Data Of Bladder Cancer Patients Research Articles

Identification of a pyroptosis-immune-related lncRNA signature for prognostic and immune landscape prediction in bladder cancer patients

PurposeIndividualized medicine has become increasingly important in bladder cancer treatment, whereas useful biomarkers for prognostic prediction are still lacking. The current study, therefore, constructed a novel risk model based on pyroptosis- and immune-related long noncoding RNAs (Pyro-Imm lncRNAs) to evaluate the potential prognosis of bladder cancer.MethodsCorresponding data of bladder cancer patients were downloaded from the Cancer Genome Atlas (TCGA) database. The univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression analysis, and multivariate Cox regression analysis were employed to establish a predictive signature, which was evaluated by receiver operator characteristic (ROC) analysis and Kaplan–Meier analysis. Furthermore, the immune infiltration, immune checkpoints, and responses to chemotherapeutic drugs were analyzed with this model.ResultsThree Pyro-Imm lncRNAs (MAFG-DT, AC024060.1, AC116914.2) were finally identified. Patients in the low-risk group demonstrated a significant survival advantage. The area under the ROC curve (AUC) at 1, 3, and 5 years was 0.694, 0.709, and 0.736 respectively in the entire cohort. KEGG and GO analyses showed that the Wnt pathway plays a crucial role in the high-risk group. The risk score was significantly related to the degree of infiltration of different immune cells, the expression of multiple immune checkpoint genes, and the sensitivity of various chemotherapeutic drugs.ConclusionThis novel signature provides a theoretical basis for cancer immunology and chemotherapy, which might help develop individualized therapy.

Establishment of prognostic model of bladder cancer based on apoptosis-related genes, in which P4HB promotes BLCA progression

BackgroundA variety of apoptosis genes have been confirmed to be related to the occurrence and development of bladder cancer patients, but few studies have paid attention to their significance in the prognosis of bladder cancer. Therefore, this study explored the value of apoptosis-related genes in the prognosis of BLCA by using the data in TCGA database.MethodsWe downloaded the mRNA expression profiles and corresponding clinical data of bladder cancer patients from TCGA database, and obtained 2411 apoptosis-related genes from Deathbase database. Screening out differentially expressed apoptosis-related genes. Cox regression was used to determine the prognostic value of apoptosis-related genes, and then a prognostic risk model was developed. A nomogram based on risk model was constructed to predict the prognosis of bladder cancer patients. At the same time, immune infiltration correlation analysis of genes in the prognosis model.ResultsA prognostic model composed of 12 apoptosis-related genes was constructed. According to the risk score calculated by the model, patients were divided into high-risk group and low-risk group. There are significant differences in the expression of immune cells, immune function and immune checkpoint molecules between high-risk group and low-risk group. P4HB may promote bladder cancer progression.ConclusionBased on the differential expression of apoptosis-related genes, we established a risk model to predict the prognosis of bladder cancer patients, in which P4HB promotes BLCA progression.

A novel signature constructed by differential genes of muscle-invasive and non-muscle-invasive bladder cancer for the prediction of prognosis in bladder cancer.

Bladder cancer (BCa) is a malignant tumor that usually forms cancer cells in the inner lining of the bladder. Hundreds of thousands of people worldwide have BCa diagnosed each year. The purpose of this study was to construct a prognostic model by differential expression of genes between muscular and non-muscular invasive BCa, and to investigate the prognosis of BCa patients. The data of BCa patients was sourced from the GEO and TCGA database. Single-cell sequencing data was obtained from three patients in the GSE135337 database, and microarray data for verification was obtained from GSE32894. Univariate, Lasso and multivariate cox regression analyses were performed to construct the prognostic model. The prognostic features, immune features and drug sensitivity of the model were further evaluated. Single-cell data and microarray data were used to validate the differential expression of model genes between muscle-invasive and non-muscle-invasive BCa. The invasion and migration of BCa cells were evaluated using the transwell assay and wound-healing assay. The cell proliferation capacity was simultaneously evaluated using Colony formation experiments. The protein expression of the specific gene was detected by western blot analysis. We identified 183 differentially expressed muscle-invasive-related differential genes (MIRDGs), among which four were selected to establish a prognostic model. Based on our signature, patients in different groups displayed varying levels of immune infiltration and immunotherapy profiles. Single-cell sequencing data and microarray data confirmed that four invasion-related genes were expressed at higher levels in muscle-invasive BCa. Given the critical role of S100A9 in the progression of BCa, we performed further analysis. The results showed that protein expression of S100A9 was high in muscle-invasive BCa, and S100A9 knockdown could inhibit the proliferation, migration and invasion of BCa. These findings demonstrated that the prognostic model for BCa patients was reasonably accurate and valid, and it may prove to be of considerable value for the treatment and prognosis of BCa patients in the future. S100A9 may become a better prognostic marker and potential therapeutic target to further guide clinical treatment decisions.

