Prognostic Biomarker For Bladder Cancer Research Articles

The Vanishing Clinical Value of PD-L1 Status as a Predictive Biomarker in the First-Line Treatment of Urothelial Carcinoma of the Bladder.

Our study endeavors to elucidate the clinical implications of PD-L1 positivity in individuals afflicted with advanced urothelial carcinoma of the bladder (UCB). Patients with advanced UCB were prospectively enrolled following a radical cystectomy (RC) performed within January 2017 to December 2022 at our tertiary referral center. The clinical outcome, defined as the progression-free survival (PFS) and overall survival (OS) on systemic treatment, was analyzed using an χ2-test, Mann-Whitney U-test, the Kaplan-Meier method, and a log-rank test. A total of 648 patients were included following an RC performed within January 2017 to December 2022. Their PD-L1 status was analyzed with the primary PD-L1-specific antibody (clone SP263, Ventana) and defined both by the CPS and IC-score in 282 patients (43.5%) with a high risk (pT3-pT4 and/or lymph node involvement) or metastatic UCB. While the median PFS was significantly prolonged 5-fold in PD-L1+ patients, we found no difference in OS, regardless of PD-L1 status, or treatment regimen. While PD-L1 positivity indicates prolonged PFS, the presence of PD-L1 does not influence OS rates, suggesting its limited usefulness as a prognostic biomarker in bladder cancer. However, the positive correlation between an PD-L1 status and a sustained response to ICI treatments indicates its potential role as a predictive biomarker. Further research is required to understand how the predictive value of PD-L1 positivity may extend to the use of ICIs in combination with antibody-drug conjugates.

Immunochemistry-based quantification of tumor-infiltrating lymphocytes and immunoscore as prognostic biomarkers in bladder cancer

BackgroundTumor-infiltrating lymphocytes (TILs) and the derived immunoscore (IS) have gained considerable attention over the last decade as prognostic markers in many solid cancers. However, in bladder cancer (BC), their prognostic value is not clearly established.MethodsThe present study aimed to quantify the TILs rates in BC, assess the derived immunoscore, and investigate their prognostic value. An immunochemistry-based quantification of the different subtypes of TILS was performed on paraffin-embedded blocks from patients with invasive urothelial carcinoma of the bladder. We have assessed the rates of TILs, respectively, on peri-tumoral (PT) and intra-tumoral (IT) areas and calculated for each case the corresponding IS which is the index: CD8+/CD3+ TILs. The IS was then classified as low (I0, I1) or high (I2, I3, I4). We included 30 cases in the analysis.ResultsThe median age of patients was 65 years with a sex ratio of 9. TILs densities and distribution were significantly variable between IT and PT areas CD3+ (p = 0.03) and CD8+ (p = 0.004) with the highest rates on the PT areas. In univariate analysis, a low density of CD8+ TILs was significantly associated with an advanced age (p = 0.05), with the presence of lympho-vascular invasion (p = 0.02) and with the absence of specific histological subtype (p = 0.05). A low immunoscore was significantly associated with the presence of lympho-vascular invasion (p = 0.004). No significant association was found between TILs subpopulations, the IS, and the other clinicopathological and survival data. The overall survival (OS) and disease-free survival (DFS) medians were slightly superior in highly T (CD3+/CD8+)-cell infiltrated tumors as well as tumors with a high IS densities. However, the univariate analysis showed that TILs and immunoscore did not impact overall survival (OS) and disease-free survival (DFS).ConclusionTILs and immunoscore might be effective prognostic tools in BC. However, standardized quantification methods and further investigation on larger samples are highly recommended to definitively attest the prognostic value of TILs and IS in BC.

