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Assessment of prognostic implication of a panel of oncogenes in bladder cancer and identification of a 3-gene signature associated with recurrence and progression risk in non-muscle-invasive bladder cancer.

ABSTRACT: This study evaluated the prognostic value of a panel of 29 oncogenes derived from the analysis of The Cancer Genome Atlas (TCGA data) or from the recent literature on bladder tumors on a well-characterized series of muscle-invasive bladder cancer (MIBC) and non-MIBC (NMIBC) samples and tried to identify molecular prognostic markers. Mutations of HRAS, FGFR3, PIK3CA and TERT were found in 2.9%, 27.2%, 14.9% and 76.7% of tumor samples, respectively. Concerning NMIBC, on multivariate analysis, RXRA and FGFR3 levels were associated with recurrence-free survival (RFS) (p = 0.0022 and p = 0.0069) and RXRA level was associated with progression to muscle-invasive disease (p = 0.0068). We identified a 3-gene molecular signature associated with NMIBC prognosis. FGFR3 overexpression was associated with reduced response to Bacillus Calmette-Guerin treatment (p = 0.037). As regards MIBC, on multivariate analysis, ERCC2 overexpression was associated with RFS (p = 0.0011) and E2F3 and EGFR overexpression were associated with overall survival (p = 0.014 and p = 0.035). RT-PCR findings were confirmed by IHC for FGFR3. Genomic alterations in MIBC revealed in TCGA data also concern NMIBC and seem to be associated with prognosis in terms of recurrence and progression. Correcting these alterations by targeted therapies seems a promising pharmacological approach.

SUBMITTER: Le Goux C

PROVIDER: S-EPMC7538919 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Assessment of prognostic implication of a panel of oncogenes in bladder cancer and identification of a 3-gene signature associated with recurrence and progression risk in non-muscle-invasive bladder cancer.

Le Goux Constance C Vacher Sophie S Schnitzler Anne A Barry Delongchamps Nicolas N Zerbib Marc M Peyromaure Michael M Sibony Mathilde M Allory Yves Y Bieche Ivan I Damotte Diane D Pignot Geraldine G

Scientific reports 20201006 1

This study evaluated the prognostic value of a panel of 29 oncogenes derived from the analysis of The Cancer Genome Atlas (TCGA data) or from the recent literature on bladder tumors on a well-characterized series of muscle-invasive bladder cancer (MIBC) and non-MIBC (NMIBC) samples and tried to identify molecular prognostic markers. Mutations of HRAS, FGFR3, PIK3CA and TERT were found in 2.9%, 27.2%, 14.9% and 76.7% of tumor samples, respectively. Concerning NMIBC, on multivariate analysis, RXRA ...[more]

PMID: 33024200

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Project description:BackgroundBladder cancer (BC) is regarded as one of the most fatal cancer around the world. Nevertheless, there still lack of sufficient markers to predict the prognosis of BC patients. Herein, we aim to establish a prognosis predicting signature based on long-noncoding RNA (lncRNA) for the invasive BC patients.MethodsThe lncRNA expression profile was downloaded from The Cancer Genome Atlas (TCGA) database, along with the correlated clinicopathological information. The univariate Cox regression test was employed to screen out the recurrence-free survival (RFS)-related lncRNAs. Then, the LASSO method was conducted to construct the signature based on these RFS-related lncRNA candidates. Genes correlated with these fourteen lncRNAs were extracted from the mRNA expression profile, with the Pearson correlation coefficient > 0.60 or < - 0.40. Subsequently, the Proteomap pathway enrichment analyses were conducted to classify the function of these correlated genes. Furthermore, the multivariate analyses were executed to reveal the independent role of the proposed signature with the clinicopathological features.ResultsWe established an lncRNA-based RFS predicting signature by the LASSO Cox regression test, and proved its usage and stability on both the training and validation cohorts by the Kaplan-Meier and receiver operating characteristic (ROC) curves. Notably, the multivariate Cox regression analysis found that our classifier was an independent indicator for muscle-invasive BC patients rather than sex, age and tumor grade, with higher predictive value than the existing ones. Besides, we did the pathway analyses for these genes that highly correlated with the proposed fourteen lncRNAs, as well as the differentially expressed genes (DEGs) derived from the high-risk vs. low-risk groups, and the recurrence vs. non-recurrence groups, respectively. Notably, these results were consistent, and these genes were mostly enriched in the transcription factors, G protein-coupled receptors, MAPK signaling pathways, which were proved significantly associated with tumor progression and drug resistance.ConclusionsOur results suggested that the fourteen-lncRNA-based RFS predicting signature is an independent indicator for BC patients. Further prospective studies with more samples are needed to verify our findings.

Project description:BackgroundBladder 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.MethodsThe 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.ResultsWe 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.ConclusionThese 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.

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.

Dataset Information

Assessment of prognostic implication of a panel of oncogenes in bladder cancer and identification of a 3-gene signature associated with recurrence and progression risk in non-muscle-invasive bladder cancer.

Publications

Assessment of prognostic implication of a panel of oncogenes in bladder cancer and identification of a 3-gene signature associated with recurrence and progression risk in non-muscle-invasive bladder cancer.

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