Hub gene associated with prognosis in bladder cancer is a novel therapeutic target.

Bladder cancer is a clinical and social conundrum due to its high incidence and recurrence rate. It is urgent to find new targets for the diagnosis and treatment of bladder cancer and improve the prognosis and survival rate of bladder cancer patients. We sought a prognosis-related gene, built related models of evaluated bladder cancer and identified the function of the hub gene in bladder cancer. We downloaded the data of bladder cancer patients from the TCGA database, and used differentially expressed genes (DEGs), copy number variation (CNV) and survival analysis to scan the hub genes associated with prognosis in bladder cancer. Then, multi-factor cox regression was used to obtain the bladder cancer prognosis correlation model. Then, we analyzed the relationship between the expression of hub gene and immune microenvironment of bladder cancer. The relationship between the expression of hub gene and prognosis in bladder cancer patients was verified by immunohistochemistry. Cell proliferation assay and drug sensitivity test in vivo were used to verify the inhibition of bladder cancer by targeted inhibitors. In bladder cancer, we screened seven hub genes (ACLY, CNP, NKIRAS2, P3H4, PDIA6, VPS25 and XPO1) associated with survival. Moreover, the multifactor regression model constructed with hub gene can well distinguish the prognosis of bladder cancer. Hub gene is mostly associated with immune microenvironment. Immunohistochemical results basically confirmed the importance of XPO1 in bladder cancer. Selinexor (an inhibitor of XPO1) could effectively inhibit the proliferation of bladder cancer in the cell proliferation experiments by CCK-8 assays and it could suppress the growth of bladder cancer in mouse bladder cancer model. In this study, a prognostic model with seven hub genes has provided great help for the prognosis prediction of bladder cancer patients. And XPO1 is an important target affecting the prognosis of bladder cancer, and inhibition of XPO1 can effectively inhibit bladder cancer proliferation and growth.

Prediction of immune and targeted drug efficacy in pain-related risk subtypes for bladder cancer patients

Bladder cancer is a complex disease with high morbidity and mortality rates. At least 430,000 cases are diagnosed annually worldwide. Cancer pain is the most common and distressing symptom in cancer patients. Studies have reported depression, anxiety, and decreased quality of life in survivors of various cancers. The study of pain-related genes in cancer patients may provide a basis for developing targeted drugs for cancer therapy, which could reduce pain and improve quality of life of cancer patients. In this study, the mRNA expression and clinical data of bladder cancer patients were downloaded from public databases. A total of 103 pain-related genes were also downloaded from the public databases. Univariate Cox regression analysis identified 17 pain-related genes that were significantly associated with overall survival. We calculated a pain-related risk score for each patient, constructed a bladder cancer pain risk model, and categorized bladder cancer patients into two risk subtypes. Differences in prognosis, differential gene expression, immune cell signatures, hallmarks, metabolic pathways, and somatic mutations between the different risk subtypes were systematically investigated. Eight drugs associated with bladder cancer risk subtypes were identified. Their differences in the high- and low-risk subtypes of bladder cancer were examined. In addition, the response to immunotherapy was analyzed in patients with different pain-related subtypes. Results revealed significant differences in these characteristics. Finally, a predictive model for pain-related risk subtypes in patients with bladder cancer was established. The study findings provide a reference for prognostication and personalized medical treatment of bladder cancer patients.

