Non-muscle-invasive bladder cancer: a vision for the future

Malmström, Per Uno; Agrawal, Sachin; Bläckberg, Mats; Boström, Peter J.; Malavaud, Bernard; Zaak, Dirk; Hermann, Gregers G.

doi:10.1080/21681805.2017.1283359

Cited by 38 publications

(29 citation statements)

References 54 publications

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“…It originates from the urothelium of the ureter, urethra (upper urinary tract), and bladder [1,2]. Clinical management of BCa [2,3], etiology, and diagnostic, prognostic, or predictive biomarkers for BCa have been described extensively [4,5]. Treatment options are available for both superficial and invasive BCa; however, metastatic disease still presents a serious clinical problem with limited therapeutic options.…”

Section: Introductionmentioning

confidence: 99%

CCL2 Expression in Tumor Cells and Tumor-Infiltrating Immune Cells Shows Divergent Prognostic Potential for Bladder Cancer Patients Depending on Lymph Node Stage

Eckstein

Epple

Jung

et al. 2020

Cancers

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Bladder cancer (BCa) is the ninth most commonly diagnosed cancer worldwide. Although there are several well-established molecular and immunological classifications, markers for tumor cells and immune cells that are associated with prognosis are still needed. The chemokine CC motif ligand 2 (CCL2) could be such a marker. We analyzed the expression of CCL2 by immunohistochemistry (IHC) in 168 muscle invasive BCa samples using a tissue microarray. Application of a single cut-off for the staining status of tumor cells (TCs; positive vs. negative) and immune cells (ICs; ≤6% of ICs vs. >6% of ICs) revealed 57 cases (33.9%) and 70 cases (41.7%) with CCL2-positive TCs or ICs, respectively. IHC results were correlated with clinicopathological and survival data. Positive CCL2 staining in TCs was associated with shorter overall survival (OS), disease-specific survival (DSS), and relapse-free survival (RFS) (p = 0.004, p = 0.036, and p = 0.047; log rank test) and appeared to be an independent prognostic factor for OS (RR = 1.70; p = 0.007; multivariate Cox’s regression analysis). In contrast, positive CCL2 staining in the ICs was associated with longer OS, DSS, and RFS (p = 0.032, p = 0.001, and p = 0.001; log rank test) and appeared to be an independent prognostic factor for DSS (RR = 1.77; p = 0.031; multivariate Cox’s regression analysis). Most interestingly, after separating the patients according to their lymph node status (N0 vs. N1+2), CCL2 staining in the ICs was differentially associated with prognosis. In the N0 group, CCL2 positivity in the ICs was a positive independent prognostic factor for OS (RR = 1.99; p = 0.014), DSS (RR = 3.17; p = 0.002), and RFS (RR = 3.10; p = 0.002), whereas in the N1+2 group, CCL2 positivity was a negative independent factor for OS (RR = 3.44; p = 0.019)) and RFS (RR = 4.47; p = 0.010; all multivariate Cox’s regression analyses). In summary, CCL2 positivity in TCs is a negative prognostic factor for OS, and CCL2 can mark ICs that are differentially associated with prognosis depending on the nodal stage of BCa patients. Therefore, CCL2 staining of TCs and ICs is suggested as a prognostic biomarker for BCa patients.

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Section: Introductionmentioning

confidence: 99%

CCL2 Expression in Tumor Cells and Tumor-Infiltrating Immune Cells Shows Divergent Prognostic Potential for Bladder Cancer Patients Depending on Lymph Node Stage

Eckstein

Epple

Jung

et al. 2020

Cancers

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“…At initial diagnosis, bladder cancer could be characterized by two different forms with specific clinical and pathologic phenotypes: Nonmuscle-invasive bladder cancers (NMIBC) represent about two thirds of newly diagnosed cases. These have a 60% recurrence rate (3) and, in 10% to 20% of cases, evolve to muscle-invasive tumors (4). Muscle-invasive bladder cancers (MIBC) occurring in one third of cases frequently cause distant metastases.…”

Section: Introductionmentioning

confidence: 99%

High Prevalence of a Hotspot of Noncoding Somatic Mutations in Intron 6 of GPR126 in Bladder Cancer