Abstract 5214: HYAL4 splice variant induces treatment-resistance in advanced bladder cancer

Abstract Introduction and Objective: Precision-based treatment approaches could improve the prognosis of patients with bladder cancer (BC). We recently discovered a first-in-class human Chondroitinase (Chase) that degrades chondroitin sulfate. This Chase is a splice variant of HYAL4 (V1) and promotes a malignant phenotype and chemoresistance in BC cells. We evaluated V1/Chase expression and functions in BC and inhibitors to overcome V1/Chase-mediated Gemcitabine (Gem) resistance. Methods: Cohort 1: 653 voided urine specimens (BC, 160; non-BC, 493); cohort 2: 40 cystectomy specimens from MIBC patients who received adjuvant Gemcitabine plus cisplatin (G+C) treatment. Gene expression was measured by q-PCR and urine was assayed by the Chase test. V1 was expressed in BC cell lines or silenced and the transfectants were analyzed for sensitivity to Gem and Cisplatin. The mechanism of Gem resistance was evaluated in preclinical in vitro and in vivo models. Results: In cohort 1, Chase levels were 7-10-fold elevated in patients with BC compared to patients with benign genitourinary conditions, history of BC, or other cancers. Chase test detected BC with 94.4% and 87.4% specificity. Chase test had 84% accuracy in correctly diagnosing the cases with atypical cytology inference. Stem cell marker CD44 was the major substrate of Chase in BC cells. V1’s Chase activity induced CD44 cleavage and shedding. Intracellularly, CD44 cleavage induced JAK2/Stat3 pathway and subsequently upregulation of cytidine deaminase. CDA induces Gem metabolism and efflux of dFdU, an inactive Gem metabolite. HPLC analysis showed, V1 transfectants have increased levels of dFdU and higher efflux. STAT3 and CDA inhibitors synergistically re-sensitized V1-expressing cells to Gem. In cohort 2, V1, p-JAK2 and CDA expression predicted failure to G+C treatment (P<0.0001). JAK2, STAT3 and CDA inhibitors synergistically re-sensitized V1-expressing cells to Gem. V1-induced muscle invasive tumors that were metastatic. While V1-expressing tumors were resistant, combination of Gem with a CDA or JAK-2 inhibitor abrogated V1 tumor growth with minimal toxicity. Conclusion: V1/Chase is a potential diagnostic and prognostic biomarker for bladder cancer and drives muscle-invasion, metastasis, and Gem resistance in BC. Inhibitors of the Chase signaling pathway overcome V1-induced Gem resistance, suggesting a precision-based treatment approach to improve treatment response. Support: 1R01CA227277-05A1; 1R01CA283699-01 Citation Format: Karina Aguilar, Sunita Panda, Joshua Van Der Eerden, Luis Lopez, Martha Terris, Pablo Santamaria, Bal Lokeshwar, Vinata B. Lokeshwar. HYAL4 splice variant induces treatment-resistance in advanced bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5214.

Unveiling the role of YARS1 in bladder cancer: A prognostic biomarker and therapeutic target.

YARS is responsible for catalysing the binding of tyrosine to its cognate tRNA and plays a crucial role in basic biosynthesis. However, its biological functions in bladder cancer remains to be proven. We analysed variations in YARS1 expression and survival in bladder cancer using multiple data sets, including TCGA-BLCA, GSE13507 and bladder cancer-specific tissue microarrays. Furthermore, we explored the biological functions of YARS1 using transcriptome data. Our findings revealed a noteworthy correlation between YARS1 and immune infiltration in bladder cancer, as determined using the XCELL algorithm and single-cell analysis. In addition, we employed the TIDE algorithm to evaluate the responsiveness of different cohorts to immune checkpoint therapy. We investigated the regulatory associations between YARS1 and various aspects of bladder cancer, including senescence, ferroptosis and stemness. Finally, we established a ceRNA network that is directly linked to the overall prognosis, YARS1 can serve as a prognostic biomarker for bladder cancer; its interaction with MYC has implications for bladder cancer cell senescence, ferroptosis and stemness. Moreover, the identified ceRNA network has potential as a therapeutic target in bladder cancer.

Survival and clinicopathological significance of B7-H3 in bladder cancer: a systematic review and meta-analysis