Validation and reliability of the Dutch version of the EORTC QLQ-BLM30 module for assessing the health-related quality of life of patients with muscle invasive bladder cancer

BackgroundQuality of Life (QoL) of bladder cancer patients has been largely neglected. This is partly due to the lack of well-validated QoL questionnaires. The aim of this study is to examine the structural validity, reliability (i.e., internal consistency and test-retest reliability), construct validity (i.e., divergent validity and known group validity) and responsiveness of the Dutch version of the European Organisation for Research and Treatment of Cancer QoL questionnaire for muscle invasive bladder cancer (EORTC-QLQ-BLM30).MethodsPatients with newly diagnosed muscle invasive bladder cancer (MIBC) participating in the population-based ‘Blaaskankerzorg In Beeld’ (BlaZIB) study who completed the EORTC-QLQ-BLM30 at baseline were included. BlaZIB is a Dutch nationwide population-based prospective cohort study collecting clinical data and QoL data of bladder cancer patients. QoL is assessed with a self-administered questionnaire at four points in time: 6 weeks (baseline), 6 months, 12 months and 24 months after diagnosis. Confirmatory factor analysis and multitrait scaling analysis were used to investigate and adapt the scale structure. Reliability, construct validity and responsiveness of the revised scales were evaluated.ResultsOf the 1542 patients invited to participate, 650 patients (42.2%) completed the QLQ-BLM30 at baseline. The questionnaire’s scale structure was revised into seven scales and eight single items. Internal consistency and test-reliability were adequate for most scales (Cronbach’s α ≥0.70 and intraclass correlation coefficient ≥ 0.70, respectively), with the exception of the revised urostomy problem scale and abdominal bloating and flatulence scale. The questionnaire exhibited little overlap with the EORTC-QLQ-C30: all correlations were < 0.40, except for the correlation between emotional function (QLQ-C30) and future worries (QLQ-BLM30). The questionnaire was able to distinguish between patient subgroups formed on the basis of physical function, but not – as hypothesized– based on stage. Changes in health due to treatment were captured by the questionnaire, indicating that the questionnaire is responsive to change.ConclusionsThis study shows that the adapted scale structure of the EORTC-QLQ-BLM30 generally exhibits good measurement properties in Dutch patients, but needs to be validated in other languages and settings.Trial registrationBlaZIB, NL8106, www.trialregister.nl

Bioinformatics analysis of prognosis and immune microenvironment of immunological cell death-related gemcitabine-resistance genes in bladder cancer.

Bladder cancer (BC) is the most common malignant tumor of the urinary system. Gemcitabine resistance partly accounts for treatment failure and recurrence in BC. Immunological cell death (ICD) is correlated with chemoresistance. The prognosis of patients with similar tumor stage still varies in response to chemotherapy, recurrence, and disease progression. Therefore, our study aimed to provide a prognostic model based on ICD-related and gemcitabine-resistance genes for BC. The data of BC patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs), and differentially expressed gemcitabine resistance-related genes (DEGRRGs) were identified using the edgeR package. The survival-associated DEGRRGs were identified by univariate Cox analysis. A prognostic model was established by univariate Cox regression analysis and validated by GEO dataset. The outcome of low-risk group and high-risk group was analyzed by the Kaplan-Meier curve. The relationship between risk score and immune cell infiltration was investigated using the TIMER online database. The prognosis of patients in the ICD-high group was significantly better than ICD-low group. A prognostic model containing 5 gemcitabine resistance-related ICD-associated genes, including PTPRR, HOXB3, SIGLEC15, UNC5CL, and CASQ1, was established. In both TCGA prognostic model and GEO validation model, patients in the low-risk group had better outcomes than high-risk group. According to the receiver operating characteristic (ROC) curves, the risk score area under ROC curve (AUC) of the TCGA prognostic model were calculated to be 0.705, while the risk score of the GEO validation model were calculated to be 0.716. Patients in the high-risk group had a significantly higher immune score, stromal score, and infiltration of M0 macrophages, M1 macrophages, M2 macrophages, and activated CD4+ T cells. Patients in the high-risk group had significantly lower infiltration of the regulatory T cells, resting dendritic cell (DCs), and activated DCs. The present study highlighted the functional role of gemcitabine resistance-related ICD-associated genes, constructed a prognostic score for the outcome evaluation and searched for potential targets to overcome gemcitabine chemoresistance in BC.

