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病例对照研究的基础上， 流行病学和临床数据以及丰富的生物样本(DNA、FISE和血清/血浆)。我们提出了一个 MicroRNAs(MiRNAs)在BC病理学、预后和卡介苗应答中的系统学研究，包括 生殖系SNP基因分型，体细胞miRNA图谱，循环miRNA的检测。我们的具体目标 1)在miRNA途径中鉴定易患BC风险的新的种系易感基因座 两阶段设计。我们将在1000个病例和1000个对照中筛选8000个SNP，然后验证前384个 在另外1000例病例和对照中发现SNPs。2)鉴定miRNA中新的种系易感基因座 使用相似的两个阶段预测非肌肉侵袭性BC(NMIBC)复发和进展的途径 设计与目标1相同。在筛查阶段，我们将从我们正在进行的病例中使用1200名NMIBC患者 对照研究。我们还将对自2005年以来接受卡介苗治疗的患者进行分层分析 卡介苗是目前治疗高危NMIBC的常用方法。在验证阶段，我们将使用300 参加卡介苗治疗临床试验的患者。3)鉴定体细胞miRNA的表达为 卡介苗反应的预测因子。我们将确定50个BC肿瘤组织中的全局miRNA表达谱 接受卡介苗治疗的患者中有50人复发和50人无复发以鉴定体细胞miRNA 预测复发的签名，然后在另外75对组织中验证签名。我们 还将把来自AIM 2的有效SNPs与来自该AIM的有效miRNAs的表达相关联。4) 确定循环miRNAs作为预测NMIBC患者术后复发和进展的指标 卡介苗治疗。与目标3类似，我们将使用两阶段设计来识别和验证miRNA签名 在卡介苗治疗背景下的复发和进展。将在100人的血清中进行筛查 卡介苗治疗的NMIBC患者和100例无复发患者，以及50例接受卡介苗治疗的NMIBC患者 有进展的患者和50名无进展的患者，将使用300名患者进行验证 在卡介苗临床试验中。

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, fissue, and serum/plasma). We propose a systemafic study of microRNAs (miRNAs) in BC efiology, prognosis, and BCG response, including germline SNP genotyping, somafic miRNA profiling, and detecfion of circulafing miRNA. Our specific aims are: 1) To identify novel germline suscepfibility 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 addifional 1000 cases and controls. 2) To identify novel germline suscepfibility loci in miRNA pathway that predict non-muscle invasive BC (NMIBC) recurrence and progression using a similar twostage 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 idenfify somatic miRNA signature that predicts recurrence and then validate the signatures in an addifional 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 idenfify 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 pafients without recurrence, and in 50 BCG-treated NMIBC patients with and 50 pafients without progression, and validation will be done using 300 pafients enrolled in the BCG clinical trial.