BackgroundB7-H3 has been implicated in clinical pathological features and prognosis across various cancer types, suggesting its potential as a cancer biomarker. Nevertheless, consensus remains elusive regarding its clinical-pathological and prognostic significance in bladder cancer. To address this gap, we conducted a systematic review and meta-analysis.MethodsWe systematically searched PubMed, Embase, Web of Science, Cochrane, and CNKI databases from their inception up to October 6, 2022. We evaluated the literature’s quality using the Newcastle-Ottawa Scale. We performed meta-analysis using Review Manager 5.3 and STATA 12.0, synthesizing data and calculating odds ratios (ORs) or hazard ratios (HRs) with corresponding 95% confidence intervals (CIs).ResultsAfter applying eligibility criteria and conducting assessments, we included data from 8 studies, encompassing 1622 bladder cancer patients. Bladder tumor tissues exhibited significantly elevated B7-H3 protein expression compared to normal bladder tissues. Elevated B7-H3 expression was notably associated with patient age, tumor infiltration, and recurrence in bladder cancer. However, no significant correlations were observed with other clinical characteristics. Our pooled HR analysis indicated no significant association between B7-H3 expression and overall survival in bladder cancer patients.ConclusionOur meta-analysis unveils the complex role of B7-H3 in bladder cancer progression. It appears to be directly involved in tumor infiltration and recurrence but cannot definitively serve as a prognostic biomarker for bladder cancer. To validate these findings, further well-designed studies, encompassing larger sample sizes and diverse racial backgrounds, are warranted.PROSPERO registrationNo. CRD42022364688.

JAM3: A prognostic biomarker for bladder cancer via epithelial–mesenchymal transition regulation

Understanding the intricate relationship between prognosis, immune function, and molecular markers in bladder cancer (BC) demands sophisticated analytical methods. To identify novel biomarkers for predicting prognosis and immune function in BC patients, we combined weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) regression analysis. This was conducted using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Ultimately, we screened the junctional adhesion molecule 3 (JAM3) as an independent risk factor in BC. High levels of JAM3 were linked to adverse clinical parameters, such as higher T and N stages. Additionally, a JAM3-based nomogram model accurately predicted 1-, 3- and 5-year survival rates of BC patients, indicating potential clinical utility. Functional enrichment analysis revealed that high JAM3 expression activated the calcium signaling pathway, the extracellular matrix (ECM)-receptor interaction, and the PI3K-Akt signaling pathway, and was positively correlated with genes associated with epithelial–mesenchymal transition (EMT). Subsequently, we found that overexpression of JAM3 promoted the migration and invasion abilities in BC cells, regulating the expression levels of N-Cadherin, matrix metallopeptidase 2 (MMP2), and Claudin-1 thereby promoting EMT levels. Additionally, we showed that JAM3 was negatively correlated with anti-tumor immune cells such as CD8+T cells, while positively correlated with pro-tumor immune cells such as M2 macrophages, suggesting its involvement in immune cell infiltration. The immune checkpoint CD200 also showed a positive correlation with JAM3. Our findings revealed that elevated JAM3 levels are predictive of poor prognosis and immune cell infiltration in BC patients by regulating the EMT process.

Multi-cohort validation of Ascore: an anoikis-based prognostic signature for predicting disease progression and immunotherapy response in bladder cancer

Bladder cancer ranks as the 10th most common cancer worldwide, with deteriorating prognosis as the disease advances. While immune checkpoint inhibitors (ICIs) have shown promise in clinical therapy in both operable and advanced bladder cancer, identifying patients who will respond is challenging. Anoikis, a specialized form of cell death that occurs when cells detach from the extracellular matrix, is closely linked to tumor progression. Here, we aimed to explore the anoikis-based biomarkers for bladder cancer prognosis and immunotherapeutic decisions. Through consensus clustering, we categorized patients from the TCGA-BLCA cohort into two clusters based on anoikis-related genes (ARGs). Significant differences in survival outcome, clinical features, tumor immune environment (TIME), and potential ICIs response were observed between clusters. We then formulated a four-gene signature, termed "Ascore", to encapsulate this gene expression pattern. The Ascore was found to be closely associated with survival outcome and served as an independent prognosticator in both the TCGA-BLCA cohort and the IMvigor210 cohort. It also demonstrated superior predictive capacity (AUC = 0.717) for bladder cancer immunotherapy response compared to biomarkers like TMB and PD-L1. Finally, we evaluated Ascore’s independent prognostic performance as a non-invasive biomarker in our clinical cohort (Gulou-Cohort1) using circulating tumor cells detection, achieving an AUC of 0.803. Another clinical cohort (Gulou-Cohort2) consisted of 40 patients undergoing neoadjuvant anti-PD-1 treatment was also examined. Immunohistochemistry of Ascore in these patients revealed its correlation with the pathological response to bladder cancer immunotherapy (P = 0.004). Impressively, Ascore (AUC = 0.913) surpassed PD-L1 (AUC = 0.662) in forecasting immunotherapy response and indicated better net benefit. In conclusion, our study introduces Ascore as a novel, robust prognostic biomarker for bladder cancer, offering a new tool for enhancing immunotherapy decisions and contributing to the tailored treatment approaches in this field.