A pyroptosis-related lncRNA signature in bladder cancer.

Pyroptosis, a type of programmed cell death, is implicated in the tumorigenesis, development and migration of cancer, which can be regulated by long non-coding RNAs (lncRNAs). Our research aimed to investigate the prognostic role of pyroptosis-related lncRNAs and the relationship to the tumor immune microenvironment through bioinformatics analysis. The clinical and RNA-sequencing data of bladder cancer patients were downloaded from The Cancer Genome Atlas (TCGA). And 412 bladder cancer subjects with clinical information were divided into training and testing cohort. And 52 reported pyroptosis-related genes were used to screen pyroptosis-related lncRNAs. A pyroptosis-related lncRNA signature was constructed based on Cox regression analyses. A 9-pyroptosis-related-lncRNA signature was identified to separate patients with bladder cancer into two groups. The prognosis of bladder cancer patients in the high-risk group was significantly inferior compared with those in the low-risk group. Risk scores were validated to develop an independent prognostic indicator based on multivariate Cox regression analysis. Receiver operating characteristic curve (ROC) analysis examined the signature on overall survival. The area under time-dependent ROC curve (AUC) at 1-, 3, and 5-years measured 0.747, 0.783, and 0.768, respectively. Analysis of the immune landscape and PD-L1 expression showed that PD-L1 is upregulated in the high-risk group. The immunocyte subtypes of the two groups were different. A novel pyroptosis-related lncRNA signature was identified with prognostic value for bladder cancer patients. Pyroptosis-related lncRNAs have a potential role in cancer immunology and may serve as prognostic or therapeutic targets.

Implications for pelvic lymph node irradiation in definitive chemoradiotherapy of node negative muscle invasive bladder cancer based on predictive factors of clinicopathologic discrepancy.

To identify pre-surgical imaging predictive value and factors associated with the clinicopathologic discrepancy for implication of definitive pelvic radiotherapy in clinically node-negative bladder cancer. The documented data of bladder cancer patients who underwent radical cystectomy plus pelvic lymphadenectomy were collected retrospectively. Patients' characteristics, last imaging, pathology reports, disease-specific survival and overall survival were retrieved. From 142 patients, pre-surgical imaging had a sensitivity of 76.4%, specificity of 73.7%, positive predictive value (PPV) of 94.9%, and negative predictive value (NPV) of 32.6% (p value < 0.0001) for detection of muscle invasion. Also, for detection of positive lymph nodes, imaging had a sensitivity of 31.8%, specificity of 85.7%, PPV of 50%, and NPV of 73.7% (p value: 0.022). 44.4% of study population were upstaged after surgery (24.6% associated with N-upstaging) and 18.3% were downstaged (12% associated with N-downstaging). Receipt of neoadjuvant chemotherapy and T-stage were not correlated with N-upstaging. On multivariate analysis, lymphovascular invasion (LVI) maintained its significance for independent prediction of upstaging (OR 3.3, 95% CI 1.5-7.5, p value: 0.004) and inversely with downstaging (OR 0.34, 95% CI 0.12-0.96, p value: 0.04). Older age (OR 1.03, 95% CI 1.0-1.05, p value 0.047), positive margins (OR 2.1, 95% CI 1.2-3.8, p value 0.011), presence of LVI (OR 2.5, 95% CI 1.4-4.7, p value 0.003), perineural invasion (OR 2.0, 95% CI 1.2-3.4, p value 0.013), and lymph node ratio (OR 1.011, 95% CI 1.001-1.021, p value 0.03) were associated with worse survival. Also, N-upstaging independently predicted a worse survival after controlling for surgical pathology stage (OR 2.3, 95% CI 1.2-4.5, p value 0.011). The optimal target volume in definitive chemoradiotherapy of node-negative bladder cancer patients remains to be established. Since then, customizing the treatment is considered especially for positive LVI in TURBT specimen.

Trends in the cause of death among patients with bladder cancer in the US SEER population, 1992-2018.

