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.
Identification of genetic susceptibility loci will help identify high-risk subgroups of individuals for bladder cancer who may be subjected to Intense surveillance and chemoprevention. In addition, by identifying biomarkers for recurrence and progression, particularly for the prediction of BCG response, this proposal may improve clinical management of non-muscle invasive bladder cancer to achieve personalized therapy biomarkers for recurrence and progression, particularly for the prediction of BCG response, this proposal may improve clinical management of non-muscle Invasive bladder cancer to achieve personalized therapy.
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