title: Frequent inactivating mutations of STAG2 in bladder cancer are associated with low tumour grade and stage and inversely related to chromosomal copy number changes.
abstract: Inactivating mutations of STAG2 have been reported at low frequency in several cancers. In glioblastoma, the function of STAG2 has been related to maintenance of euploidy via its role in the cohesin complex. In a screen of a large series of bladder tumours and cell lines, we found inactivating mutations (nonsense, frameshift and splicing) in 67 of 307 tumours (21.8%) and 6 of 47 cell lines. Thirteen missense mutations of unknown significance were also identified. Inactivating mutation was associated with low tumour stage (P = 0.001) and low grade (P = 0.0002). There was also a relationship with female patient gender (P = 0.042). Examination of copy number profiles revealed an inverse relationship of mutation with both fraction of genome altered and whole chromosome copy number changes. Immunohistochemistry showed that in the majority of cases with inactivating mutations, STAG2 protein expression was absent. Strikingly, we identified a relatively large subset of tumours (12%) with areas of both positive and negative immunoreactivity, in only four of which a potentially function-altering mutation was detected. Regions of differential expression were contiguous and showed similar morphological phenotype in all cases. Microdissected positive and negative areas from one tumour showed an inactivating mutation to be present only in the negative area, suggesting intra-tumoral sub-clonal genomic evolution. Our findings indicate that loss of STAG2 function plays a more important role in non-invasive than that in muscle-invasive bladder cancer and suggest that cohesin complex-independent functions are likely to be important in these cases.
authors.affiliation: Cancer Research UK Centre Genomics Facility.
authors.forename: Claire F
authors.initials: CF
authors.lastname: Taylor
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Platt
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: Hurst
authors.forename: Helene H
authors.initials: HH
authors.lastname: Thygesen
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Knowles
mesh_terms: D034961:Antigens, Nuclear / Q000235:genetics*; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D002295:Carcinoma, Transitional Cell / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins; D043171:Chromosomal Instability / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D019042:Muscle Neoplasms / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D000097722:Cohesins
chemical_list: D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D012333:RNA, Messenger; C508565:STAG2 protein, human; D000097722:Cohesins