Frequent truncating mutations of the cohesin complex gene STAG2 in urothelial carcinoma of the bladder.

Abstract

290 Background: We have recently identified the cohesin complex subunit STAG2 as a gene that is somatically mutated in human cancer and whose inactivation leads directly to chromosomal instability and aneuploidy (Solomon et al, Science, 2011 Aug 19). However, the complete tumor spectrum harboring STAG2 mutations and the clinical significance of STAG2 inactivation in cancer remain undefined. Methods: Immunohistochemistry was used to screen 2,214 tumors from each of the major tumor types for somatic loss of STAG2 expression. Sequencing of the STAG2 gene was performed on 111 urothelial carcinomas, and Affymetrix CytoscanHD Arrays were performed on STAG2 mutant tumors. Clinical data from 34 patients with non-muscle invasive urothelial carcinoma treated with transurethral resection and 349 patients with invasive urothelial carcinoma treated with radical cystectomy was correlated with tumor STAG2 status. Results: Complete loss of STAG2 expression was discovered in 52/295 urothelial carcinomas (18%), ranging from low grade papillary to high grade muscle invasive tumors. DNA sequencing revealed somatic truncating mutations of STAG2 in 23/111 urothelial carcinomas of the bladder, including 9/25 papillary non-invasive carcinomas (36%), 6/22 superficially invasive carcinomas (27%), and 8/64 muscle invasive carcinomas (16%). STAG2 mutation was found to be an early event in bladder tumorigenesis, frequently associated with alterations in p53 signaling, and often correlated with numerous chromosomal copy number aberrations per tumor. STAG2 loss in non-muscle invasive urothelial carcinomas treated with transurethral resection was found to be associated with increased disease-free survival (p=0.05), while STAG2 loss in invasive urothelial carcinomas treated with radical cystectomy was found to be associated with increased lymph node metastasis (p=0.03), earlier disease recurrence (p=0.04), and reduced cancer-specific survival (p=0.04). Conclusions: These results identify STAG2 as one of the most commonly mutated genes in bladder cancer, and demonstrate that STAG2 loss defines molecular subgroups of urothelial carcinomas with distinct clinical outcomes.