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

MicroRNA 在膀胱癌风险和结果中的作用：全基因组分析

• 批准号: 8745031
• 负责人: ASHISH M KAMAT
• 金额: $ 22.58万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8745031
• 关键词: Accounting; Age; Biogenesis; Biological; Biological Markers; Cancer Etiology; Cancer Prognosis; Case-Control Studies; Caucasians; Caucasoid Race; Chemoprevention; Clinical Data; Clinical Management; Clinical Trials; DNA; Data; Detection; Early Diagnosis; Enrollment; Epidemiology; Ethnic Origin; Etiology; Event; Functional RNA; Gender; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genotype; Health Benefit; Human; Individual; Joints; Light; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; MicroRNAs; Modeling; Molecular Profiling; Muscle; Newly Diagnosed; Occupational Exposure; Outcome; Pathogenesis; Pathway interactions; Patients; Phase; Phenotype; Plasma; Play; Predictive Value; Predisposition; Public Health; Recurrence; Risk Factors; Role; SNP genotyping; Serum; Site; Staging; Subgroup; Technology; Testing; Tissues; Toxic effect; Training; Tumor Tissue; Up-Regulation; Urogenital Cancer; Validation; cancer recurrence; cancer risk; cancer therapy; case control; cigarette smoking; cohort; design; epidemiologic data; follow-up; genome wide association study; genome-wide; genome-wide analysis; high risk; improved; intravesical; novel; outcome forecast; prevent; residence; response; screening; treatment response; tumor

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.

该项目以美国最大的膀胱癌 (BC) 病例对照研究为基础，拥有广泛的流行病学和临床数据以及丰富的生物样本（DNA、组织和血清/血浆）。我们建议对 BC 病因学、预后和 BCG 反应中的 microRNA (miRNA) 进行系统研究，包括种系 SNP 基因分型、体细胞 miRNA 分析和循环 miRNA 检测。我们的具体目标是：1) 使用两阶段设计识别 miRNA 通路中易患 BC 风险的新种系易感位点。我们将在 1000 个病例和 1000 个对照中筛选 -8000 个 SNP，然后在另外 1000 个病例和对照中验证前 384 个 SNP。 2) 使用与目标 1 类似的两阶段设计来确定 miRNA 通路中预测非肌肉侵袭性 BC (NMIBC) 复发和进展的新型种系易感位点。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 的普遍膀胱内治疗方法。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 反应的预测因子。我们将确定接受 BCG 治疗的患者中 50 个复发的 BC 肿瘤组织和 50 个未复发的 BC 肿瘤组织中的全局 miRNA 表达谱，以确定预测复发的体细胞 miRNA 特征，然后在另外 75 对组织中验证这些特征。我们还将把目标 2 中经过验证的 SNP 与该目标中经过验证的 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识别和验证 BCG 治疗背景下复发和进展的 miRNA 特征。将对 100 名接受 BCG 治疗的 NMIBC 患者和 100 名未复发患者以及 50 名接受 BCG 治疗的 NMIBC 患者和 50 名无进展患者的血清进行筛查，并将使用参加 BCG 临床试验的 300 名患者进行验证。