STAG2 Expression as a Prognostic Marker in Bladder Cancer - Expert Commentary

The stromal antigen 2 protein is 1231-amino-acid protein cohesin subunit A2 encoded by the STAG2 gene on the X chromosome. This protein plays a critical role in chromatid separation. The deficiency of STAG2 due to truncating somatic mutations has been described as an early event in urothelial carcinogenesis. The loss of STAG2 expression is observed in up to 36% of patients with non-muscle invasive bladder cancer. Previous studies have shown that STAG2 loss is associated with better patient prognosis, but its potential use as a prognostic marker has not been routinely validated in the clinical setting. A recent study by Gordon et al. evaluated STAG2 expression in the context of clinical parameters and molecular tumor signatures.

Out of 748 urothelial bladder cancer samples in this study, 19% showed total loss of STAG2. STAG2 loss was four times more frequent in grade 1 tumors than grade 3 tumors and was more common in females than males across all grades. Parallel data on mutations in STAG2 was available for 79 tumor samples and revealed that mutation was associated with loss of STAG2 as 87.5% of mutated samples showed loss of expression. Analysis of the available RNA-sequencing data from samples with STAG2 loss revealed a distinct differential expression pattern. The loss of STAG2 expression was a significant predictor of longer disease-specific survival, and higher expression was associated with disease progression in high-risk non-muscle invasive bladder cancer samples. Interestingly, these associations were not observed in female patient samples, although the loss of expression of STAG2 was 1.6 times more frequent among female versus male patients. Notably, the association between disease-specific survival and STAG2 expression was not as significant when muscle-invasive and non-muscle invasive bladder cancers were analyzed separately.

Gordon et al. confirmed the pattern of lower STAG2 expression in low-grade compared to high-grade tumors. STAG2 expression reflects the risk of progression from non-muscle invasive to muscle-invasive bladder cancer. Gordon et al. propose adding STAG2 biomarker panels for non-muscle invasive bladder cancer.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

References:

  1. Gordon, N. S., Humayun-Zakaria, N., Goel, A., Abbotts, B., Zeegers, M. P., Cheng, K. K., James, N. D., Arnold, R., Bryan, R. T., & Ward, D. G. (2022). STAG2 Protein Expression in Non-muscle-invasive Bladder Cancer: Associations with Sex, Genomic and Transcriptomic Changes, and Clinical Outcomes. European urology open science, 38, 88–95. https://doi.org/10.1016/j.euros.2022.02.004.

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