A Prognostic Biomarker for Bladder Cancer Correlated with Immune Infiltration Is PAEP

A Prognostic Biomarker for Bladder Cancer Correlated with Immune Infiltration Is PAEP

Prognostic potential of m7G-associated lncRNA signature in predicting bladder cancer response to immunotherapy and chemotherapy

Abstract Objectives The influence of N7-methylguanosine (m7G) on cancer prognosis and immune response has been well-reported. However, the role of m7G-related long non-coding RNAs (lncRNAs) in bladder cancer (BC) remains largely unexplored. This study wanted to explore the relationship between m7G-related lncRNAs and BC. Methods To construct the m7G-related lncRNA signature, we utilized data obtained from TCGA. The collected data was then analyzed using R (version 4.2.1, Bell Laboratories, Boston, USA) and relevant packages. Results The m7G-related lncRNA signature consisted of seven lncRNAs (including GATA3-AS1, LINC00930, LINC01341, MED14OS, MIR100HG, RUSC1-AS1, SNHG4). The prognostic and clinical relevance of the risk score was corroborated in both the TCGA and IMvigor210 datasets. Individuals characterized by a high-risk score displayed substantial enrichment in pathways associated with immunity, notably those pertaining to the innate immune response, cytokine-mediated signaling pathways, and the adaptive immune system. Additionally, the high-risk score group showed a positive correlation with many immune checkpoints, including CD274, CD40, CTLA4, PDCD1, PDCD1LG2, among others. Moreover, a significant difference in the TCIA score was observed between the high-risk and low-risk score groups, indicating the potential distinct immunotherapy response rates. Furthermore, patients with a high-risk score demonstrated increased sensitivity to cisplatin, docetaxel, doxorubicin, gemcitabine, and vinblastine. Conclusions This m7G-related lncRNA signature demonstrates considerable promise as a prognostic biomarker in BC, facilitating the anticipation of responses to both immunotherapy and chemotherapy. This study provides a solid foundation for future investigations into the role of m7G-related lncRNAs in BC.

Homeobox Gene Expression Dysregulation as Potential Diagnostic and Prognostic Biomarkers in Bladder Cancer.

Homeobox genes serve as master regulatory transcription factors that regulate gene expression during embryogenesis. A homeobox gene may have either tumor-promoting or tumor-suppressive properties depending on the specific organ or cell lineage where it is expressed. The dysregulation of homeobox genes has been reported in various human cancers, including bladder cancer. The dysregulated expression of homeobox genes has been associated with bladder cancer clinical outcomes. Although bladder cancer has high risk of tumor recurrence and progression, it is highly challenging for clinicians to accurately predict the risk of tumor recurrence and progression at the initial point of diagnosis. Cystoscopy is the routine surveillance method used to detect tumor recurrence. However, the procedure causes significant discomfort and pain that results in poor surveillance follow-up amongst patients. Therefore, the development of reliable non-invasive biomarkers for the early detection and monitoring of bladder cancer is crucial. This review provides a comprehensive overview of the diagnostic and prognostic potential of homeobox gene expression dysregulation in bladder cancer.

NMR metabolomics in bladder cancer: Identification and monitoring of serum biomarkers during Pt-based treatment.

