Targeting splicing factors as molecular non-muscle invasive bladder cancer predictors.
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ABSTRACT:
SUBMITTER: Lee KH
PROVIDER: S-EPMC6323290 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
Publications
Targeting splicing factors as molecular non-muscle invasive bladder cancer predictors.
Lee Kyoung-Hwa KH Ku Ja Hyeon JH
Translational andrology and urology 20181201 Suppl 6
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Project description:MicroRNAs (miRNAs) are implicated in the development of nearly all cancers and may function as promising biomarkers for early detection, diagnosis and prognosis. We sought to investigate the role of serum miRNAs as potential diagnostic biomarkers or biomarkers of risk for early-stage bladder cancer. First, we profiled global serum miRNAs in a pilot set of 10 non-muscle invasive bladder cancer (NMIBC) cases and 10 healthy controls matched on age, gender and smoking status. Eighty nine stably detectable miRNAs were selected for further testing and quantification by high-throughput Taqman analysis using the Fluidigm BioMark HD System to assess their association with NMIBC risk in both discovery and validation sets totaling 280 cases and 278 controls. We found miR-409-3p and six miRNAs expression ratios were significantly associated with risk of bladder cancer in both discovery and validation sets. Interestingly, we identified expression of miR-409-3p and miR-342-3p inversely correlated with age and age of onset of NMIBC. A risk score was generated based on the combination of three miRNA ratios (miR-29a-3p/miR-222-3p, miR-150-5p/miR-331-3p, miR-409-3p/miR-423-5p). In dichotomized analysis, we found individuals with high risk score showed increased risk of bladder cancer in the discovery, validation, and combined sets. Pathway enrichment analyses suggested altered miRNAs and cognate target genes are linked to the retinoid acid receptor (RAR) signaling pathway. Overall, these results suggested specific serum miRNA signatures may serve as noninvasive predictors of NMIBC risk. Biological insights underlying bladder cancer development based on the pathway enrichment analysis may reveal novel therapeutic targets for personalized medicine.
| S-EPMC5871085 | biostudies-literature
Project description:Purpose: Bladder cancer (BCa) is generally considered one of the most prevalent deadly diseases worldwide. Patients suffering from muscle-invasive bladder cancer (MIBC) possess dismal prognoses, while those with non-muscle-invasive bladder cancer (NMIBC) generally have a favorable outcome after local treatment. However, some NMIBCs relapse and progress to MIBC, with an unclarified mechanism. Hence, insight into the genetic drivers of BCa progression has tremendous potential benefits for precision therapeutics, risk stratification, and molecular diagnosis. Methods: In this study, three cohorts profile datasets (GSE13507, GSE32584, and GSE89) consisting of NMIBC and MIBC samples were integrated to address the differently expressed genes (DEGs). Subsequently, the protein-protein interaction (PPI) network and pathway enrichment analysis of DGEs were performed. Results: Six collagen members (COL1A1, COL1A2, COL5A2, COL6A1, COL6A2, and COL6A3) were up-regulated and gathered in the ECM-receptor interaction signal pathway identified by KEGG pathway analysis and GSEA. Evidence derived from the Oncomine and TCGA databases indicated that the 6 collagen genes promote the progression of BCa and are negatively associated with patient prognosis. Moreover, taking COL1A1 as a further research object, the results showed that COL1A1 was up-regulated in MIBC and its knockdown significantly inhibited the proliferation, migration, and invasion of 5637 and T24 cells by inhibiting epithelial-mesenchymal transition (EMT) process and the TGF-β signaling pathway. Conclusion: With integrated bioinformatic analysis and cell experiments, we showed that 6 collagen family members are high progression risk factors and that they can be used as independent effective diagnostic and prognostic biomarkers for BCa.
| S-EPMC6511250 | biostudies-literature
Project description:Although non muscle-invasive bladder cancer can be treated successfully by surgical resection, there is a high rate of recurrence, which frequently develops into an invasive form of cancer. Due to the lack of marker molecules to predict recurrence, it is currently recommended that after resection each patient is screened via cystoscopy at least twice a year. This results in a psychic burden to the patient and substantial economic costs to the health care system. Using antibody microarrays targeting 724 different cancer-related proteins, we studied protein profiles of patients with and without recurrence. The analysis revealed 255 proteins of differential abundance. Most are involved in the regulation and execution of apoptosis and cell proliferation. For prognosis, a signature of 20 proteins was determined that predicts bladder cancer recurrence with 100% sensitivity and 80% specificity. As a measure of overall accuracy, the area under the curve (AUC) value was found to be 90%. This is well within a clinically relevant window of quality and should support decision making about the stringency of surveillance or even different treatment options.
