Abstract 1203: Molecular stratification of bladder cancer reveals distinct subtypes associated with unique clinical behaviors.
Authors: Kim Doris , Choi YJ , French Dorothy , Patel Rajesh , Fu Ling , Wong Cheryl , Abbas Ilma , Tam Rachel , Schleifman Erica , Sumiyoshi Teiko , Faarborg Anna , Yauch Bob , Hampton Garret , Amler Lukas , Raja Rajiv , Kabbarah Omar 
Published: August 2014

Abstract
Bladder cancer is a common malignancy, and in the US approximately 15,000 patients a year succumb to metastatic disease. The transition from the non-invasive to the lethal invasive variety is poorly understood, and this is reflected by the lack of efficacious treatment options for patients presenting with advanced disease. Notably, a significant fraction of superficial cancers can recur, requiring additional surgeries and conferring a higher risk for disease progression. Stratifying bladder cancers into molecular subtypes with defined clinical attributes could highlight non-invasive tumors with high risk of recurrence and reveal opportunities for therapeutic intervention in advanced disease. To this end, we molecularly characterized a collection of ∼200 clinically-annotated, formalin-fixed, paraffin-embedded tissues that represent non-invasive and invasive/advanced stage histopathologies. Tumors were assessed for mutation status at ∼100 mutation hotspots in key oncogenes as well as for the expression levels of ∼100 genes on a custom Fluidigm™ platform to interrogate key bladder cancer pathways, such as the FGFR3, PI3K and MAPK signaling axes. Integrative analysis of gene expression, mutation, and clinical data identified non-invasive subtypes that were FGFR3 mutation positive and exhibited a pathway up regulation gene expression signature. In contrast, invasive tumors were FGFR3 wild type and displayed less prominent pathway up regulation. As expected, invasive tumors had significantly worse disease-free survival (DFS) than their non-invasive counterparts (HR = 0.54; P = 0.03). On the molecular level, advanced tumors exhibited dysregulation of key pathways, including p53 and PI3K. Although similar histologically, and of common FGFR3 mutation status, tumors of the non-invasive type could be further classified into two distinct transcriptional subtypes associated with remarkably different DFS profiles (HR = 0.29; P = 0.004). Our molecular stratification of bladder cancer identified distinct subtypes associated with their respective clinical behaviors. In advanced disease, we defined molecular alterations that highlight opportunities for therapeutic intervention. We also identified a novel subtype of non-invasive malignancies associated with a surprisingly high risk of recurrence, highlighting the value of molecular stratification for identifying bladder cancer patients who might benefit from more aggressive treatment than the current standard of care.
Citation Format: Doris Kim, YJ Choi, Dorothy French, Rajesh Patel, Ling Fu, Cheryl Wong, Ilma Abbas, Rachel Tam, Erica Schleifman, Teiko Sumiyoshi, Anna Faarborg, Bob Yauch, Garret Hampton, Lukas Amler, Rajiv Raja, Omar Kabbarah. Molecular stratification of bladder cancer reveals distinct subtypes associated with unique clinical behaviors. [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 1203. doi:10.1158/1538-7445.AM2013-1203