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PubMed2026

Impact of BCL-2 rs2279115 and rs3943258 variants on protein expression and clinical outcome of urothelial bladder carcinoma.

BACKGROUND: Urothelial bladder carcinoma (UBC) is the ninth most common malignancy worldwide and ranks thirteenth in cancer-related mortality. A significant challenge in managing non-muscle-invasive UBC (NMIBC) is the high recurrence rate, compounded by a paucity of robust prognostic biomarkers. Given that evasion of apoptosis is a hallmark of carcinogenesis, the apoptosis regulator BCL-2 oncogene plays a critical role by negatively regulating the intrinsic apoptotic pathway, often leading to protein overexpression and malignant cell immortalization. METHODS AND RESULTS: This study evaluated the BCL-2 allelic variants rs2279115 (G > T) and rs3943258 (T > C), including their haplotype structures, in association with BCL-2 immunohistochemical expression in UBC patients. Genetic and immunostaining data were analyzed alongside prognostic factors, environmental exposure, and clinical history. Furthermore, we sought to exhibit BCL-2 immunohistochemical staining patterns via immunofluorescence in selected samples. Our findings revealed that the rs2279115 variant is significantly associated with BCL-2 positive expression. Specifically, the TT genotype in the genotypic model (p = 0.035) and the GT genotype in the overdominant model (p = 0.045) were linked to protein status. Additionally, the CT haplotype was independently associated with high-grade tumors. CONCLUSIONS: The presence of the CT haplotype - in either homozygosity or heterozygosity - exerted a risk effect of high-grade (p = 0.020). In conclusion, these findings suggest that BCL-2 variants, haplotype structures, and immunohistochemical expression may offer relevant insights into the molecular characteristics of urothelial bladder cancer. Further prospective validation is needed to determine whether BCL-2 profiling can serve as a useful complementary tool for risk assessment in clinical practice.

Humans↗

PubMed2026

Clinical Validation of a Multiplex Urine Biomarker Assay for Surveillance of Recurrent Bladder Cancer.

PURPOSE: More than 50% of patients with non-muscle-invasive bladder cancer experience recurrence, requiring lifelong surveillance with repeated cystoscopy. Given the invasive nature and cost of cystoscopy, accurate noninvasive tools are needed to support risk-adapted monitoring. We evaluated the ability of Oncuria-Monitor, a multiplex urine biomarker assay, to detect recurrent bladder cancer during surveillance. PATIENTS AND METHODS: Between February 2017 and August 2020, six medical centers in the United States and Japan prospectively enrolled 300 patients with a history of bladder cancer, generating 1,248 serial urine samples. Participants were divided into training and validation cohorts. At each surveillance visit over 2 years, urine samples were analyzed in a blinded manner using Oncuria-Monitor and BladderChek, alongside urine cytology. Test performance was compared with cystoscopy and histopathology-confirmed recurrence. RESULTS: Recurrent bladder cancer was identified in 31% (93/300) of participants, with 143 total recurrences during follow-up, including 90 tumors in the validation cohort. In the validation cohort, Oncuria-Monitor achieved a sensitivity of 85.6% [95% confidence interval (CI), 78.1%-92.2%] and a negative predictive value (NPV) of 93% (95% CI, 89.2%-96.4%). In comparison, BladderChek demonstrated a sensitivity of 20.0% and an NPV of 88%, whereas urine cytology showed a sensitivity of 36.9% and an NPV of 91.6%. The number needed to evaluate to detect one recurrence was 3 for both cystoscopy and Oncuria-Monitor, compared with 15 for BladderChek and 8 for cytology. CONCLUSIONS: In this large prospective longitudinal study, Oncuria-Monitor demonstrated clinically actionable performance, enabling a rule-out strategy that could safely reduce cystoscopy in approximately 25% of surveillance visits. These findings support a paradigm shift toward biomarker-guided, risk-adapted surveillance in bladder cancer that reduces unnecessary invasive procedures while maintaining oncologic safety.

Humans↗

PubMed2026

Intravesical mitomycin-C administered immediately before transurethral resection of bladder tumor in non-muscle-invasive bladder cancer: Clinical outcomes and molecular predictors from over 3 years of extended follow-up in a phase II trial.

