similar two stage design as in Aim 1. In screening phase, we will use 1,200 NMIBC patients from our ongoing case control study. We will also performed stratified analysis on those patients receiving BCG treatment since BCG is the prevalent intravesical therapy for high risk NMIBC. In the validation phase, we will use 300 patients who were enrolled in a clinical trial of BCG treatment. 3) To identify somatic miRNA expression as predictors of BCG response. We will determine global miRNA expression profiles in 50 BC tumor tissues with recurrence and 50 without recurrence in patients receiving BCG treatment to identify somatic miRNA signature that predicts recurrence and then validate the signatures in an additional 75 pairs of tissues. We will also correlate the validated SNPs from Aim 2 with the expression of validated miRNAs from this aim. 4) To identify circulating miRNAs as predictors of recurrence and progression in NMIBC patients receiving BCG treatment. Similar to Aim 3, we will use a two stage design to identify and validate miRNA signatures for recurrence and progression in the context of BCG treatment. Screening will be done in serum of 100 BCG-treated NMIBC patients with and 100 patients without recurrence, and in 50 BCG-treated NMIBC patients with and 50 patients without progression, and validation will be done using 300 patients enrolled in the BCG clinical trial.