Bladder cancer (BC) survival has shown no significant improvement. This study investigated the trends in the common causes of death among patients with BC to improve the management and survival of BC. The Surveillance, Epidemiology, and End Results (SEER) (1992-2018) database was utilized to get the data of BC patients. We presented the proportion of six common causes of death in BC patients. We calculated the annual incidence of death due to the six most common causes and analyzed temporal trends in mortality rates using joinpoint regression. The competitive risk model was utilized to analyze the risk factors for death of BC and other causes. 198037 BC patients were enrolled. BC was the most common cause of death (30.62%), followed by other cancers (22.22%), circulatory diseases (20.28%), non-disease causes (11.58%), other non-cancer diseases (8.29%), and respiratory diseases (7.01%). However, the proportion of cases dying from BC gradually decreased from 44.87% in 1992-1996 to 26.74% in 2012-2018. The proportion of deaths due to BC decreased gradually with survival time from diagnosis. Age-standardized temporal trends present an initial increase in BC-specific and other-cause mortality rates. Advanced stage and older age were the most influential risk factors for BC-specific and other-cause death, respectively. Although BC was still the leading cause of death, other causes, especially other cancers and circulatory diseases, gradually became more critical. The management of other comorbid conditions will be a crucial part of the treatment for BC patients, especially for those with prolonged survival and NMIBC tumors.

MHC-II Signature Correlates With Anti-Tumor Immunity and Predicts anti-PD-L1 Response of Bladder Cancer.

A large proportion of anti-tumor immunity research is focused on major histocompatibility complex class I (MHC-I) molecules and CD8+ T cells. Despite mounting evidence has shown that CD4+ T cells play a major role in anti-tumor immunity, the role of the MHC-II molecules in tumor immunotherapy has not been thoroughly researched and reported. In this study, we defined a MHC-II signature for the first time by calculating the enrichment score of MHC-II protein binding pathway with a single sample gene set enrichment analysis (ssGSEA) algorithm. To evaluate and validate the predictive value of the MHC class II (MHC-II) signature, we collected the transcriptome, mutation data and matched clinical data of bladder cancer patients from IMvigor210, The Cancer Genome Atlas (TCGA) databases and Gene Expression Omnibus (GEO) databases. Comprehensive analyses of immunome, transcriptome, metabolome, genome and drugome were performed in order to determine the association of MHC-II signature and tumor immunotherapy. We identified that MHC-II signature is an independent and favorable predictor of immune response and the prognosis of bladder cancer treated with immune checkpoint inhibitors (ICIs), one that may be superior to tumor mutation burden. MHC-II signature was significantly associated with increased immune cell infiltration and levels of immune-related gene expression signatures. Additionally, transcriptomic analysis showed immune activation in the high-MHC-II signature subgroup, whereas it showed fatty acid metabolism and glucuronidation in the low-MHC-II signature subgroup. Moreover, exploration of corresponding genomic profiles highlighted the significance of tumor protein p53 (TP53) and fibroblast growth factor receptor 3 (FGFR3) alterations. Our results also allowed for the identification of candidate compounds for combined immunotherapy treatment that may be beneficial for patients with bladder cancer and a high MHC-II signature. In conclusion, this study provides a new perspective on MHC-II signature, as an independent and favorable predictor of immune response and prognosis of bladder cancer treated with ICIs.

Prognosis Risk Model Based on Pyroptosis-Related lncRNAs for Bladder Cancer.

