STAG2 as a prognostic biomarker in low-grade non-muscle invasive bladder cancer

Abstract

Objective: Improvements to bladder cancer risk stratification guidelines are needed to better tailor post-operative surveillance and adjuvant therapy to individual patients. We previously identified STAG2 as a commonly mutated tumor suppressor gene in bladder cancer and an independent predictor of progression in NMIBC. Here we test the value of combining STAG2 immunostaining with other risk stratification biomarkers in NMIBC, and as an individual biomarker in MIBC.

Materials and methods: STAG2 immunohistochemistry was performed on a progressor-enriched cohort of tumors from 297 patients with NMIBC, and on tumors from 406 patients with MIBC from Aarhus University Hospital in Denmark. Survival analysis was performed using Kaplan-Meier survival analysis, the log rank test, and Cox proportional hazards models.

Results: STAG2-negative low-grade NMIBC tumors were 2.5 times less likely to progress to muscle invasion than STAG2-positive low-grade NMIBC tumors (Log-rank test, P = 0.008). In a composite group of patients with AUA intermediate and high-risk NMIBC tumors, STAG2-negative tumors were less likely to progress (Log-rank test, P = 0.02). In contrast to NMIBC, we show that STAG2 is not useful as a prognostic biomarker in MIBC.

Conclusions: STAG2 immunostaining can be used to subdivide low-grade NMIBC tumors into two groups with substantially different risks of disease progression. Furthermore, STAG2 immunostaining may be useful to enhance NMIBC risk stratification guidelines, though larger cohorts are needed to solidify this conclusion in individual risk groups. STAG2 is not useful as a biomarker in MIBC. Further study of the use of STAG2 immunostaining as a biomarker for predicting the clinical behavior in NMIBC is warranted.

Keywords: Bladder cancer; Bladder cancer recurrence and progression; Risk stratification guidelines; STAG2.

Figure 1.

Disease-specific survival and STAG2 expression in the bladder cancer cohort studied. (A) Overview of the bladder cancer (BC) cohort. Tumors were grouped based on pathological stage and stratified by clinical outcome. 20 patients had cores taken from more than one tumor; hence, the entire cohort consisted of 707 bladder tumors from 687 patients with BC. One of the 20 patients had two NMIBC tumors, whereas the remaining patients had both NMIBC and MIBC tumors. TX: tumor of unknown pathological stage. (B) Kaplan Meier curve depicting disease-specific survival by pathological stage. (C) Examples of STAG2 staining of NMIBC and MIBC tumors. (C) Frequency of maintenance (red) and loss (blue) of STAG2 expression in NMIBC and MIBC in this cohort. (D) Concordance of STAG2 status in patients with two tumors represented in the cohort. 20 patients had two tumors in the cohort; in 19 patients they were tumors from an initial NMIBC and a subsequent MIBC, in one patient they were two independent NMIBC tumors. Unfortunately, in only 11 of these patients could STAG2 status be determined for both tumors of the pair. STAG2 staining was discordant in 3/11 of these pairs (Fig. 1E); each of the three discordant pairs were comprised of one NMIBC tumor and one MIBC tumor.

Figure 2.

Predictive value of STAG2 staining as an individual biomarker in NMIBC (A-C) and MIBC (D-E) on recurrence-free survival (A,D), progression-free survival (B) and disease-specific survival (C,E).

Figure 3.

STAG2 expression and tumor grade. (A) STAG2 expression compared to tumor grade (n = 296). For one patient tumor grade could not be determined. (B) Predictive value of a combination of STAG2 staining and tumor grade on progression-free survival in NMIBC. LG, low grade; HG, high grade. (C) Receiver operating characteristics (ROC) curve for predicting progression using logistic regression models (n = 289).

Figure 4.

Predictive value of STAG2 staining on progression-free survival in NMIBC risk groups based on the American Urological Association risk stratification guidelines.