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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA091846-13
Application #
8745031
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
City
Houston
State
TX
Country
United States
Zip Code
77030
Lin, Moubin; Zhang, Liren; Hildebrandt, Michelle A T et al. (2017) Common, germline genetic variations in the novel tumor suppressor BAP1 and risk of developing different types of cancer. Oncotarget 8:74936-74946
Shore, Neal D; Boorjian, Stephen A; Canter, Daniel J et al. (2017) Intravesical rAd-IFN?/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study. J Clin Oncol 35:3410-3416
Wang, Gang; Huang, He; Kamat, Ashish M et al. (2017) High-grade neuroendocrine carcinoma of the urachus-report of 3 cases. Hum Pathol 67:126-133
Robertson, A Gordon; Kim, Jaegil; Al-Ahmadie, Hikmat et al. (2017) Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell 171:540-556.e25
von Rundstedt, Friedrich-Carl; Mata, Douglas A; Kryvenko, Oleksandr N et al. (2017) Utility of Clinical Risk Stratification in the Selection of Muscle-Invasive Bladder Cancer Patients for Neoadjuvant Chemotherapy: A Retrospective Cohort Study. Bladder Cancer 3:35-44
Williams, Stephen B; Kamat, Ashish M; Mmeje, Chinedu et al. (2017) Genetic variants in the inflammation pathway as predictors of recurrence and progression in non-muscle invasive bladder cancer treated with Bacillus Calmette-Guérin. Oncotarget 8:88782-88791
Mobley, Aaron; Zhang, Shizhen; Bondaruk, Jolanta et al. (2017) Aurora Kinase A is a Biomarker for Bladder Cancer Detection and Contributes to its Aggressive Behavior. Sci Rep 7:40714
Roth, Beat; Jayaratna, Isuru; Sundi, Debasish et al. (2017) Employing an orthotopic model to study the role of epithelial-mesenchymal transition in bladder cancer metastasis. Oncotarget 8:34205-34222
Metcalfe, Michael J; Ferguson, James E; Li, Roger et al. (2017) Impact of High-risk Features and Effect of Neoadjuvant Chemotherapy in Urothelial Cancer Patients with Invasion into the Lamina Propria on Transurethral Resection in the Absence of Deep Muscle Invasion. Eur Urol Focus :
Choi, Woonyoung; Ochoa, Andrea; McConkey, David J et al. (2017) Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas Dataset. Eur Urol 72:354-365

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