Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy

Urothelial bladder cancer (UBC) is heterogeneous at the clinical, pathological, and genetic levels. Tumor invasiveness (T) and grade (G) are the main factors associated with outcome and determine patient management (1). A discovery exome sequencing screen (n=17), followed by a prevalence screen (n=60), identified new genes mutated in this tumor coding for proteins involved in chromatin modification (MLL2, ASXL2, BPTF), cell division (STAG2, SMC1A, SMC1B), and DNA repair (ATM, ERCC2, FANCA). STAG2, a subunit of cohesin, was significantly and commonly mutated/lost in UBC, mainly in tumors of low stage/grade, and its loss was associated with improved outcome. Loss of expression was often observed in chromosomally-stable tumors and STAG2 knockdown in bladder cancer cells did not increase aneuploidy. STAG2 reintroduction in non-expressing cells led to reduced colony formation. Our findings indicate that STAG2 is a novel UBC tumor suppressor acting through mechanisms that are different from its role to prevent aneuploidy.