3057 Background: To date, predictive and prognostic biomarkers for Bladder Cancer (BC) are lacking. Metabolomics, the study of small molecules involved in metabolism, aims to identify diagnostic, predictive and prognostic biomarkers. Overall, BC shows perturbations of various metabolic pathways, involved in biochemical reactions essential for energy production and for the maintenance of the REDOX balance, as well as in the metabolism of purines and pyrimidines. The main objective of this study is to characterize the serum metabolic profile of patients with BC undergoing platinum-based chemotherapy (Pt-CT), to identify the alterations induced by CT and evaluate the associated deregulated metabolic pathways, in order to identify potential biomarkers, prognostic and predictive of response to treatment. Methods: We enrolled patients with BC undergoing Pt-CT in different settings (neoadjuvant, adjuvant or metastatic). For each patient, a blood sample was collected before the start of each CT cycle (T0, T1, Tn). Metabolomic analysis was performed using the Bruker Avance 600 spectrometer. At baseline (T0), the metabolomic profiles of BC patients were compared with that of age- and sex-matched healthy controls. Major metabolites up- or down-regulated in patients with BC at baseline, were then monitored during CT (T1, Tn). Results: 14 patients were enrolled. When compared with age- and sex-matched healthy controls, patients with BC had elevated levels of acetate and acetone (ketone bodies), hypoxanthine, trimethylamine N-oxide (TMAO), glutamate, lactate, phenylalanine, and ornithine, and decreased levels of carnitine, choline, betaine, aspartate, threonine, 2-hydroxybutyrate, 2-aminobutyrate and histidine. When monitored during CT, hypoxanthine, glutamate, and aspartate levels increased; acetone, acetate and TMAO instead had a decreasing trend. Conclusions: The results of our pilot study confirm perturbations in several metabolic pathways: up-regulation of lactate, ketone bodies, hypoxanthine, phenylalanine, and glutamate levels in BC patients reflects altered glycolysis, fatty acid, purine, and amino acid metabolism, respectively. In addition, TMAO may play a role in the development of BC by promoting a pro-inflammatory and oxidative stress state. Furthermore, monitoring these metabolites could be a useful tool for predicting response to treatments. To our knowledge, there are no metabolomic studies that evaluated BC patients receiving CT and that included longitudinal monitoring to identify any changes in the metabolic profile induced by treatment.

The Evaluation of Vascular Endothelial Growth Factor A (VEGFA) and VEGFR2 Receptor as Prognostic Biomarkers in Bladder Cancer

Vascular endothelial growth factor (VEGF) and its receptors (VEGFR1 and VEGFR2) are the most important tissue factors involved in tumor growth and angiogenesis. The aim of this study was to evaluate the promoter mutational status of VEGFA and the expression levels of VEGFA, VEGFR1, and VEGFR2 in bladder cancer (BC) tissues and to correlate the results with the clinical-pathological parameters of BC patients. A total of 70 BC patients were recruited at the Urology Department of the Mohammed V Military Training Hospital in Rabat, Morocco. Sanger sequencing was performed to investigate the mutational status of VEGFA, and RT-QPCR was used to evaluate the expression levels of VEGFA, VEGFR1, and VEGFR2. Sequencing of the VEGFA gene promoter revealed the presence of -460T/C, -2578C/A, and -2549I/D polymorphisms, and statistical analyses showed a significant correlation between -460T/C SNP and smoking (p = 0.02). VEGFA and VEGFR2 expressions were significantly up-regulated in patients with NMIBC (p = 0.003) and MIBC (p = 0.03), respectively. Kaplan-Meier analyses showed that patients with high VEGFA expression had significantly longer disease-free survival (p = 0.014) and overall survival (p = 0.009). This study was very informative, showing the implication of VEGF alterations in BC, suggesting that VEGFA and VEGFR2 expressions could be promising biomarkers for the better management of BC.

Identification of immunotherapy-related lncRNA signature for predicting prognosis, immunotherapy responses and drug candidates in bladder cancer

