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STAG2 expression is associated with adverse survival outcomes and regulates cell phenotype in muscle-invasive bladder cancer.

ABSTRACT: STAG2 (Stromal Antigen 2), in healthy somatic cells, functions in sister chromatid cohesion, DNA damage repair, and genome organization, but its role in muscle invasive bladder cancer (MIBC) remains unknown. Here, using whole-exome and targeted sequencing (n=119 bladder cancer clinical samples), we found several STAG2 mutations in MIBC that correlate with loss of protein expression. The analysis of a bladder cancer tissue microarray (n=346) revealed that decreased STAG2 protein expression is associated with improved overall and progression-free survival for MIBC patients. In mouse xenograft studies, STAG2 knockdown (KD) decelerated MIBC tumor growth, whereas STAG2 overexpression accelerated tumor growth. In cell line studies, STAG2 loss augmented treatment with cisplatin, a first-line therapy for MIBC. STAG2 KD or overexpression did not alter degree of aneuploidy, copy number variations, or cell cycle distribution. However, unbiased RNA sequencing analysis revealed that STAG2 KD altered gene expression. STAG2 KD led to significant downregulation of several gene sets, such as collagen containing extracellular matrix, external encapsulating structure organization, and regulation of chemotaxis. Therefore, we investigated the effect of STAG2 KD on cell migration and invasion in vitro. We found that STAG2 KD minimized cell speed, displacement, and invasion. Altogether, our results present a non-canonical function of STAG2 in promoting cell motility and invasion of MIBC cells. This work forms the basis for additional investigation into the role of STAG2 in transcriptional regulation and how it becomes dysregulated in STAG2-mutant MIBC.

SUBMITTER: Athans S

PROVIDER: S-EPMC9583756 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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STAG2 expression is associated with adverse survival outcomes and regulates cell phenotype in muscle-invasive bladder cancer.

Athans Sarah S Krishnan Nithya N Ramakrishnan Swathi S Cortes Gomez Eduardo E Lage-Vickers Sofía S Rak Monika M Kazmierczak Zara Z Ohm Joyce J Attwood Kristopher K Wang Jianmin J Woloszynska Anna A

Cancer research communications 20221006 10

STAG2 (Stromal Antigen 2), in healthy somatic cells, functions in sister chromatid cohesion, DNA damage repair, and genome organization, but its role in muscle invasive bladder cancer (MIBC) remains unknown. Here, using whole-exome and targeted sequencing (n=119 bladder cancer clinical samples), we found several STAG2 mutations in MIBC that correlate with loss of protein expression. The analysis of a bladder cancer tissue microarray (n=346) revealed that decreased STAG2 protein expression is ass ...[more]

PMID: 36275363

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Project description:ObjectiveCD47 is an antiphagocytic molecule that plays a critical role in immune surveillance. A variety of malignancies have been shown to evade the immune system by increasing the expression of CD47 on the cell surface. As a result, anti-CD47 therapy is under clinical investigation for a subset of these tumors. Interestingly, CD47 overexpression is associated with negative clinical outcomes in lung and gastric cancers; however, the expression and functional significance of CD47 in bladder cancer is not fully understood.Materials and methodsWe retrospectively studied patients with muscle invasion bladder cancer (MIBC) who underwent a transurethral resection of bladder tumor (TURBT) and subsequently underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC). CD47 expression was examined by IHC in both TURBT and matched RC specimens. The difference in CD47 expression levels between TURBT and RC was also compared. The association of CD47 levels (TURBT) with clinicopathological parameters and survival outcomes was evaluated by Pearson's chi-squared tests and the Kaplan-Meier method, respectively.ResultsA total of 87 MIBC patients were included. The median age was 66 (39-84) years. Most patients were Caucasian (95%), male (79%), and aged >60 (63%) and most often (75%) underwent NAC prior to RC. Of those who received NAC, 35.6% were responders and 64.4% were non-responders. The final reported stages as per AJCC for all patients were as follows: stage 0 (32%), stage 1 (1%), stage 2 (20%), stage 3 (43%), and stage 4a (5%). A total of 60% of patients were alive; of those, 30% had disease recurrence and 40% died from bladder cancer at a median follow-up of 3.1 (0.2-14.2) years. CD47 levels were detectable in 38 (44%) TURBT samples. There was no association between CD47 levels and clinicopathological parameters such as age, gender, race, NAC, final stage, disease recurrence, and overall survival (OS). Patients aged >60 (p = 0.006), non-responders (p = 0.002), and at stage ≥ 3 (p < 0.001) were associated with worse OS by a univariate analysis and stage ≥ 3 remained significant even after a multivariate analysis. In patients managed with NAC, there were decreased CD47 levels in RC specimens compared to the TURBT specimens, but this did not reach statistical significance.ConclusionCD47 expression was not a predictive nor prognostic marker for MIBC patients. However, expression of CD47 was detected in nearly half of MIBCs, and future studies are needed to explore the potential role of anti-CD47 therapy in these patients. Furthermore, there was a slight positive trend in decreased CD47 levels (from TURBT to RC) in patients receiving NAC. As a result, more research is needed to understand how NAC may modify immune surveillance mechanisms in MIBC.

Project description:BackgroundThe gold standard treatment for localized muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy with radical cystectomy (RC). Guidelines suggest concurrent chemoradiation (CRT) could be considered as an alternative, and partial cystectomy (PC) may be considered in carefully selected individuals. The bladder preservation strategies are gaining popularity, and due to the concerns about morbidity associated with RC and limited life expectancy, the octogenarian population is exploring strategies that help preserve bladder function. Hence, it is crucial to understand the outcome of various bladder preservation strategies. Using the National Cancer Database (NCDB), we compared the overall survival (OS) of octogenarians treated with PC and CRT.MethodsWe retrospectively evaluated the octogenarians with localized MIBC (cT2N0M0) ≤5 cm and urothelial histology between 2004 and 2018. Our analytic cohorts were the PC cohort, which included patients who underwent PC, and the CRT cohort, which included patients who received chemotherapy and radiotherapy within a 90-day timeframe. After propensity-matching with race and ethnicity, gender, facility type, median income, comorbidity index, and tumor grade, we compared the OS between PC and CRT cohorts.ResultsA total of 1,038 were octogenarians who met our selection criteria. Among them, 248 (23.8%) underwent PC, and 790 (76.2%) received CRT. In the PC cohort, tumors were located predominantly in the dome (34.3%) and anterior wall (10.5%), while in the CRT cohort, tumors were in the trigone (8.4%), lateral (22.0%) and posterior walls (10.6%). The median OS for the matched PC and CRT cohort was 38.3 and 32.9 months, respectively (P=0.66). Multivariate Cox regression showed no difference in survival hazards between PC and CRT [hazard ratio =1.07 (95% confidence interval: 0.82-1.39)] (P=0.63).ConclusionsOur study comparing PC and CRT in octogenarians with T2 ≤5 cm tumors showed that PC had comparable OS to CRT. Therefore, PC can be considered a viable option in carefully selected octogenarians.

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STAG2 expression is associated with adverse survival outcomes and regulates cell phenotype in muscle-invasive bladder cancer.

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STAG2 expression is associated with adverse survival outcomes and regulates cell phenotype in muscle-invasive bladder cancer.

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