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Journal of Hematology & Oncology Jun 2022Urothelial carcinoma (UC) is the most common pathological type of bladder cancer, a malignant tumor. However, an integrated multi-omics analysis of the Chinese UC...
BACKGROUND
Urothelial carcinoma (UC) is the most common pathological type of bladder cancer, a malignant tumor. However, an integrated multi-omics analysis of the Chinese UC patient cohort is lacking.
METHODS
We performed an integrated multi-omics analysis, including whole-exome sequencing, RNA-seq, proteomic, and phosphoproteomic analysis of 116 Chinese UC patients, comprising 45 non-muscle-invasive bladder cancer patients (NMIBCs) and 71 muscle-invasive bladder cancer patients (MIBCs).
RESULT
Proteogenomic integration analysis indicated that SND1 and CDK5 amplifications on chromosome 7q were associated with the activation of STAT3, which was relevant to tumor proliferation. Chromosome 5p gain in NMIBC patients was a high-risk factor, through modulating actin cytoskeleton implicating in tumor cells invasion. Phosphoproteomic analysis of tumors and morphologically normal human urothelium produced UC-associated activated kinases, including CDK1 and PRKDC. Proteomic analysis identified three groups, U-I, U-II, and U-III, reflecting distinct clinical prognosis and molecular signatures. Immune subtypes of UC tumors revealed a complex immune landscape and suggested the amplification of TRAF2 related to the increased expression of PD-L1. Additionally, increased GARS, related to subtype U-II, was validated to promote pentose phosphate pathway by inhibiting activities of PGK1 and PKM2.
CONCLUSIONS
This study provides a valuable resource for researchers and clinicians to further identify molecular pathogenesis and therapeutic opportunities in urothelial carcinoma of the bladder.
Topics: Biomarkers, Tumor; Carcinoma, Transitional Cell; Endonucleases; Humans; Proteogenomics; Proteomics; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 35659036
DOI: 10.1186/s13045-022-01291-7 -
Cancer Treatment and Research... 2021The role of immunotherapy in bladder urothelial cancers is rapidly expanding. Since the initial second-line therapy approval for patients who fail prior platinum-based... (Review)
Review
The role of immunotherapy in bladder urothelial cancers is rapidly expanding. Since the initial second-line therapy approval for patients who fail prior platinum-based chemotherapy, the use of immunotherapy with checkpoint inhibitors has been rapidly evolving. There are approved indications for first-line metastatic disease in the platinum-ineligible patients or the cisplatin-ineligible PD-L1 positive patients, and there is a label for high-risk non-muscle-invasive bladder cancer who are BCG-refractory. In addition, a trial on maintenance immunotherapy with avelumab showed positive findings with improvement in overall survival that has also changed standard of care for these patients. There are ongoing clinical trials evaluating its use in the neoadjuvant and adjuvant perioperative muscle-invasive bladder cancer setting. The pivotal trials that led to these FDA approvals and promising and ongoing trials are discussed herein.
Topics: Administration, Intravesical; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; BCG Vaccine; Carcinoma, Transitional Cell; Chemotherapy, Adjuvant; Cystectomy; Humans; Immune Checkpoint Inhibitors; Induction Chemotherapy; Maintenance Chemotherapy; Neoadjuvant Therapy; Programmed Cell Death 1 Receptor; Progression-Free Survival; Randomized Controlled Trials as Topic; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 33421822
DOI: 10.1016/j.ctarc.2020.100296 -
Advanced Science (Weinheim,... Sep 2023Although immune checkpoint blockade (ICB) therapies have been approved for bladder cancer (BLCA), only a minority of patients respond to these therapies, and there is an...