2014-04-07 | E-MEXP-3625 | biostudies-arrayexpress
Project description:We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.
| S-EPMC5687509 | biostudies-literature
Project description:BackgroundBladder cancer is one of the most lethal malignancy in urological system, and 20-25% of bladder cancer patients are muscle invasive with unfavorable prognosis. However, the role of alternative splicing (AS) in muscle-invasive bladder cancer (MIBC) remains to be elucidated.MethodsPercent spliced in (PSI) data obtained from the Cancer Genome Atlas (TCGA) SpliceSeq database (n = 394) were utilized to evaluate the AS events in MIBC. Prognosis-associated AS events were screened out by univariate Cox regression. LASSO Cox regression was used to identify reliable prognostic patterns in a training set and further validated in a test set. Splicing regulatory networks were constructed by correlations between PSI of AS events and RNA expression of splicing factors.ResultsAs a result, a total of 2589 prognosis-related AS events in MIBC were identified. Pathways of spliceosomal complex (FDR = 0.017), DNA-directed RNA polymerase II, core complex (FDR = 0.032), and base excision repair (FDR = 0.038) were observed to be significantly enriched. Additionally, we noticed that most of the prognosis-related AS events were favorable factors. According to the LASSO and multivariate Cox regression analyses, 15-AS-based signature was established with the area under curve (AUC) of 0.709, 0.823, and 0.857 at 1-, 3-, and 5- years, respectively. The MIBC patients were further divided into high- and low-risk groups based on median risk sores. Interestingly, we observed that the prevalence of FGFR3 with mutations and focal amplification was significantly higher in low-risk group. Functional and immune infiltration analysis suggested potential signaling pathways and distinct immune states between these two groups. Moreover, splicing correlation network displayed a regulatory mode of prognostic splicing factors (SF) in MIBC patients.ConclusionsThis study not only provided novel insights into deciphering the possible mechanism of tumorgenesis and pathogenesis but also help refine risk stratification systems and potential treatment of decision-making for MIBC.
| S-EPMC9277948 | biostudies-literature
Project description:BackgroundMuscle-invasive bladder cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, but the diversity of their subtype sets impedes their clinical application.ObjectiveTo achieve an international consensus on MIBC molecular subtypes that reconciles the published classification schemes.Design, setting, and participantsWe used 1750 MIBC transcriptomic profiles from 16 published datasets and two additional cohorts.Outcome measurements and statistical analysisWe performed a network-based analysis of six independent MIBC classification systems to identify a consensus set of molecular classes. Association with survival was assessed using multivariable Cox models.Results and limitationsWe report the results of an international effort to reach a consensus on MIBC molecular subtypes. We identified a consensus set of six molecular classes: luminal papillary (24%), luminal nonspecified (8%), luminal unstable (15%), stroma-rich (15%), basal/squamous (35%), and neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics, including outcomes. We provide a single-sample classifier that assigns a consensus class label to a tumor sample's transcriptome. Limitations of the work are retrospective clinical data collection and a lack of complete information regarding patient treatment.ConclusionsThis consensus system offers a robust framework that will enable testing and validation of predictive biomarkers in future prospective clinical trials.Patient summaryBladder cancers are heterogeneous at the molecular level, and scientists have proposed several classifications into sets of molecular classes. While these classifications may be useful to stratify patients for prognosis or response to treatment, a consensus classification would facilitate the clinical use of molecular classes. Conducted by multidisciplinary expert teams in the field, this study proposes such a consensus and provides a tool for applying the consensus classification in the clinical setting.
| S-EPMC7690647 | biostudies-literature
Project description:High-grade T1 (HGT1) bladder cancer is the highest risk subtype of non-muscle-invasive bladder cancer with unpredictable outcome and poorly understood risk factors. Here, we examined the association of somatic mutation profiles with nonrecurrent disease (GO, good outcome), recurrence (R), or progression (PD) in a cohort of HGT1 patients. Exome sequencing was performed on 62 HGT1 and 15 matched normal tissue samples. Both tumor only (TO) and paired analyses were performed, focusing on 95 genes known to be mutated in bladder cancer. Somatic mutations, copy-number alterations, mutation load, and mutation signatures were studied. Thirty-three GO, 10 R, 18 PD, and 1 unknown outcome patients were analyzed. Tumor mutational burden (TMB) was similar to muscle-invasive disease and was highest in GO, intermediate in PD, and lowest in R patients (P = 0.017). DNA damage response gene mutations were associated with higher TMB (P < 0.0001) and GO (P = 0.003). ERCC2 and BRCA2 mutations were associated with GO. TP53, ATM, ARID1A, AHR, and SMARCB1 mutations were more frequent in PD. Focal copy-number gain in CCNE1 and CDKN2A deletion was enriched in PD or R (P = 0.047; P = 0.06). APOBEC (46%) and COSMIC5 (34%) signatures were most frequent. APOBEC-A and ERCC2 mutant tumors (COSMIC5) were associated with GO (P = 0.047; P = 0.0002). pT1b microstaging was associated with a genomic cluster (P = 0.05) with focal amplifications of E2F3/SOX4, PVRL4, CCNE1, and TP53 mutations. Findings were validated using external public datasets. These findings require confirmation but suggest that management of HGT1 bladder cancer may be improved via molecular characterization to predict outcome. SIGNIFICANCE: Detailed genetic analyses of HGT1 bladder tumors identify features that correlate with outcome, e.g., high mutational burden, ERCC2 mutations, and high APOBEC-A/ERCC2 mutation signatures were associated with good outcome.
