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Molecular Diagnostics and Therapeutic Targets in Bladder Cancer (Second Edition)

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 September 2026 | Viewed by 3770

Special Issue Editor


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Guest Editor
1. Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
2. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Interests: urinary biomarkers for early detection, prognostics, and prediction of the response to treatment of bladder cancer; the role of sphingolipid signaling cascade in cancers, such as colon, breast, and bladder
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Special Issue Information

Dear Colleagues,

Bladder cancer is the sixth most common cancer in the United States and the tenth worldwide. Despite advances in treatment, it remains one of the most challenging and costly malignancies to manage due to its high recurrence rate and biological heterogeneity. While early-stage disease (non-muscle invasive bladder cancer, NMIBC; stages 0–1) has a 5-year survival rate of ~94%, this drops to ~50% for muscle-invasive bladder cancer (MIBC; stage 2) and below 20% for metastatic disease (stages 3–4). These stark differences underscore the need for accurate early detection, refined risk stratification, and targeted therapeutic interventions.

Currently, diagnosis relies heavily on cystoscopy, an invasive and expensive procedure. There is an urgent need for non-invasive, accurate diagnostic approaches that can detect disease earlier, predict progression, and guide therapy. Promising avenues include DNA- and RNA-based assays, protein biomarkers, metabolomic profiling, circulating tumor cells (CTCs), and imaging-based biomarkers. The integration of liquid biopsy, genomic profiling, and multi-omics technologies offers exciting opportunities for innovation.

Therapeutic development in bladder cancer has expanded considerably for MIBC, with immune checkpoint inhibitors, antibody–drug conjugates, and FGFR-targeted therapies now in clinical use. However, treatment for NMIBC remains largely dependent on transurethral resection and intravesical bacillus Calmette–Guérin (BCG). There is a pressing need for novel strategies, including immune-based therapies, targeting key signal transduction pathways, modulation of the DNA damage response, tumor microenvironment reprogramming, and drug repurposing.

This Special Issue invites original research articles, reviews, and perspectives spanning basic, translational, and clinical studies on bladder cancer molecular diagnostics and therapeutic targets. Topics of interest include, but are not limited to, the following:

  • Biomarkers for early detection, prognosis, and treatment response, including genomic, transcriptomic, proteomic, metabolomic, and imaging-based markers.
  • Liquid biopsy approaches such as circulating tumor DNA (ctDNA), RNA, exosomes, and CTCs.
  • Novel therapeutic targets identified through molecular profiling, including genetic alterations, epigenetic regulators, and components of the tumor immune microenvironment.
  • Therapeutic strategies, including small molecules, biologics, antibody–drug conjugates, immune checkpoint blockade, cancer vaccines, cell-based therapies, and drug repurposing.
  • Integration of multi-omics data to inform personalized treatment selection.
  • Preclinical and clinical validation of diagnostic and therapeutic innovations.

We aim to attract a diverse set of manuscripts that will advance the precision diagnosis and targeted treatment of bladder cancer, ultimately improving patient care and outcomes.

Dr. Hideki Furuya
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • non-muscle invasive bladder cancer
  • muscle-invasive bladder cancer
  • metastatic bladder cancer
  • diagnostic biomarkers
  • therapeutic targets
  • early detection
  • progression biomarkers
  • liquid biopsy
  • genomic profiling
  • proteomics
  • metabolomics
  • imaging biomarkers
  • multi-omics
  • targeted therapy
  • immunotherapy
  • antibody–drug conjugates
  • DNA damage response
  • tumor microenvironment

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Published Papers (4 papers)