PURPOSE: To evaluate the long-term outcomes and molecular correlates of response after immediate preoperative intravesical chemotherapy (IPeIC) with mitomycin-C (MMC) in patients with non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: In this single-center, open-label, randomized phase II trial, 33 patients received two split doses of IPeIC/MMC (40 mg/20 mL), whereas 38 patients underwent transurethral resection of bladder tumor (TURBT) alone. The primary endpoint was 3-year recurrence-free survival (RFS), and secondary endpoints included progression-free survival (PFS). Exploratory RNA sequencing was performed on IPeIC-treated patients (three with recurrence, 25 without) using a Monte Carlo-based resampling strategy. RESULTS: The median follow-up durations were comparable between the intervention (60.0 months) and control arms (60.4 months). IPeIC/MMC reduced recurrence risk by 76.8% versus TURBT alone (p=0.024), yielding a 3-year RFS rate of 90.7% versus 78.6%. On multivariable analysis, IPeIC/MMC independently improved RFS (hazard ratio [HR] 0.266, p=0.044). IPeIC was associated with superior PFS, with 3-year and 5-year rates of 100% versus 92.1% and 85.8%, respectively, in the controls (HR 0.078, p=0.014). Exploratory transcriptomics identified low Glutathione S-transferase Mu 1 (GSTM1) expression as the factor most strongly associated with recurrence. CONCLUSIONS: IPeIC/MMC is associated with improved long-term oncological outcomes compared with TURBT alone and represents a safe prophylactic option for patients with NMIBC who are unable to receive standard immediate postoperative intravesical chemotherapy because of safety concerns or practical constraints. The GSTM1 findings are hypothesis-generating and support future biomarker-driven validation studies.

Aged↗

PubMed2025

Genomic subtypes of non-muscle-invasive bladder cancer: guiding immunotherapy decision-making for patients exposed to aristolochic acid.

BACKGROUND: The limited genomic data on non-muscle-invasive bladder cancer (NMIBC) hampers our understanding of its carcinogenesis and development. Specifically, Aristolochic acid (AA), a potent human carcinogenic compound from aristolochia plants and commonly found in Chinese herbal medicine, has been extensively documented as being closely associated with the onset and progression of bladder cancer. However, the field of AA-induced NMIBC remains largely unexplored in terms of its genomic and molecular characteristics, as well as clinical therapeutic strategies. METHODS: To bridge this knowledge gap, we conducted a comprehensive study using a cohort of 81 NMIBC samples. We performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) to obtain detailed genomic and transcriptomic data. We subjected these datasets to genomic analysis and subtype analysis to gain valuable insights into NMIBC. RESULTS: By temporally dissecting mutations in NMIBC specimens, we identified a comprehensive mutational landscape of NMIBC and the associations of these mutations with recurrence-free survival. Additionally, we discerned four genomic subtypes of NMIBC: AA-like, FGFR3/HRAS, FGFR3 & chr9Del, and genome instability (GI). The AA-like subtype presented a high frequency of gene mutations along with a pronounced AA mutagenesis signature of SBS22 (Fisher test: P-value 3.5e-4, OR 25.25) even after temporal dissection. The FGFR3/HRAS subtype exhibited FGFR3 or HRAS mutations with few copy number alterations (CNAs). The FGFR3 & chr9Del subtype was characterized by the co-occurrence of chr9p and chr9q deletions as well as FGFR3 mutations, while the GI subtype showed a high frequency of CNAs. Notably, the AA-like and GI subtypes demonstrated better outcomes after immunotherapy, whereas the FGFR3/HRAS subtype showed poorer outcomes. CONCLUSIONS: Our findings provide novel perspectives on the genomics of NMIBC, unveiling four prominent genomic subtypes, each showing different outcomes following immunotherapy. TRIAL REGISTRATION: No. 2019PHB268-01 (retrospectively registered on February 14, 2020).

Humans↗

PubMed2025

Identification of multicohort-based predictive signature for NMIBC recurrence reveals SDCBP as a novel oncogene in bladder cancer.

