Bladder cancer is a heterogeneous epithelial malignancy that presents most commonly as an exophytic tumor confined to the mucosa or lamina propria.30 The recurrence and invasiveness of bladder cancer are associated with poor prognosis. Thus, additional biomarkers are required assessment of recurrence risk, progression, and treatment response.
Recent studies indicate that STAG2 mutation is strongly associated with prognosis.17–19 However, some studies have reached the opposite conclusion. In the current study, high expression of STAG2 was closely related to recurrence and poor prognosis in NMIBC patients. In MIBC patients, however, low STAG2 expression promoted bladder cancer progression. In our study, we also found similar conclusions. The biological basis for the different effects of STAG2 expression on the clinical outcomes of non-muscle-invasive papillary carcinomas versus muscle-invasive carcinomas is currently unknown.
To further examine the relationship between STAG2 and bladder cancer prognosis, we analyzed other prognostic factors, including expression of the tumor suppressor p53. Indeed, P53 gene mutation(the mutant P53 gene was highly expressed after immunohistochemical staining)significantly affected prognosis of STAG2(+) patients. Recurrences was higher in STAG2(+)/P53(+) patients than STAG2(+)/P53(-) patients (84.5% vs. 58%), indicating that P53 mutation is a major cause of BCa recurrence.31,32 All NMIBC patients were treated with intravesical chemotherapy after operation, and P53 mutation may reduce chemosensitivity.33 Similarly, previous studies have shown that STAG2 is an important gene for homologous recombination repair.34 STAG2 overexpression may increase chemotherapy resistance by enhancing tumor cell DNA damage repair capacity. We found that both STAG2 mutation [STAG2(-)] and P53 mutation [P53(+)] promoted progression in MIBC patients who underwent RCPLT. Indeed, no STAG2(-)/P53(+) patient in our study survived for 5 years, while 5-year survival was relatively high in STAG2(+)/P53(-) patients (69.7%). This suggests that like P53, STAG2 may be a suppressor of tumor progression. But why do STAG2(+) BCa patients relapse more easily after TURBT? Poor sensitivity to chemotherapy in patients with STAG2 (+) may be one of the causes of its recurrence.
Chemotherapy may improves tumor prognosis and many chemotherapeutic drugs induce tumor cell apoptosis by damaging DNA.35,36 The sensitivity of tumor cells to chemotherapeutic drugs influences tumor prognosis.37,38 In this study, we found that systemic chemotherapy did not improve the 5-year survival rate of MIBC patients. Alternatively, STAG2(-) patients receiving chemotherapy demonstrated higher 3-year survival than those not receiving chemotherapy (45.5% vs. 16.7%). Alternatively, chemotherapy provided no survival benefit to STAG2(+) patients. Furthermore, univariate analysis suggested that STAG2(-) patients were more sensitive to chemotherapy than STAG2(+) patients, but it was difficult to draw conclusions because of the insufficient sample size. From these results, we speculate that chemotherapy (intravesical instillation chemotherapy) reduces relapse of STAG2(-) NMIBC due to a superior effect of intravesical instillation chemotherapy versus systemic chemotherapy for bladder cancer.39
Cancer prognosis is strongly related to the genotype of tumor cells and specifically how different genotypes and expression phenotypes affect growth, progression, and treatment response.40,41 In this study, we also compared the prognosis of MIBC patients with different expression phenotypes after chemotherapy. STAG2(+)/P53(-) patients still had better prognosis than STAG2(-)/P53(+) patients even after chemotherapy, possibly due to sustaining progression of mutant tumor cells and (or) inefficacy of chemotherapy. In bladder cancer, mutations in the P53 gene and STAG2 gene lead to tumor progression, and systemic chemotherapy cannot effectively inhibit this process, resulting in poor prognosis in STAG2(-)/P53(+) patients.
Our previous colleagues found that total resection of early bladder cancer significantly reduced recurrence and mortality. In clinical treatment, patients are willing to choose total cystectomy and bladder substitution after knowing that the diagnosis of bladder cancer is bladder cancer, which leads to partial bladder surgery for early stage tumors. We will follow up these patients for a long time to see if their long-term survival rate has improved. Preoperative chemotherapy may cause changes in STAG2 or P53 expression in surgical specimens. We excluded patients who received preoperative chemotherapy or radiotherapy. After total cystectomy, some patients received cisplatin combined with gemcitabine systemic chemotherapy (other drug chemotherapy patients were excluded), and some patients did not undergo systemic chemotherapy because of the low stage of the tumor during the operation.
However, this does not affect our purpose. We focus on identifying the factors that influence the relationship between STAG2 and the prognosis of bladder cancer. STAG2 is a functional gene on X chromosome. Recently, it has been found that X chromosome can regulate P53 pathway. Therefore, we first speculate that STAG2 may affect the prognosis of bladder cancer through its association with P53. In addition, the most important way to affect the prognosis of bladder cancer is clinical treatment and chemotherapy. Therefore, the focus of our study is to analyze whether these factors are related to STAG2.
We tested different thresholds used to define positivity or loss of expression of STAG2. We found that defined 15% as the cutoff frequency for STAG2 and P53 to classify transitional cell carcinoma data into categorical groups is the most reasonable result.