Abstract 558: Mutational heterogeneity related to neoadjuvant therapy response in muscle invasive urothelial cell carcinoma revealed by whole-exome sequencing
Authors: Hayashi Masamichi , Munari Enrico , Michailidi Christina , Brait Mariana , Schoenberg Mark , Bivalacqua Trinity , Netto George , Koch Wayne , Sidransky David , Hoque Mohammad O. 
Published: May 2015

Twenty five to thirty-five percent of urothelial cell carcinoma (UCC) patients either present with or develop muscle-invasive disease (MIUCC). Cisplatin-eligible MIUCC patients is treated with neoadjuvant cisplatin-based combination chemotherapy followed by radical cystoprostatectomy and pelvic lymph node dissection. In spite of this approach, the incidence of systemic relapse of MIUCC is high with only 50% of patients remaining alive and disease free at 5 years. Therapies targeted at altered genetic pathways have proven efficacy in different localized solid tumors. However, no such targeted therapies have proven clinical benefit in MIUCC. This may partially due to comparatively few genetic characterizations or no characterization of neoadjuvant therapy sensitive (NAS) and neoadjuvant therapy resistant (NAR) MIUCC patient's samples. So, we attempted to define molecular signatures of NAR and NAS MIUCC samples to identify differential mutational events that could predict therapy response and may eventually use for targeted therapy. To this end, we performed whole exome sequencing of three pairs of urothelial cell carcinomas and matched normal tissues. One patient was neoadjuvant therapy responder (NAS) and the other two were non-responders (NAR). Using these pilot data, candidate tumor-specific mutations in NAS and NAR were extracted. Initially we determined tumor specific mutations in MIUCC. The numbers of identified tumor-specific mutated genes in each of the 3 samples were 127, 57 and 68 respectively. Only two genes (FAM75A3 and GOLGA6L10) were detected as common tumor-specific mutations in all three tissue sets. Eight genes (TP53, CUL1, CENPC1, IGSF10, OR2AG2, ZNF93, LRRFIP1 and CRIPAK) were detected as candidate non responder-specific mutations in both of the NAR samples but not in the NAS samples. In conclusion, genome-wide mutation analysis of coding genes successfully revealed candidate lists of novel tumor-specific gene mutations in MIUCC and neoadjuvant therapy response specific gene mutations that were not reported previously. Further studies in extended set of NAS and NAR samples and technical validation are in progress to well define the molecules that are related to neoadjuvant therapy response. Functional studies of the selected molecules will be undertaken to understand the molecular basis of these genes to modulate neoadjuvant therapy response.

Citation Format: Masamichi Hayashi, Enrico Munari, Christina Michailidi, Mariana Brait, Mark Schoenberg, Trinity Bivalacqua, George Netto, Wayne Koch, David Sidransky, Mohammad O. Hoque. Mutational heterogeneity related to neoadjuvant therapy response in muscle invasive urothelial cell carcinoma revealed by whole-exome sequencing. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 558. doi:10.1158/1538-7445.AM2014-558