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Research

16 pages, 11811 KB  
Article
Serum Trimethylamine-N-Oxide and Its Precursors as a Diagnostic Biomarker Panel for Non-Muscle-Invasive Bladder Cancer
by Aleyna Baltacıoğlu, Osman Acar, Ceyda Sönmez, Yeşim Sağlıcan, Ömer Burak Argun, Ali Rıza Kural, Asıf Yıldırım, Ümit İnce, Muhittin Abdulkadir Serdar and Aysel Özpınar
Int. J. Mol. Sci. 2026, 27(8), 3591; https://doi.org/10.3390/ijms27083591 - 17 Apr 2026
Viewed by 457
Abstract
Non-muscle-invasive bladder cancer (NMIBC) is characterized by high recurrence rates and necessitates lifelong cystoscopic surveillance, underscoring the need for minimally invasive biomarkers to improve early detection and risk stratification. Therefore, this study aimed to investigate the role of trimethylamine-N-oxide (TMAO) and [...] Read more.
Non-muscle-invasive bladder cancer (NMIBC) is characterized by high recurrence rates and necessitates lifelong cystoscopic surveillance, underscoring the need for minimally invasive biomarkers to improve early detection and risk stratification. Therefore, this study aimed to investigate the role of trimethylamine-N-oxide (TMAO) and its precursors as diagnostic biomarkers for NMIBC. A total of 50 male patients with NMIBC (25 pTa and 25 pT1) were included in this study. Additionally, 52 age-matched healthy individuals were included as controls. Serum TMAO and its dietary precursors were quantified using liquid chromatography–tandem mass spectrometry. Group differences were analyzed using nonparametric tests, associations were assessed using Spearman’s correlation, and diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis. Multivariate logistic regression was performed to identify independent predictors, and a composite risk score was generated. Serum TMAO, carnitine, and choline levels were significantly higher in patients with NMIBC than in controls (p ≤ 0.0001), whereas betaine showed a nonsignificant trend toward higher levels (p ≥ 0.05). The pathological stage (pTa vs. pT1) showed the strongest correlation with TMAO levels. The ROC analysis revealed that TMAO had the highest individual diagnostic accuracy (area under the curve [AUC] = 0.875, 95% confidence interval [CI] 0.812–0.939), whereas carnitine and choline provided complementary diagnostic performance. In multivariate models, TMAO, carnitine, and choline remained independent predictors of NMIBC (p ≤ 0.0001). A composite risk score integrating all four metabolites demonstrated excellent discriminatory capacity (AUC = 0.958, 95% CI 0.926–0.991). The TMAO metabolic axis can be used as a minimally invasive biomarker panel for NMIBC. Further large, prospective, multicenter studies integrating metabolomic and microbiome profiling are needed to validate the findings. Full article
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21 pages, 477 KB  
Article
Association of IL6 rs1800795, TNF rs1800629, CCL2 rs1024611 and VEGFA rs699947 Polymorphisms with Bladder Cancer Risk, Tumor Aggressiveness, and HRV Parameters of Autonomic Nervous System Regulation
by Vladimira Durmanova, Iveta Mikolaskova, Juraj Javor, Agata Ocenasova, Magda Suchankova, Boris Kollarik, Milan Zvarik, Maria Bucova and Luba Hunakova
Int. J. Mol. Sci. 2026, 27(8), 3361; https://doi.org/10.3390/ijms27083361 - 9 Apr 2026
Viewed by 465
Abstract
Chronic inflammation contributes to bladder cancer (BC) development and progression through dysregulated cytokine signaling and tumor–immune interactions. This case–control study investigated associations between IL6 rs1800795, TNF rs1800629, CCL2 rs1024611, and VEGFA rs699947 polymorphisms, circulating cytokine levels, clinicopathological characteristics, and autonomic nervous system balance [...] Read more.
Chronic inflammation contributes to bladder cancer (BC) development and progression through dysregulated cytokine signaling and tumor–immune interactions. This case–control study investigated associations between IL6 rs1800795, TNF rs1800629, CCL2 rs1024611, and VEGFA rs699947 polymorphisms, circulating cytokine levels, clinicopathological characteristics, and autonomic nervous system balance assessed by heart rate variability (HRV) in 73 BC patients and 88 controls. Genotyping was performed using PCR–RFLP, serum cytokine levels were measured by ELISA, and associations were evaluated using logistic, linear regression, and survival analyses. No significant associations with BC risk were observed for IL6, TNF, or VEGFA variants. However, the CCL2 rs1024611 GG genotype was associated with increased BC risk (recessive model: OR = 5.82, p = 0.026). Stratified analyses showed a lower frequency of the IL6 rs1800795 C allele and TNF rs1800629 GA genotype in high-grade and muscle-invasive tumors, suggesting potential associations with reduced tumor aggressiveness. No polymorphism was associated with serum cytokine levels or disease-free survival. In BC patients, the TNF rs1800629 A allele was associated with higher parasympathetic-related HRV indices and lower sympathetic parameters, whereas no such associations were observed in controls. These findings indicate that genetic variation within inflammatory pathways may contribute to BC susceptibility and tumor phenotype and may also modulate neuroimmune interactions. Full article