Objective Bladder cancer (BC) is the most common malignancy in the urinary system and is prone to recurrence and metastasis. Pyroptosis is a kind of cell necrosis that is triggered by the gasdermin protein family. lncRNAs are noncoding RNAs that are more than 200 nucleotides long. Both pyroptosis and lncRNAs are associated with tumor development and progression. This study is aimed at exploring and establishing a prognostic signature of BC based on pyroptosis-related lncRNAs. Methods In this study, The Cancer Genome Atlas (TCGA) database provided us with the RNA sequencing transcriptome data of bladder cancer patients, and we identified differentially expressed pyroptosis-related lncRNAs in bladder cancer. Then, the prognostic significance of these lncRNAs was assessed using univariate Cox regression analysis and LASSO regression analysis. Subsequently, 4 pyroptosis-related lncRNAs, namely, AL121652.1, AL161729.4, AC007128.1, and AC124312.3, were identified by multivariate Cox regression analysis, thus constructing the prognostic risk model. Then, we compared the levels of immune infiltration, differences in cell function, immune checkpoints, and m6A-related gene expression levels between the high- and low-risk groups. Result Patients were divided into low-risk or high-risk groups based on the median risk score. Kaplan–Meier survival analysis indicated that the overall survival of bladder cancer patients in the low-risk group was substantially superior to that in the high-risk group (p < 0.001). The receiver operating characteristic (ROC) curve further confirmed the credibility of our model. Moreover, gene set enrichment analysis (GSEA) indicated that these were different signal pathways significantly enriched between the two groups. Immune infiltration, immune checkpoint, and N6-methyladenosine-related gene analysis also reflected that there were notable differences between the two groups. Conclusion Therefore, this prognostic risk model is based on the level of pyroptotic lncRNAs, which is conducive to individualized assessment of the risk of patients and provides a reference for clinical treatment. This will also help provide insights into the prognosis and treatment of bladder cancer.

Bladder cancer biomarker screening based on non-targeted urine metabolomics.

Bladder cancer is one of the most common malignancies of the urinary system, and its screening relies heavily on invasive cystoscopy, which increases the risk of urethral injury and infection. This study aims to use non-targeted metabolomics methods to screen for metabolites that are significantly different between the urine of bladder cancer patients and cancer-free controls. In this study, liquid chromatography-mass spectrometry was used to analyze the urine of bladder cancer patients (n = 57) and the cancer-free controls (n = 38) by non-targeted metabolomic analysis and metabolite identification. The results showed that there were significant differences in the expression of 27 metabolites between bladder cancer patients and the cancer-free controls. In the multivariate statistical analysis of this study, the urinary metabolic profile data of bladder cancer patients were analyzed, and the receiver operating characteristic curve analysis showed that it is possible to perform non-invasive clinical diagnoses of bladder cancer through these candidate biomarkers.

Novel lncRNA LINC01614 Facilitates Bladder Cancer Proliferation, Migration and Invasion Through the miR-217/RUNX2/Wnt/β-Catenin Axis.

BackgroundLncRNA plays a vital role in tumorigenesis and development. This study aimed to explore the novel lncRNA affecting bladder cancer progression.MethodsThe open-access data of bladder cancer patients, including transcriptome profiles and corresponding clinical information were all obtained from The Cancer Genome Atlas database. All the statistical analysis were performed using R software, SPSS and GraphPad Prism 8. CCK8, colony formation, apoptosis detection and tumorigenicity assay were used to assess cell proliferation ability. Transwell assay and wound-healing assay were used to evaluate cell metastasis potential.ResultsOur result showed that the lncRNA LINC01614 was highly expressed in bladder cancer tissue and cell lines. Meanwhile, patients with high LINC01614 expression level tend to have poor clinical features and shorter survival time. Further experiments demonstrated that the inhibition of LINC01614 could significantly hamper the proliferation and invasion of bladder cancer cells. Then, we found that the LINC01614 could regulate RUNX2 expression through miR-137. GSEA analysis indicated that the Wnt/β-catenin signaling pathway might be the downstream pathway of LINC01614. Further experiments showed that the LINC01614 act as an oncogene in bladder cancer partly depending on the RUNX2/Wnt/β-catenin axis, making it an underlying therapeutic target.ConclusionIn all, LINC01614 facilitates bladder cancer cells proliferation, migration and invasion through the miR-217/RUNX2/Wnt/β-catenin axis.

Identification of a Novel Pyroptosis-Related Gene Signature for Predicting Prognosis in Bladder Cancer

Bladder cancer (BC) has an unpredictable prognosis. Pyroptosis is a novel form of programmed cell death. However, whether the pyroptosis-related genes have a prognostic value remains unknown. In this study, we downloaded the mRNA expression and clinical data of BC patients and used the LASSO Cox analysis was employed to build a signature. High-risk patients had a significantly lower overall survival (OS) (p < .0001). Single-sample gene set enrichment analysis (ssGSEA) indicated that the tumor immune microenvironment was different between the two risk groups. In conclusion, a pyroptosis-related signature can be used for OS prediction of patients with BCs.

