Abstract 4149: Transcriptomic and pathogen analysis in bladder cancer primary tumor and metastasis pairs.

Abstract

Abstract Urothelial carcinoma (also called transitional cell carcinoma, most commonly of the bladder) is the fourth leading cause of new cancers in men in the United States, and accounts for 13,000 deaths per year. Five-year survival for patients with muscle invasive disease is below 50%. Both genetic mutations and epigenetic events are important in urothelial cancer pathogenesis and prognosis, and environmental triggers such as Schistosoma infection and tobacco have been identified. In this study we have undertaken a transcriptomic analysis of fourteen paired primary tumors and distant metastases in order to identify mutations and potential pathogenic viruses that may play a role in the pathogenesis of urothelial cancer. The contribution of infections to urothelial cancer pathogenesis remains a hotly contested issue with data both supporting and refuting the role of polyomaviruses in the disease. Recently, our colleagues at the Broad Institute discovered a striking similarity in DNA mutation pattern between cervical cancer, which is virally driven, and bladder cancer. Based on this finding, we hypothesize that a subset of urothelial cancers are triggered by a microbial pathogen that can be detected using nucleic acid sequencing methods. The majority of clinical translational studies to date have investigated patient urine samples. While these studies have been unsuccessful in identifying a strong candidate microbial trigger of urothelial cancer, direct analysis of tumor tissue for pathogen discovery has not been rigorously pursued. In order to investigate a potential microbial cause of urothelial cancer, we propose undertaking a “deep sequencing” approach where all RNA will be sequenced, followed by taxonomic classification of microbial sequences. In addition to the microbial characterization of these samples, the transcriptomic data will be analyzed to identify disease-associated mutations, fusions and splicing variants of significance in primary and matched metastasis pairs. This study represents an analysis of the largest matched primary tumor-distant metastasis cohort to our knowledge, to date. We anticipate that discovery of a novel pathogen or significant transcriptomic changes that trigger urothelial cancer could dramatically alter clinical management by enabling development of screening methods and protocols, targeted therapies and vaccines. Citation Format: Ami S. Bhatt, Chandra Sekhar Pedamallu, Fujiko Duke, Joonil Jung, Samuel S. Freeman, Andrew Cherniak, Rachel Park, Jaegil Kim, David Kwiatkowski, Jonathan Rosenberg, Matthew Meyerson. Transcriptomic and pathogen analysis in bladder cancer primary tumor and metastasis pairs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4149. doi:10.1158/1538-7445.AM2013-4149