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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
United States
Zip Code
Dadhania, Vipulkumar; Zhang, Miao; Zhang, Li et al. (2016) Meta-Analysis of the Luminal and Basal Subtypes of Bladder Cancer and the Identification of Signature Immunohistochemical Markers for Clinical Use. EBioMedicine 12:105-117
von Rundstedt, Friedrich-Carl; Mata, Douglas A; Shen, Steven et al. (2016) Transurethral biopsy of the prostatic urethra is associated with final apical margin status at radical cystoprostatectomy. J Clin Urol 9:404-408
McConkey, David J; Choi, Woonyoung; Shen, Yu et al. (2016) A Prognostic Gene Expression Signature in the Molecular Classification of Chemotherapy-naïve Urothelial Cancer is Predictive of Clinical Outcomes from Neoadjuvant Chemotherapy: A Phase 2 Trial of Dose-dense Methotrexate, Vinblastine, Doxorubicin, and Cis Eur Urol 69:855-62
Kamat, Ashish M; Briggman, Joseph; Urbauer, Diana L et al. (2016) Cytokine Panel for Response to Intravesical Therapy (CyPRIT): Nomogram of Changes in Urinary Cytokine Levels Predicts Patient Response to Bacillus Calmette-Guérin. Eur Urol 69:197-200
Machiela, Mitchell J; Zhou, Weiyin; Karlins, Eric et al. (2016) Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome. Nat Commun 7:11843
Figueroa, Jonine D; Middlebrooks, Candace D; Banday, A Rouf et al. (2016) Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry. Hum Mol Genet 25:1203-14
Kamat, Ashish M; Willis, Daniel L; Dickstein, Rian J et al. (2016) Novel fluorescence in situ hybridization-based definition of bacille Calmette-Guérin (BCG) failure for use in enhancing recruitment into clinical trials of intravesical therapies. BJU Int 117:754-60
Sircar, Kanishka; Yoo, Suk-Young; Majewski, Tadeusz et al. (2015) Biphasic components of sarcomatoid clear cell renal cell carcinomas are molecularly similar to each other, but distinct from, non-sarcomatoid renal carcinomas. J Pathol Clin Res 1:212-24
Ke, Hung-Lung; Lin, Jie; Ye, Yuanqing et al. (2015) Genetic Variations in Glutathione Pathway Genes Predict Cancer Recurrence in Patients Treated with Transurethral Resection and Bacillus Calmette-Guerin Instillation for Non-muscle Invasive Bladder Cancer. Ann Surg Oncol 22:4104-10
(2015) Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types. J Natl Cancer Inst 107:djv279

Showing the most recent 10 out of 221 publications