BACKGROUND: Despite surgical and intravesical chemotherapy interventions, non-muscle invasive bladder cancer (NMIBC) poses a high risk of recurrence, which significantly impacts patient survival. Traditional clinical characteristics alone are inadequate for accurately assessing the risk of NMIBC recurrence, necessitating the development of novel predictive tools. METHODS: We analyzed microarray data of NMIBC samples obtained from the ArrayExpress and GEO databases. LASSO regression was utilized to develop the predictive signature. We combined gene signature and clinicopathological factors to construct a clinical nomogram for estimating NMIBC recurrence in a local cohort. Finally. the biological functions and potential mechanisms of SDCBP in bladder cancer were investigated experimentally in vitro and in vivo. RESULTS: An 8-gene signature was developed, and its efficiency for predicting NMIBC recurrence was evaluated using Kaplan-Meier and time-dependent ROC curves in both training and validation datasets. Immunohistochemical testing revealed elevated levels of ACTN4 and SDCBP in recurrent NMIBC tissues. We integrated the two proteins with clinical factors to develop a nomogram model, which showed superior accuracy compared to individual parameters. Gene Set Variation Analysis and Gene Set Enrichment Analysis unveiled SDCBP exerted cancer-promoting biological processes, such as angiogenesis, EMT, metastasis and proliferation. Experimental procedures demonstrated that silencing SDCBP attenuated cell growth, glucose metabolism and extracellular acidification rate, accompanied by decreased expression of p-AKT, p-ERK1/2, LDHA and Vimentin. CONCLUSIONS: The established 8-gene signature holds promise as a tool for predicting NMIBC recurrence, while targeting SDCBP may represent a potential strategy for delaying disease relapse.

Urinary Bladder Neoplasms↗

PubMed2026

Transcriptomic profiling across stages of non-muscle-invasive bladder cancer identifies fibroblast activation protein-alpha as a stromal biomarker associated with progression.

BACKGROUND: T1 non-muscle-invasive bladder cancer (NMIBC) represents a biologically aggressive subgroup with substantial heterogeneity in recurrence and progression risk. Current clinicopathological risk stratification tools lack sufficient precision to identify patients at the highest risk of progression to muscle-invasive bladder cancer (MIBC). OBJECTIVE: To characterize transcriptomic differences between T1 and < T1 (Ta/Tis) NMIBC and to explore the association of fibroblast activation protein-α (FAP) gene expression with disease progression. METHODS: Transcriptomic profiling was performed on formalin-fixed paraffin-embedded (FFPE) tumor tissue from 66 patients with primary, treatment-naïve NMIBC and 5 patients with T2 disease (included for exploratory comparisons). Analyses included differential gene expression, gene set enrichment analysis (GSEA), molecular subtyping, immune cell deconvolution, and evaluation of FAP expression in relation to recurrence and progression. External validation of FAP was conducted in three independent NMIBC cohorts. RESULTS: T1 tumors demonstrated a distinct transcriptomic profile compared with < T1 tumors, characterized by enrichment of cell cycle-related and metabolic pathways and a higher prevalence of aggressive molecular subtypes. Despite these molecular differences, no statistically significant differences in recurrence-free, progression-free, cancer-specific, and overall survival were observed, likely reflecting limited event numbers. Among recurrent tumors, early recurrences (≤ 24 months) were associated with epithelial-mesenchymal transition signatures. FAP expression increased with tumor stage (p = 0.0005) and was associated with progression (p = 0.002) and mortality (p = 0.01). Patients with tumors in the highest quartile of FAP expression had worse progression-free survival. This association was consistently observed in three external NMIBC cohorts. CONCLUSIONS: T1 NMIBC exhibits distinct transcriptomic features suggestive of increased biological aggressiveness. Elevated FAP expression is reproducibly associated with progression risk across multiple cohorts, supporting its potential role as a biomarker of aggressive disease. Given the limited number of progression events, these findings should be considered hypothesis-generating and warrant prospective validation before clinical implementation.

Humans↗

PubMed2026

A stratified urine-based molecular diagnostic and prognostic model for non-muscle-invasive bladder cancer management.