Although immune checkpoint blockade (ICB) therapies have been approved for bladder cancer (BLCA), only a minority of patients respond to these therapies, and there is an urgent need to explore combined therapies. Systematic multi-omics analysis identified S100A5 as a novel immunosuppressive target for BLCA. The expression of S100A5 in malignant cells inhibited CD8 T cell recruitment by decreasing pro-inflammatory chemokine secretion. Furthermore, S100A5 attenuated effector T cell killing of cancer cells by inhibiting CD8 T cell proliferation and cytotoxicity. In addition, S100A5 acted as an oncogene, thereby promoting tumor proliferation and invasion. Targeting S100A5 synergized with the efficacy of anti-PD-1 treatment by enhancing infiltration and cytotoxicity of CD8 T cells in vivo. Clinically, there was a spatially exclusive relationship between S100A5 tumor cells and CD8 T cells in tissue microarrays. Moreover, S100A5 negatively correlated with immunotherapy efficacy in our real-world and several public immunotherapy cohorts. In summary, S100A5 shapes a non-inflamed tumor microenvironment in BLCA by inhibiting the secretion of pro-inflammatory chemokines and the recruitment and cytotoxicity of CD8 T cells. Targeting S100A5 converts cold tumors into hot tumors, thus enhancing the efficacy of ICB therapy in BLCA.
Topics: Humans; CD8-Positive T-Lymphocytes; Urinary Bladder; Immunotherapy; Urinary Bladder Neoplasms; Carcinoma; Tumor Microenvironment
PubMed: 37414584
DOI: 10.1002/advs.202300110 -
Molecular Biology Reports Sep 2023Urothelial bladder carcinoma (UC) ranks among the top ten most commonly diagnosed cancers worldwide on an annual basis. The standardized classification system for... (Review)
Review
Urothelial bladder carcinoma (UC) ranks among the top ten most commonly diagnosed cancers worldwide on an annual basis. The standardized classification system for urothelial bladder tumors is the Tumor, Node, Metastasis classification, which reflects differences between non-muscle-invasive bladder carcinoma (NMIBC) and muscle-invasive bladder carcinoma (MIBC) and it depends on the extent to which tumor has infiltrated the bladder wall and other tissues and organs. NMIBC and MIBC exhibit great intrinsic heterogeneity regarding different prognoses, survival, progression, and treatment outcomes. In recent years, studies based on mRNA expression profiling revealed the existence of biologically relevant molecular subtypes of UC, which show variant molecular features that can provide more precise stratification of UC patients. Here, we present a complex classification of UC based on mRNA expression studies and molecular subtypes of NMIBC and MIBC in detail with regard to different mRNA expression profiles, mutational signatures, and infiltration by non-tumor cells. The possible impact of molecular subtyping on treatment decisions and patients' outcomes is outlined, too.
Topics: Humans; Urinary Bladder; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Mutation; Neoplasm Invasiveness
PubMed: 37525073
DOI: 10.1007/s11033-023-08689-7 -
Nature Communications Apr 2021The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we...
The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
Topics: Aged; BCG Vaccine; Biomarkers, Tumor; Carcinoma, Transitional Cell; Chromosomal Instability; Cystectomy; Denmark; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Genomics; Humans; Kaplan-Meier Estimate; Male; Mutation; Neoplasm Recurrence, Local; Prognosis; Progression-Free Survival; RNA-Seq; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 33863885
DOI: 10.1038/s41467-021-22465-w -
Revista Da Associacao Medica Brasileira... May 2022
Topics: Alphapapillomavirus; Carcinoma, Transitional Cell; Humans; Papillomaviridae; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 35584471
DOI: 10.1590/1806-9282.20220154 -
European Urology Oncology Aug 2023Bladder cancer (BLCA) is a highly prevalent tumour and a health problem worldwide, especially among men. Recent work has highlighted the relevance of the tumour... (Review)
Review
CONTEXT
Bladder cancer (BLCA) is a highly prevalent tumour and a health problem worldwide, especially among men. Recent work has highlighted the relevance of the tumour microenvironment (TME) in cancer biology with translational implications. Cancer-associated fibroblasts (CAFs) are a prominent, heterogeneous population of cells in the TME. CAFs have been associated with tumour development, progression, and poor prognosis in several neoplasms. However, their role in BLCA has not yet been exploited deeply.