BackgroundBladder cancer (BC) is one of the most common malignant diseases and the most common causes of cancer death worldwide. Immunotherapy has opened new avenues for precision treatment of bladder tumours, and immune checkpoint inhibitors (ICIs) have revolutionized the clinical treatment strategy of bladder tumours. In addition, long non-coding RNA (lncRNA) plays an important role in regulating tumour development and immunotherapy efficacy.MethodsWe obtained genes with significant differences between anti-PD-L1 response and non-response from the Imvogor210 data set and combined with the bladder cancer expression data in the TCGA cohort to obtain immunotherapy-related lncRNA. Based on these lncRNAs, the prognostic risk model of bladder cancer was constructed and verified by GEO external data set. The characterization of immune cell infiltration and immunotherapy effects between high-risk and low-risk groups were then analysed. We predicted the ceRNA network and performed molecular docking of key target proteins. The functional experiments verified the function of SBF2-AS1.ResultsThree immunotherapy-related lncRNAs were identified as independent prognostic biomarkers for bladder cancer and a prognostic model of immunotherapy-related prognosis was constructed. Prognosis, immune cell infiltration, and immunotherapy efficacy were significantly different between high- and low-risk groups based on risk scores. Additionally, we established a ceRNA network of lncRNA(SBF2-AS1)-miRNA(has-miR-582-5p)-mRNA (HNRNPA2B1). Targeting the protein HNRNPA2B1 identified the top eight small molecule drugs with the highest affinity.ConclusionWe developed a prognostic risk score model based on immune-therapy-related lncRNA, which was subsequently determined to be significantly associated with immune cell infiltration and immunotherapy response. This study not only helps to promote our understanding of immunotherapy-related lncRNA in the prognosis of BC, but also provides new ideas for clinical immunotherapy and the development of novel therapeutic drugs for patients.

Screening ANLN and ASPM as bladder urothelial carcinoma-related biomarkers based on weighted gene co-expression network analysis.

Introduction: Bladder cancer (BLCA) is one of the most common malignancies in the urinary system with a poor prognosis and high treatment costs. Identifying potential prognostic biomarkers is significant for exploring new therapeutic and predictive targets of BLCA. Methods: In this study, we screened differentially expressed genes using the GSE37815 dataset. We then performed a weighted gene co-expression network analysis (WGCNA) to identify the genes correlated with the histologic grade and T stage of BLCA using the GSE32548 dataset. Subsequently, Kaplan Meier survival analysis and Cox regression were used to further identify prognosis-related hub genes using the datasets GSE13507 and TCGA-BLCA. Moreover, we detected the expression of the hub genes in 35 paired samples, including BLCA and paracancerous tissue, from the Shantou Central Hospital by qRT-polymerase chain reaction. Results: This study showed that Anillin (ANLN) and Abnormal spindle-like microcephaly-associated gene (ASPM) were prognostic biomarkers for BLCA. High expression of ANLN and ASPM was associated with poor overall survival.The qRT-PCR results revealed that ANLN and ASPM genes were upregulated in BLCA, and there was a correlation between the expression of ANLN and ASPM in cancer tissues and paracancerous tissue. Additionally, the increasing multiples in the ANLN gene was obvious in high-grade BLCA. Discussion: In summary, this preliminary exploration indicated a correlation between ANLN and ASPM expression. These two genes, serving as the risk factors for BLCA progression, might be promising targets to improve the occurrence and progression of BLCA.

Expression pattern of the histone lysine demethylase family and its potential role in bladder cancer: a multi-omics analysis

To investigate the expression patterns of 19 histone lysine demethylases (KDMs) and their role in bladder cancer. In this study, UALCAN and GSCALite were used to analyze the transcriptional expression, methylation level and somatic variation of KDMs in bladder cancer samples from TCGA. Kaplan Meier-Plotter and Assistant for clinical bioinformatics were used to investigate the effect of KDMs expression on the prognosis of BLCA samples. The immune infiltration and drug sensitivity of KDMs in bladder cancer were analyzed by Timer and GSCALite. The KDMs did not show consistent expressions patterns in bladder cancer, where the expressions of KDM1A/1B/2B/4A/4B/5B/5C were significantly upregulated while those of KDM3B/6B/7C were significantly downregulated. Methylation data analysis showed that methylation levels of KDM1A/3B/4A/4B/4C/5A/5B/5C/7B were significantly downregulated and that of KDM7C was upregulated. The transcription levels of 14 KDMs had significant negative correlations with their methylation levels, and among them KDM1A showed the strongest correlation. Mutation analysis revealed that KDM6A had the highest frequency of nonsynonymous mutations with the largest variety, and these mutations were complementary to nonsynonymous mutations of the other KDMs. Survival analysis showed that KDM3A/4C/5D/6A/7B were protective for OS while KDM3B/5B/5C adversely affected RFS of BLCA patients. Further comprehensive prognostic modeling confirmed that KDM4C/6A/7B were potential prognostic biomarkers of bladder cancer, and their expressions were positively correlated with immune infiltration in BLCA patients. KDM2B/3B/4B/4C/5A were negatively correlated with the sensitivity to most anticancer drugs, while KDM2B/4B were positively correlated with the sensitivity to 4 anticancer drugs. The expression patterns of the KDMs in bladder cancer highlight a high mutation complementarity and a negative correlation between over-expression and hypomethylation level closely related with the prognosis, immune infiltration and drug sensitivity.