| S-EPMC9361191 | biostudies-literature
Project description:BackgroundAlthough non muscle invasive bladder cancer (NMIBC) generally has a good long-term prognosis, up to 80% of patients will nevertheless experience local recurrence after the primary tumor resection. The search for markers capable of accurately identifying patients at high risk of recurrence is ongoing. We retrospectively evaluated the methylation status of a panel of 24 tumor suppressor genes (TIMP3, APC, CDKN2A, MLH1, ATM, RARB, CDKN2B, HIC1, CHFR, BRCA1, CASP8, CDKN1B, PTEN, BRCA2, CD44, RASSF1, DAPK1, FHIT, VHL, ESR1, TP73, IGSF4, GSTP1 and CDH13) in primary lesions to obtain information about their role in predicting local recurrence in NMIBC.MethodsFormaldehyde-fixed paraffin-embedded (FFPE) samples from 74 patients operated on for bladder cancer were analyzed by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA): 36 patients had relapsed and 38 were disease-free at the 5-year follow up. Methylation status was considered as a dichotomous variable and genes showing methylation ≥20% were defined as "positive".ResultsMethylation frequencies were higher in non recurring than recurring tumors. A statistically significant difference was observed for HIC1 (P = 0.03), GSTP1 (P = 0.02) and RASSF1 (P = 0.03). The combination of the three genes showed 78% sensitivity and 66% specificity in identifying recurrent patients, with an overall accuracy of 72%.ConclusionsOur preliminary data suggest a potential role of HIC1, GSTP1 and RASSF1 in predicting local recurrence in NMIBC. Such information could help clinicians to identify patients at high risk of recurrence who require close monitoring during follow up.
| S-EPMC4176288 | biostudies-literature
Project description:BACKGROUND:The high rate of non-muscle-invasive bladder cancer recurrence is a major challenge in patient management. miRNAs functionally regulate tumor cell proliferation and invasion, and have strong potential as biomarkers because they are robust to degradation. The objective of this project was to identify reproducible prognostic miRNAs in resected non-muscle-invasive bladder tumor tissue that are predictive of the recurrent tumor phenotype. METHODS:We utilized patients diagnosed with primary non-muscle-invasive bladder cancer in three independent cohorts for a biomarker discovery/validation approach. Baseline tumor tissue from patients with the clinically challenging, non-muscle-invasive primary low stage (Ta), high grade, and T1 tumors (tumors extending into the lamina propria) comprised the discovery cohort (n = 38). We isolated the tumor tissue RNA and assessed a panel of approximately 800 miRNAs. RESULTS:miR-26b-5p was the top-ranking prognostic tumor tissue miRNA, with a time-to-recurrence HR 0.043 for levels above versus below median, (P adj = 0.0003). miR-26b-5p was related to a dose-response reduction in tumor recurrence, and levels above the median were also associated with reduced time-to-progression (P adj = 0.02). We used two independent longitudinal cohorts that included both low-grade and high-grade Ta and T1 tumors for validation and found a consistent relationship between miR-26b-5p and recurrence and progression. CONCLUSIONS:Our results suggest that miR-26b-5p levels may be prognostic for non-muscle-invasive bladder cancer recurrence, and can feasibly be assessed in baseline tumor tissue from a wide variety of clinical settings. IMPACT:Early identification of those non-muscle-invasive bladder tumor patients with refractory phenotypes would enable individualized treatment and surveillance.
| S-EPMC6473178 | biostudies-literature
Project description:The biological behaviors, clinical treatment, prognosis of nonmuscle-invasive bladder cancers (NMIBCs) and muscle-invasive bladder cancers (MIBCs) are distinct. Therefore, we performed high-through microarray screening of mRNA expression in 30 bladder tumors, to filter out some of the differential expression genes in NMIBCs and MIBCs.A total of 11 Genes in MIBCs versus in NMIBCs were considered differentially transcribed if they were transcribed ≤2.0 fold change and p<0.001 by unpaired T-test, including 9 up-regulated genes and 2 down-regulated genes in MIBCs (NR4A2, PLK3, CYR61, APOLD1, C13ORF33, LIG4, RBMS3, PCK2, AK098422, HSD17B3, RTN4). These candidate genes were validated in further and provide further insight into the discovery of new putative markers to identify MIBCs preoperatively.
2018-12-01 | GSE77952 | GEO