OBJECTIVE
To review the role of CAFs in BLCA biology and provide an understanding of CAF origin, subtypes, markers, and phenotypic and functional characteristics to improve patient management.
EVIDENCE ACQUISITION
A PubMed search was performed to review manuscripts published using the terms "cancer associated fibroblast" and "bladder cancer" or "urothelial cancer". All abstracts were reviewed, and the full content of all relevant manuscripts was analysed. In addition, selected manuscripts on CAFs in other tumours were considered.
EVIDENCE SYNTHESIS
CAFs have been studied less extensively in BLCA than in other tumours. Thanks to new techniques, such as single-cell RNA-seq and spatial transcriptomics, it is now possible to accurately map and molecularly define the phenotype of fibroblasts in normal bladder and BLCA. Bulk transcriptomic analyses have revealed the existence of subtypes among both non-muscle-invasive and muscle-invasive BLCA; these subtypes display distinct features regarding their CAF content. We provide a higher-resolution map of the phenotypic diversity of CAFs in these tumour subtypes. Preclinical studies and recent promising clinical trials leverage on this knowledge through the combined targeting of CAFs or their effectors and the immune microenvironment.
CONCLUSIONS
Current knowledge of BLCA CAFs and the TME is being increasingly applied to improve BLCA therapy. There is a need to acquire a deeper understanding of CAF biology in BLCA.
PATIENT SUMMARY
Tumour cells are surrounded by nontumoural cells that contribute to the determination of the behaviour of cancers. Among them are cancer-associated fibroblasts. The "neighbourhoods" established through these cellular interactions can now be studied with much greater resolution. Understanding these features of tumours will contribute to the designing of more effective therapies, especially in relationship to bladder cancer immunotherapy.
Topics: Humans; Male; Urinary Bladder; Cancer-Associated Fibroblasts; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Biology; Tumor Microenvironment
PubMed: 36890105
DOI: 10.1016/j.euo.2023.02.011 -
Journal of Clinical Oncology : Official... Dec 2014Multiple prospective Radiation Therapy Oncology Group (RTOG) protocols have evaluated bladder-preserving combined-modality therapy (CMT) for muscle-invasive bladder... (Meta-Analysis)
Meta-Analysis
Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233.
PURPOSE
Multiple prospective Radiation Therapy Oncology Group (RTOG) protocols have evaluated bladder-preserving combined-modality therapy (CMT) for muscle-invasive bladder cancer (MIBC), reserving cystectomy for salvage treatment. We performed a pooled analysis of long-term outcomes in patients with MIBC enrolled across multiple studies.
PATIENTS AND METHODS
Four hundred sixty-eight patients with MIBC were enrolled onto six RTOG bladder-preservation studies, including five phase II studies (RTOG 8802, 9506, 9706, 9906, and 0233) and one phase III study (RTOG 8903). Overall survival (OS) was estimated using the Kaplan-Meier method, and disease-specific survival (DSS), muscle-invasive and non-muscle-invasive local failure (LF), and distant metastasis (DM) were estimated by the cumulative incidence method.
RESULTS
The median age of patients was 66 years (range, 34 to 93 years), and clinical T stage was T2 in 61%, T3 in 35%, and T4a in 4% of patients. Complete response to CMT was documented in 69% of patients. With a median follow-up of 4.3 years among all patients and 7.8 years among survivors (n = 205), the 5- and 10-year OS rates were 57% and 36%, respectively, and the 5- and 10-year DSS rates were 71% and 65%, respectively. The 5- and 10-year estimates of muscle-invasive LF, non-muscle-invasive LF, and DM were 13% and 14%, 31% and 36%, and 31% and 35%, respectively.
