Abstract 3830: E2F1-FOXM1 activation predicts progression of non-muscle invasive bladder cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Backgrounds: Bladder cancer is a genetic disorder driven by the accumulative changes of the multiple genes, such as E2F1, FOXM1, and EZH2. The objective of this study is to estimate a prognostic value of gene expression signature and identify putative signaling pathway for mediating progression of non-muscle invasive bladder cancer (NMIBC). Methods: Gene expression profiling was performed using primary NMIBC cohort to identify a signature correlated with disease progression. The signature was validated in three independent cohorts. The association between the signature and prognosis of NMIBC patients was assessed using various statistical methods including a leave-one-out cross-validation and multivariate Cox regression analyses. The upstream regulator analysis of the genes in the signature was performed by Ingenuity Pathway Analysis TM. We also confirmed a prognostic relevance of the signature with experimental assays using bladder cancer cell lines. Results: Kaplan-Meier analysis in the discovery cohort revealed significant differences in disease progression associated with the expression signature of E2F1-associated genes (p = 0.003), which produced consistent prognostic pattern in the validation cohorts. Multivariate Cox regression analysis revealed that the signature was an independent strong predictor of disease progression (hazard ratio = 6.082, 95% confidence interval = 3.280 to 11.279, p < 0.001). In subset analyses, the signature could identify patients who would benefit from intravesical immunotherapy. Lastly, upstream regulator analyses and experimental assays of the signature revealed that NMIBC progression could be mediated by E2F1-FOXM1 pathways. Conclusion: The prognostic molecular signature defined by activation of E2F1 and FOXM1 represents a promising diagnostic tool to identify high risk NMIBC patients. Citation Format: Seon-Kyu Kim, Se-Ra Lee, Yun-Gil Roh, Bicna Song, Kiejung Park, Sun-Hee Leem, In-Sun Chu. E2F1-FOXM1 activation predicts progression of non-muscle invasive bladder cancer. [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 3830. doi:10.1158/1538-7445.AM2014-3830