Journal
NATURE GENETICS
Volume 45, Issue 12, Pages 1464-U221Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2799
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Funding
- Ministerio de Economia y Competitividad, Madrid [SAF-2010-21517, SAF2011-15934-E]
- Instituto de Salud Carlos III [G03/174, 00/0745, PI051436, PI061614, PI080440, PI120425]
- Asociacion Espanola Contra el Cancer [EU-FP7-201663]
- US National Institutes of Health [RO1 CA089715]
- La Caixa International PhD Fellowship
- Fundacion Banco Santander Postdoctoral Programme
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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 and BPTF), cell division (STAG2, SMC1A and SMC1B) and DNA repair (ATM, ERCC2 and FANCA). STAG2, a subunit of cohesin, was significantly and commonly mutated or lost in UBC, mainly in tumors of low stage or 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 new UBC tumor suppressor acting through mechanisms that are different from its role in preventing aneuploidy.
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