CONCLUSION
This pooled analysis of multicenter, prospective RTOG bladder-preserving CMT protocols demonstrates long-term DSS comparable to modern immediate cystectomy studies, for patients with similarly staged MIBC. Given the low incidence of late recurrences with long-term follow-up, CMT can be considered as an alternative to radical cystectomy, especially in elderly patients not well suited for surgery.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Adjuvant; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cystectomy; Disease Progression; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Multicenter Studies as Topic; Multivariate Analysis; Muscle, Smooth; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Staging; Odds Ratio; Organ Sparing Treatments; Proportional Hazards Models; Radiotherapy, Adjuvant; Risk Factors; Salvage Therapy; Time Factors; Treatment Outcome; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 25366678
DOI: 10.1200/JCO.2014.57.5548 -
International Journal of Molecular... Aug 2023Bladder cancer and upper urothelial tract carcinoma are common diseases with a high risk of recurrence, thus necessitating follow-up after initial treatment. The... (Review)
Review
Bladder cancer and upper urothelial tract carcinoma are common diseases with a high risk of recurrence, thus necessitating follow-up after initial treatment. The management of non-muscle invasive bladder carcinoma (NMIBC) after transurethral resection involves surveillance, intravesical therapy, and cytology with cystoscopy. Urinary cytology, cystoscopy, and radiological evaluation of the upper urinary tract are recommended during follow-up in the international urological guidelines. Cystoscopy is the standard examination for the first assessment and follow-up of NMIBC, and urine cytology is a widely used urinary test with high sensitivity for high-grade urothelial carcinoma (HGUC) and carcinoma in situ (CIS). In recent years, various urinary assays, including DNA methylation markers, have been used to detect bladder tumors. Among these, the Bladder EpiCheck test is one of the most widely used and is based on analysis of the methylation profile of urothelial cells to detect bladder neoplasms. This review assesses the importance of methylation analysis and the Bladder EpiCheck test as urinary biomarkers for diagnosing urothelial carcinomas in patients in follow-up for NMIBC, helping cytology and cystoscopy in doubtful cases. A combined approach of cytology and methylation analysis is suggested not only to diagnose HGUC, but also to predict clinical and histological recurrences.
Topics: Humans; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Urinary Bladder; Cystoscopy; Epithelial Cells; Urine
PubMed: 37569864
DOI: 10.3390/ijms241512489 -
Virchows Archiv : An International... May 2022The aim of the study was to stratify high-grade T1 (HGT1) bladder urothelial carcinoma into risk categories based on the presence of variant histology when compared to...
The aim of the study was to stratify high-grade T1 (HGT1) bladder urothelial carcinoma into risk categories based on the presence of variant histology when compared to conventional urothelial carcinoma. The clinicopathological features of 104 HGT1 cases of urothelial carcinoma of the bladder with variant histology present in 34 (37%) were assessed. The endpoint of the study was disease-free survival and cancer-specific survival. Overall, variant histology was identified as a significant predictor of disease-free survival (P = 0.035). The presence of any specific variant histology (squamous, glandular, micropapillary, nested, microcystic, inverted growth, villous-like, basaloid, and lymphoepithelioma-like) was identified as a significant predictor of disease-free survival (P = 0.008) and cancer-specific survival (P = 0.0001) in HGT1 bladder cancer. Therefore, our results support including micropapillary HGT1 urothelial carcinoma within the aggressive high-risk category, as suggested by some recent clinical guidelines, but also favor nested, glandular, and basaloid to be placed in the high-risk category due to their potential of aggressive, life-threatening behavior and their limited response to bacillus Calmette-Guerin therapy. Conversely, the low-risk category would include urothelial carcinomas with squamous, inverted growth, or microcystic morphology, all with limited life-threatening potential and good response to current therapy. A very low-risk category would finally include patients whose tumors present villous-like or lymphoepithelioma-like morphology. In conclusion, our findings support the value of reporting the variant histology as a feature of variable aggressiveness in HGT1 urothelial carcinoma of the bladder.
Topics: Carcinoma, Papillary; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Female; Humans; Male; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 35122124
DOI: 10.1007/s00428-021-03264-6