Identification and validation of a hypoxia-related prognostic and immune microenvironment signature in bladder cancer

BackgroundBladder cancer is the leading causes of cancer-associated mortality and seriously affects population health. Hypoxia plays a key role in tumor development and immune escape, which contributes to malignant behaviors.MethodsIn this study, we analyzed the RNA-seq and clinical information of bladder cancer patients from The Cancer Genome Atlas (TCGA) database. To investigate the hypoxia-related prognostic and immune microenvironment in bladder cancer, we constructed a hypoxia-related risk model for overall survival (OS). The RNA-seq and clinical data of bladder cancer patients from the Gene Expression Omnibus (GEO) database were used as validation sets.ResultsThe hypoxia-related risk signature was significantly correlated with clinical outcomes and could independently predict OS outcomes. Furthermore, the hypoxia-related risk signature could effectively reflected the levels of immune cell type fractions and the expression of critical immune checkpoint genes were higher in the high-risk group compared to the low-risk group. We also validated the expression levels of the prognostic genes in bladder cancer and paracancerous tissue samples through qRT-PCR analysis.ConclusionWe established a 7 hypoxia-related gene (HRG) signature that can be used as an independent clinical predictor and provided a potential mechanism in bladder cancer immunotherapy.

Impact of Long Non-coding RNAs Associated With Microenvironment on Survival for Bladder Cancer Patients.

BackgroundCumulative evidence from several tumor studies, including bladder cancer, emphasizes the importance of the tumor microenvironment (TME) in tumorigenesis, development, and metastasis, which can be regulated by long non-coding RNAs (lncRNAs). This study aims to identify bladder cancer (BC) microenvironment–associated lncRNAs for their prognostic value predicting the survival of BC patients.MethodsThe data of BC patients regarding lncRNA expression and corresponding clinical characteristics were obtained from The Cancer Genome Atlas (TCGA). The Cox regression analysis and the least absolute shrinkage and selection operator (LASSO) regression analysis were performed to screen lncRNAs following the calculation of the immune score for each sample. For the screened lncRNAs, a risk score model was constructed to predict the survival, and 3- and 5-year overall survival (OS) rates were assessed using a nomogram. The calibration curve and concordance index (C-index) validated the performance of the nomogram. Finally, to explore the potential function related to the screened lncRNAs, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed.ResultsThe multivariate Cox regression analysis screened five TME-associated lncRNAs regarded as independent factors influencing the tumor progression. The corresponding risk score model was established as follows: (−0.15816 AC064805.1) + (0.10015 AC084033.3) + (−0.17977 AC092112.1) + (−0.05673AC103691.1) + (0.17789 AL391704.1) + (−0.16258 LINC00892). The C-index for the nomogram was 0.63 (95% CI: 0.625–0.635). Also, the calibration curve verified the predictive effectiveness by showing a good concordance between the nomogram prediction and the actual observation. GO and KEGG analysis demonstrated that six TME-associated lncRNAs were most likely linked to tumor metastasis and progression.ConclusionThe present study determined six lncRNAs as independent immuno-biomarkers in the TME, constructed a nomogram to predict their prognostic value, and investigated the potential biological processes to understand their regulatory roles in the progression of BC.