Prognostic Signature GXYLT2 Is Correlated with Immune Infiltration in Bladder Cancer.

Background GXYLT2 (glucoside xylosyltransferase 2) was known as an important gene that regulates classical Notch signaling and is involved in progression in human tumors. However, the correlation between GXYLT2 expression and bladder cancer remains unclear. Methods GXYLT2 expression was analyzed by ONCOMINE database, GEPIA database, and TIMER database. The Cancer Genome Atlas (TCGA) was utilized to confirm relationships between GXYLT2 and molecular subtypes of BLCA (bladder cancer). We discovered prognostic value of GXYLT2 in BLCA using GEPIA, LinkedOmics database, and Kaplan-Meier Plotter database. Subsequently, correlations between GXYLT2 and tumor immune infiltration were investigated through TIMER and TISIDB website. We then downloaded data of patients with BLCA from TCGA website, to conduct functional annotations and to construct protein-protein interaction network through STRING and Enrich web servers. Results Significant differences were observed between GXYLT2 expression of bladder cancer and normal tissues. GXYLT2 was a poor prognostic biomarker in BLCA with impact on diverse clinical characteristics. We found that GXYLT2 was closely related to tumor immune infiltrated cells and immune genes. Functional annotations indicated that GXYLT2 was linked to immune-related pathways. Conclusions The results suggested that GXYLT2 was associated with a poor prognosis and tumor immune cell infiltration of BLCA. GXYLT2 could be a promising therapeutic target in bladder cancer.

Interaction between HER2 and ATM predicts poor survival in bladder cancer patients.

Human Epidermal Growth Factor Receptor 2 (HER2) overexpression is considered one of the interesting prognostic biomarkers in bladder cancer. However, the mechanism of bladder cancer development in relation to HER2 status remains to be elucidated. In this study, we investigated HER2‐Ataxia telangiectasia mutated (ATM) kinase interaction and their impact on patient survival and cancer aggressiveness. Using the Cancer Genome Atlas (TCGA) cohorts, we demonstrated that ATM expression (protein/mRNA) is increased in HER2 deficient compared with proficient HER2 patients. This finding was then validated using the Gene Expression Omnibus database (GEO). Correlation analysis (using low expression vs high expression as a discriminator) revealed a significant association of ATM low and HER2 high status with several clinicopathological variables such as high tumour grade, late disease stage and tumour shape. Kaplan–Meier survival analysis indicated that ATM low and HER2 high is a powerful prognosticator of both overall survival (OS) and disease‐free survival (DFS). Furthermore, using bioinformatics and protein/protein interaction analyses, we identified 66 putative overlapping proteins with direct link between HER2 and ATM most of which are functionally involved in transcription regulation, apoptotic process and cell proliferation. Interestingly, the results showed that these proteins are strongly linked with PI3K‐Akt pathway, p53 pathway and microRNAs in cancer. Altogether, our data pinpoint an important biological role of the interconnection between HER2 and ATM. The latter appear to be an independent prognostic biomarker and may serve as targets to develop novel combination therapies to improve the outcome of patients with bladder cancer.

Identification of ISCA1 as novel immunological and prognostic biomarker for bladder cancer.