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12 pages, 234 KB  
Article
Genomic Characteristics of Bladder Cancer: An AACR Project GENIE Study
by John Paul Braun, Kenneth A. D. Palattao, Jr., Elijah Torbenson, Beau Hsia and Abubakar Tauseef
Int. J. Mol. Sci. 2025, 26(23), 11653; https://doi.org/10.3390/ijms262311653 - 1 Dec 2025
Cited by 2 | Viewed by 1142
Abstract
Bladder and urothelial carcinoma are marked by profound genomic diversity. Using a large, multi-institutional dataset, we performed comprehensive genomic profiling of 4631 tumor samples from 4050 individuals. A retrospective analysis of bladder and urothelial cancer was performed using the AACR Project GENIE database. [...] Read more.
Bladder and urothelial carcinoma are marked by profound genomic diversity. Using a large, multi-institutional dataset, we performed comprehensive genomic profiling of 4631 tumor samples from 4050 individuals. A retrospective analysis of bladder and urothelial cancer was performed using the AACR Project GENIE database. Demographic associations, mutation frequencies, copy number changes, and survival correlations were analyzed with a p-value < 0.05. Frequent mutations were identified in TP53, TERT, KDM6A, KMT2D, ARID1A, and FGFR3. Mutation frequencies varied by sex and race, with specific alterations enriched in female and Asian patients. Distinct patterns of co-occurrence, including TP53 with RB1, and mutual exclusivity, including TP53 with FGFR3 or KDM6A, revealed distinct molecular subtypes. This study highlights the extensive heterogeneity of bladder cancer, and our findings emphasize the clinical importance of molecular stratification and support the need for further mechanistic and prospective studies to inform the development of targeted therapies. Full article
18 pages, 3621 KB  
Article
Comparative Analysis of CT and MRI Combined with RNA Sequencing for Radiogenomic Staging of Bladder Cancer
by Joshua Levy, Toru Sakatani, Kaoru Murakami, Yuki Kita, Takashi Kobayashi, Susan Win, Saro Manoukian, Charles J. Rosser and Hideki Furuya
Int. J. Mol. Sci. 2025, 26(19), 9570; https://doi.org/10.3390/ijms26199570 - 30 Sep 2025
Cited by 2 | Viewed by 1305
Abstract
Accurate staging of bladder cancer (BCa) is important for identifying optimal treatment. Currently, clinical tumor staging for BCa relies on computed tomography (CT) scans, but these can lead to under- or overstaging of patients. Recent research suggests that using magnetic resonance imaging (MRI) [...] Read more.
Accurate staging of bladder cancer (BCa) is important for identifying optimal treatment. Currently, clinical tumor staging for BCa relies on computed tomography (CT) scans, but these can lead to under- or overstaging of patients. Recent research suggests that using magnetic resonance imaging (MRI) along with RNA sequencing (RNASeq) gene expression analysis can provide more precise staging. In this study, 31 matched CT scans, MRI images, and formalin-fixed, paraffin-embedded (FFPE) tissues were collected. First, two radiologists reviewed the images for staging BCa. Next, radiomics features were extracted from both CT and MR images, and computational radiogenomics analyses were performed. Subsequently, RNASeq was performed using FFPE tissues of TURBT prior to cystectomy. A radiogenomic analysis was conducted to identify advanced T-stage signatures. Regarding imaging alone, MRI was found to be more accurate in staging >T2 compared to CT scans. Within a retrospective cohort, MRI radiogenomic signatures were more effective in staging patients than CT, with genomic features playing a significant role. Using canonical correlation analysis, we additionally identified radiomic features underlying genomic signatures of advanced tumor stage. When applying these signatures across a small prospective cohort, MRI radiomic data were able to stratify stage; however, the addition of the same genomic features did not improve the sensitivity and specificity of the model. These preliminary results are promising, but additional research with larger sample sizes is needed to draw definitive conclusions and explore further correlations and statistical interactions between genes and imaging features through machine learning techniques as we move radiogenomics to the clinic. Full article
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