A STAT3- and p63-dependent transcriptional network to define a lethal basal subset of human bladder cancers.

Abstract

4538 Background: Muscle-invasive bladder cancers (MIBCs) are a heterogeneous group of tumors that display widely variable clinical outcomes and responses to conventional chemotherapy. Methods: We used whole genome mRNA expression profiling and unsupervised hierarchical cluster analyses on a cohort of 73 flash frozen primary tumors to identify 3 distinct subsets of muscle-invasive bladder cancer (MIBC). We confirmed the existence of these 3 subsets in a second cohort of 57 formalin-fixed, paraffin-embedded (FFPE) MIBCs and in 2 other public datasets. Analysis of primary tumors and mechanistic studies in human bladder cancer cell lines identified tumors that respond to FGFR inhibitors or chemotherapy. Results: The first subset was driven by an active "basal" EGFR-STAT3-p63 transcriptional network, and was associated with poor clinical outcomes. High miR-200c expression stratified the survival of these basal tumors. The second subset was characterized by active p53 pathway activation, and tumors and cell lines with these features were resistant to cis-platinum based chemotherapy. The third subset expressed "luminal" markers and active estrogen receptor (ER) and PPARγ signaling, and luminal cell lines were sensitive to fibroblast growth factor receptor (FGFR) inhibition. Conclusions: Molecular subtyping of MIBCs can be used to identify lethal cancers and enrich for tumors that will respond to FGFR inhibitors or conventional chemotherapy.