BackgroundIron-sulfur cluster assembly 1 (ISCA1) has a significant effect on respiratory complexes and energy metabolism. Although there is some evidence that ISCA1 gene expression impacts energy metabolism and consequently has a role in tumorigenesis and cancer metastasis in different types of malignancies, no systematic pan-cancer study of the ISCA1 has been conducted. As a result, we sought to investigate ISCA1’s predictive value in 33 cancer types as well as its possible immunological function.MethodsWe included the pan-cancer expression profile dataset and clinical data from the public database. Firstly, the single-sample Gene Set Enrichment Analysis (ssGSEa) approach was employed for analyzing the immune link in pan-cancer, while the limma package was utilized for analyzing the differential expression in cancer species. Subsequently, ciberport, MCP-counter, TIMER2, quanTIseq, and xCELL were employed for analyzing bladder cancer (BLCA)’s immune infiltration. Least absolute shrinkage and selection operator (Lasso) were employed for choosing the best gene to develop the immune risk scoring model.Results ISCA1 gene expression was positively related to four immune signatures (chemokine, immunostimulator, MHC, and receptor) in BLCA. Samples of BLCA were sorted into two groups by the best cut-off of ISCA1 expression degree. The group with a high level of ISCA1 expression had a higher risk, suggesting that the ISCA1 gene was a risk factor in BLCA, and its high expression resulted in a poorer prognosis. Additionally, it was noted that ISCA1 was positively linked with these immune checkpoints. Moreover, there was a considerable positive link between ISCA1 and different immune properties in subgroups with different immune checkpoint inhibiting responses. Finally, an immune risk scoring model was made and it showed a better score in comparison to that of TIDE.Conclusion ISCA1 can be a prognostic marker for a variety of cancers, particularly BLCA. Its high level of expression has a deleterious impact on the prognosis of BLCA patients. This strongly shows that ISCA1 is a significant prognostic factor for BLCA and that it could be used as a new prognostic detection target and treatment approach.

Identification of Long Non-Coding RNA MIR4435-2HG as a Prognostic Biomarker in Bladder Cancer.

The abnormal expression of long non-coding RNAs(lncRNAs) is closely related to the prognosis of patients. This finding may indicate a new target for the treatment of malignant tumors. Non-muscle invasive bladder cancer (NMIBC) is the most common subtype of bladder cancer, and BCG intravesical therapy is the first-line treatment for NMIBC, but about half of NMIBC patients relapse within two years after BCG treatment. Therefore, it is necessary to screen out lncRNAs related to the prognosis and treatment of BGC-resistant patients. Here, we performed differential expression analysis of lncRNAs in the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, and screened MIR4435-2HG as the only BCG-response-related lncRNA. Then, the prognosis value of MIR4435-2HG was validated in several publicly available cohorts, and confirmed its prognostic value in bladder cancer of different stages. In addition, we also analyzed its genetic alterations, clinical relevance, function enrichment, and association with other biomarkers. Further validation of the expression of MIR4435-2HG might be helpful to instruct NMIBC prognosis and treatment.

NEAT1/MALAT1/XIST/PKD--Hsa-Mir-101-3p--DLGAP5 Axis as a Novel Diagnostic and Prognostic Biomarker Associated With Immune Cell Infiltration in Bladder Cancer.

Background: The clinical value of the biomarkers of bladder cancer (BC) is limited due to their low sensitivity or specificity. As a biomarker, DLG associated protein 5 (DLGAP5) is a potential cell cycle regulator in cancer cell carcinogenesis. However, its functional part in BC remains unclear. Therefore, this study aims to identify DLGAP5 expression in BC and its potential diagnostic and prognostic values. Eventually, it predicts the possible RNA regulatory pathways of BC. Methods: Data on DLGAP5 expression levels in BC and normal bladder tissues were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. The receiver operating characteristic (ROC), Kaplan–Meier survival curves, and the univariate and multivariate Cox regression analysis determined the diagnostic and prognostic values of DLGAP5 in BC patients. Finally, the StarBase predicted the target RNAs and constructed networks using Cytoscape. Results: DLGAP5 expression was significantly upregulated in BC tissue, verified by the TCGA (p < 0.001), GSE3167, GSE7476, and GSE65635 datasets (p < 0.01). BC patients with increased DLGAP5 had poor overall survival (OS) (p = 0.01), disease specific survival (DSS) (p = 0.006) and progress free interval (DFI) (p = 0.007). The area under the ROC curve (AUC) was 0.913. The multivariate Cox analysis identified that lymphovascular invasion (p = 0.007) and DLGAP5 (p = 0.002) were independent prognostic factors. Conclusion: Increased DLGAP5 expression was closely associated with a poor prognosis in BC patients. In this case, DLGAP5 might be a diagnostic and prognostic biomarker for BC. DLGAP5 expression might be regulated by NEAT1/MALAT1/XIST/PKD--Hsa-mir-101-3p pathways.