An improved ileal conduit surgery for bladder cancer with fewer complications

BackgroundRadical cystectomy and urinary diversion remains the standard surgical treatment for patients with muscle-invasive or high-risk or recurrent non-muscle-invasive bladder cancer. Although this approach prolongs patient survival remarkably, there are postoperative complications associated with urinary diversion. This study aimed to assess the efficacy of modified ileal conduit surgery for reducing early and late stoma- and ureteroileal anastomosis-related complications, as compared with conventional ileal conduit urinary diversion.MethodsWe retrospectively evaluated the clinical data of bladder cancer patients treated with radical cystectomy and ileal conduit urinary diversion at Sun Yat-sen University Cancer Center between January 1, 2000 and June 30, 2016. Ileal conduit was created by the conventional or a modified technique. The clinicopathologic features of the conventional and the modified ileal conduit groups were compared using the t test and the Chi square test. Multivariable logistic regression analysis and multivariable Cox regression analysis were performed to determine the odds of developing stoma- and ureteroileal anastomosis-related complications in the two groups.Results145 and 100 patients underwent the modified and conventional ileal conduit surgery, respectively. The two groups were comparable with regard to clinicopathologic features. The rate of stoma-related complications was significantly lower in the modified ileal conduit group than in the conventional ileal conduit group (0.7% vs. 17.0%, P < 0.001). No late stoma-related complications were seen in the modified ileal conduit group, but were seen in 13 (13.0%) patients in the conventional ileal conduit group. The rate of ureteroileal anastomosis-related complications was significantly lower in the modified ileal conduit group than in the conventional ileal conduit group (4.8% vs. 15.0%, P = 0.001). In multivariable analyses, the modified ileal conduit group was significantly less likely to develop stoma- (odds ratio [OR] = 0.024, 95% confidence interval [CI] 0.003–0.235; P = 0.001) or ureteroileal anastomosis-related complications (OR = 0.141, 95% CI 0.042–0.476; P = 0.002) than the conventional ileal conduit group.ConclusionsOur modified surgical technique for ileal conduit urinary diversion may be effective for reducing early and late complications related to the stoma and the ureteroileal anastomosis. Prospective randomized clinical trials are needed to confirm our results.

90 - Meta-analysis of clinicopathological and survival data of bladder cancer patients treated with platinum-based chemotherapy

90 - Meta-analysis of clinicopathological and survival data of bladder cancer patients treated with platinum-based chemotherapy

Abstract 2457: Investigating the functional significance of novel, recurrent noncoding mutations of TBC1D12 in bladder cancer

Abstract Somatic noncoding mutations remain widely unexplored despite examples of critical importance such as driver mutations in the promoter of the TERT gene. We recently identified novel somatic mutations in the regulatory Kozak sequence (just upstream of the translation start site) of TBC1D12 in ~15% of bladder cancer patients, making it one of the most frequently mutated noncoding regions in any cancer (Araya et. al 2016). TBC1D12 was not previously implicated in cancer, and little is currently known about its function. It is a member of the TBC1 superfamily, suggesting a role in intracellular trafficking as a RAB-specific GTPase-activating protein (GAP). To investigate the functional implications of TBC1D12 mutations in bladder cancer, we undertook a combined computational and experimental approach. We analyzed clinical correlates, identified downstream effector candidates, and assessed the impact of these mutations on gene expression. To determine the clinical relevance of the TBC1D12 mutation, we did correlation and survival analyses of clinical data of bladder cancer patients from TCGA. We found that TBC1D12 mutations confer slightly worse survival but were not linked to other clinical correlates. To identify potential downstream effectors, we used reverse phase protein array (RPPA) data from 127 patients to search for proteins that were differentially expressed or phosphorylated between patients with or without TBC1D12 mutations. We found differential expression of GSK3 and differential phosphorylation of p90RSK and c-Jun, suggesting three potential downstream effector candidates. Hierarchical clustering of RPPA data for these three proteins revealed 4 subgroups with distinct molecular phenotypes. Furthermore, most of the TBC1D12 mutants were clustered within one molecular subtype. To experimentally test these downstream effector candidates and identify new ones, we modulated the levels of TBC1D12 in bladder cancer cell line Ku-19-19 using overexpression plasmids or siRNAs. After validating that these transfections were effective in changing TBC1D12 expression, we performed RNA-Seq experiments. Results from this study are expected to be presented at the meeting. In summary, these studies suggest that the novel and recurrent noncoding mutations in TBC1D12 may affect patient survival and alter the expression or post-translational modification of downstream targets. Potential molecular mechanisms associated with the presence of TBC1D12 mutations will be discussed, and a series of follow-up studies are underway. These studies also demonstrate that applying both computational and experimental approaches can help develop and test evidence-based hypotheses, contributing to an understanding of the clinical and functional impact of TBC1D12. Citation Format: Angela S. Li, Jason A. Reuter, Can Cenik, Michael P. Synder. Investigating the functional significance of novel, recurrent noncoding mutations of TBC1D12 in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2457. doi:10.1158/1538-7445.AM2017-2457