Garinet

Pignot

Vacher

et al. 2019

Molecular Cancer Research

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Numerous pangenomic studies identified protein-coding genes and signaling pathways involved in bladder carcinogenesis. However, noncoding somatic alterations remain unexplored. A recent study revealed a mutational hotspot in intron 6 of GPR126 gene in 2.7% of a large breast cancer series. As GPR126 is highly expressed in bladder tissues, we investigated here the prevalence and the prognostic significance of these mutations in bladder cancer. We analyzed a cohort of 103 bladder cancers including 44 nonmuscle-invasive bladder cancers (NMIBC) and 59 muscle-invasive bladder cancers (MIBC). GPR126 mutations were analyzed by high-resolution melting and Sanger sequencing, and GPR126 expression levels were assessed using real-time quantitative RT-PCR. In NMIBC, somatic GPR126 noncoding mutations occurred in 47.7% of samples and were negatively associated with GPR126 mRNA levels. GPR126 mutations had higher frequencies in nonsmok-er patients and were associated with a prior history of NMIBC. GPR126 overexpression was detected in 70.5% of samples. GPR126 mutation and overexpression status were not associated with outcome. In MIBC, somatic GPR126 mutations occurred in 44.1% of samples. Mutations were more frequent in females. GPR126 overexpression was detected in 27.1% of the sample. A trend toward significance was observed between GPR126 overexpression and better outcome. We identified the second most frequent mutational hotspot after TERT promoter ($70%) in bladder cancer, with a mutation rate of approximately 50%.Implications: The GPR126 intronic mutational hotspot could be a promising clinical biomarker candidate to monitor tumor burden using circulating tumor DNA in bladder cancer.

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“…With the aging of population, the incidence of BC is rising year by year, and BC in elder patients will become even more frequent and evolved into a public health challenge in future. For patients with superficial BC, telescopic removal of the cancer (transurethral resection of bladder tumor, TURBT) followed by instillation of chemotherapy or vaccine-based therapy into the bladder with prolonged telescopic checking of the bladder are usually recommended, and the 5-year overall survival for these patients reaches 90%, while about 40–80% of these patients will develop disease recurrence or progression (Malmström et al, 2017 ). For patients with invasive BC, radical cystectomy plus pelvic lymph node dissection (PLND) followed by neo-adjuvant chemotherapy is recommended as a standard of care, and once it becomes metastatic cancer, the 5-year overall survival for patients with invasive BC is a dismal 6% (Salama et al, 2016 ; Sargos et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of Biomarkers Correlated with the TNM Staging and Overall Survival of Patients with Bladder Cancer

Liu

et al. 2017

Front. Physiol.

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Objective: To identify candidate biomarkers correlated with clinical prognosis of patients with bladder cancer (BC).Methods: Weighted gene co-expression network analysis was applied to build a co-expression network to identify hub genes correlated with tumor node metastasis (TNM) staging of BC patients. Functional enrichment analysis was conducted to functionally annotate the hub genes. Protein-protein interaction network analysis of hub genes was performed to identify the interactions among the hub genes. Survival analyses were conducted to characterize the role of hub genes on the survival of BC patients. Gene set enrichment analyses were conducted to find the potential mechanisms involved in the tumor proliferation promoted by hub genes.Results: Based on the results of topological overlap measure based clustering and the inclusion criteria, top 50 hub genes were identified. Hub genes were enriched in cell proliferation associated gene ontology terms (mitotic sister chromatid segregation, mitotic cell cycle and, cell cycle, etc.) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways (cell cycle, Oocyte meiosis, etc.). 17 hub genes were found to interact with ≥5 of the hub genes. Survival analysis of hub genes suggested that lower expression of MMP11, COL5A2, CDC25B, TOP2A, CENPF, CDCA3, TK1, TPX2, CDCA8, AEBP1, and FOXM1were associated with better overall survival of BC patients. BC samples with higher expression of hub genes were enriched in gene sets associated with P53 pathway, apical junction, mitotic spindle, G2M checkpoint, and myogenesis, etc.Conclusions: We identified several candidate biomarkers correlated with the TNM staging and overall survival of BC patients. Accordingly, they might be used as potential diagnostic biomarkers and therapeutic targets with clinical utility.

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Non-muscle-invasive bladder cancer: a vision for the future

Cited by 38 publications

References 54 publications

CCL2 Expression in Tumor Cells and Tumor-Infiltrating Immune Cells Shows Divergent Prognostic Potential for Bladder Cancer Patients Depending on Lymph Node Stage

CCL2 Expression in Tumor Cells and Tumor-Infiltrating Immune Cells Shows Divergent Prognostic Potential for Bladder Cancer Patients Depending on Lymph Node Stage

High Prevalence of a Hotspot of Noncoding Somatic Mutations in Intron 6 of GPR126 in Bladder Cancer

Identification of Biomarkers Correlated with the TNM Staging and Overall Survival of Patients with Bladder Cancer

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