STAG2 Protein Expression in Non–muscle-invasive Bladder Cancer: Associations with Sex, Genomic and Transcriptomic Changes, and Clinical Outcomes

BACKGROUND: Mutations in STAG2 cause complete loss of STAG2 protein in approximately one-third of non–muscle-invasive bladder cancers (NMIBCs). STAG2 protein expression is easily determined via immunohistochemistry (IHC) and published data suggest that loss of STAG2 expression is a good prognostic indicator in NMIBC. OBJECTIVE: To confirm the relationship between STAG2 protein expression and clinical outcomes and tumour characteristics in NMIBC. DESIGN, SETTING, AND PARTICIPANTS: IHC was used to determine STAG2 expression in 748 incident urothelial bladder cancers (UBCs) and recurrence-free, progression-free, and disease-specific survival were compared for patients with and without STAG2 loss. Exome and RNA sequencing were used to explore links between STAG2 loss and tumour molecular characteristics. RESULTS AND LIMITATIONS: STAG2 loss was observed in 19% of UBC patients and was 1.6-fold more common among female patients. Loss was frequent among grade 1 pTa tumours (40%), decreasing with stage and grade to only 5% among grade 3 pT2+ tumours. Loss was associated with fewer copy-number changes and less aggressive expression subtypes. In UBC, STAG2 loss was a highly significant prognostic indicator of better disease-free survival but was not independent of stage and grade. STAG2 loss was not a statistically significant predictor of NMIBC recurrence. STAG2 loss was significantly associated with better progression-free survival in NMIBC and appeared to be more prognostic for males than for females. CONCLUSIONS: A simple IHC-based STAG2 test shows promise for identifying NMIBC patients at lower risk of progression to MIBC for whom more conservative treatments may be suitable. PATIENT SUMMARY: A protein called STAG2 is frequently lost in early bladder cancers, most often in less aggressive tumours. STAG2 loss is easily measured and could be used as a biomarker to help guide treatment decisions.