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 by immunohistochemistry (IHC) and published data suggest that loss of STAG2 expression is a good prognostic indicator in NMIBC.
Objectives: 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 in 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 BC patients and was 1.6-fold more common in female patients. Loss was frequent in G1pTa tumours (40%), decreasing with stage and grade to only 5% in G3pT2+ tumours. Loss was associated with fewer copy number changes and less aggressive expression subtypes. In UBC STAG2 loss is a highly significant prognostic indicator of better disease-free survival but is not independent of stage and grade. STAG2 loss is not a statistically significant predictor of NMIBC recurrence. STAG2 loss is significant associated with better progression-free survival in NMIBC and appears to be more prognostic in males than females.
Conclusions: A simple IHC-based STAG2 test shows promise to identify NMIBC patients at lower risk of progression to MIBC in 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.