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) is characterized by a high recurrence rate requiring lifelong cystoscopic surveillance. Existing urine-based molecular assays mainly rely on mutations or methylation, which fail to capture large-scale genomic instability. Copy number variation (CNV) profiling offers complementary information on tumor evolution and aggressiveness, but its application in urinary diagnosis remains limited. We aimed to integrate CNV and DNA methylation signals from urinary DNA to establish a noninvasive and biologically informed stratified diagnostic model for NMIBC recurrence surveillance and risk stratification. METHODS: Urine samples were prospectively collected from 91 patients (75 evaluable) between June 2021 and August 2023. Shallow whole-genome sequencing (sWGS) was used to detect CNVs at chromosomal arm and focal gene levels, while ONECUT2 promoter methylation was quantified by qPCR. Diagnostic and prognostic performance was evaluated by ROC analysis, Kaplan-Meier survival, and stratified recurrence assessment. RESULTS: We evaluated a stratified diagnostic model combining CNV and ONECUT2 methylation testing in a cohort of 79 patients. CNV analysis alone showed high specificity (0.923) for NMIBC diagnosis. A combined model, using CNV as an initial screen followed by ONECUT2 methylation testing in CNV-positive cases, achieved a sensitivity of 0.783, specificity of 0.981, and a negative predictive value (NPV) of 0.911. This approach reduced the number of required ONECUT2 tests by 35% and identified a high proportion of true-negative patients (98.1%), which may help reduce unnecessary cystoscopy procedures. The model also demonstrated significant prognostic value, with the molecularly defined high-risk group showing significantly shorter recurrence-free survival (RFS) than the low-risk group (median RFS: 4.33 months vs. not reached; p < 0.001). Additional, in patients with initially negative cystoscopy after urine sample collection, the model demonstrated a predictive accuracy of 0.922 for recurrence, with molecular positivity observed a median of 9.6 months prior to clinical diagnosis. CONCLUSIONS: Integrating CNV and DNA methylation profiling from urinary DNA provides a powerful and noninvasive molecular framework for NMIBC surveillance. By combining early epigenetic changes with genomic instability signals, this approach enhances recurrence risk assessment and enables earlier detection compared with conventional cystoscopy. It offers a practical route toward personalized and adaptive post-treatment monitoring of NMIBC. TRIAL REGISTRATION: NCT04994197.

Humans↗

PubMed2026

Transcriptome-based high-frequency recurrence index predicts frequent recurrence in non-muscle-invasive bladder cancer after Bacillus Calmette-Guérin therapy.

BACKGROUND: High-frequency recurrence (HfR, ≥ 2 recurrences) in non-muscle-invasive bladder cancer (NMIBC) poses a significant clinical burden. Current risk models, such as the European Organization for Research and Treatment of Cancer (EORTC), the European Association of Urology (EAU), and the UROMOL classification, offer limited predictive accuracy for identifying patients at risk for frequent recurrence despite appropriate treatment. METHODS: A 75-gene high-frequency recurrence index (HfRI) was constructed by selecting recurrence-associated genes using differential expression and Cox regression analyses. The HfRI was computed as a weighted sum of normalized gene expression values. The model was trained on a discovery cohort and validated in multiple cohorts (n = 1379) using machine-learning approaches. Clinical relevance was assessed using recurrence-free survival (RFS) and Cox models, and predictive performance was compared with that of the EORTC, EAU, and UROMOL classifications using the area under the curve (AUC) and the concordance index (c-index). RESULTS: The HfRI robustly stratified patients into high-risk and low-risk groups across six independent NMIBC cohorts. Patients classified as HfRI-high had a significantly greater likelihood of experiencing ≥ 2 recurrences (χ2, p = 0.001) and showed markedly reduced RFS (log-rank test, p < 0.001). The adverse prognostic effect of the HfRI persisted even among patients treated with BCG therapy (log-rank test, p = 0.02). Multivariate analysis revealed that the HfRI was an independent predictor of HfR (HR = 2.82, 95% CI = 1.89-4.20, p < 0.001). Compared with established clinical risk classifiers, the HfRI demonstrated superior predictive performance (AUC = 0.736, c-index = 0.673) in terms of the EORTC (AUC = 0.594), EAU (AUC = 0.557) risk groups, and UROMOL2021 (AUC = 0.596) classification. Pathway analysis revealed that HfRI-high tumors were characterized by upregulation of cell cycle progression and DNA replication pathways, accompanied by suppression of immune signaling pathways. These biological features provide a mechanistic explanation for the reduced responsiveness to intravesical BCG therapy, underscoring the role of HfRI not only as a predictor of recurrence risk but also as a biomarker capable of identifying patients unlikely to benefit from standard BCG treatment. CONCLUSIONS: HfRI represents a robust, transcriptome-based tool for predicting frequent recurrence in NMIBC patients. The HfRI supports earlier identification of patients at risk of high-frequency recurrence, thereby supporting personalized treatment strategies.

Humans↗