Overall Survival In ccRCC Research Articles

Genome-wide screening and cohorts validation identifying novel lncRNAs as prognostic biomarkers for clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the main subtype of renal cell carcinoma with varied prognosis. We aimed to identify and assess the possible prognostic long noncoding RNA (lncRNA) biomarkers. LncRNAs expression data and corresponding clinical information of 619 ccRCC patients were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. Differentially expressed genes analysis, univariate Cox regression, the least absolute shrinkage and selection operator Cox regression model were utilized to identify hub lncRNAs. Multivariate Cox regression was used to establish the risk model. Statistical analysis was performed using R 3.5.3. The expression value of five lncRNAs and the risk-score levels were significantly associated with a survival prognosis of ccRCC patients (all P < .001). In the TCGA validation cohort, the area under the curve (AUC) for the integrated nomogram was 0.905 and 0.91 for 3-, 5-year prediction separately. The AUC reached up to 0.757 in an independent ICGC cohort. Besides, the calibration plots also illustrated well curve-fitting between observation values and predictive values. Weighted gene co-expression network analysis and subsequent pathway analysis revealed that the PI3K-Akt-mTOR and hypoxia-inducible factor signaling crosstalk might function as the most essential mechanisms related to the five-lncRNAs signature. Our study suggested that lncRNA AC009654.1, AC092490.2, LINC00524, LINC01234, and LINC01885 were significantly associated with ccRCC prognosis. The prognostic model based on this five lncRNA may predict the overall survival of ccRCC.

Prognostic significance of long non-coding RNAs in clear cell renal cell carcinoma: A meta-analysis.

Background:Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer in adults, and patients with advanced ccRCC have a 5-year survival rate of <30%. The poor prognosis of ccRCC is closely related to its lacking of potential therapeutic and prognostic biomarkers. This meta-analysis aimed to elucidate the precise prognostic value of long non-coding RNAs (lncRNAs) in patients with ccRCC.Methods:A literature search was performed in related databases up to January 31, 2019. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated to explore the relationship between special lncRNAs expression and survival in patients with ccRCC.Results:After literature researching, a total of 16 studies, including 13 lncRNAs were identified. The data from studies that investigated the association between lncRNA expression and survival outcomes in patients with ccRCC were extracted. Results revealed that lncRNAs expression was significantly associated with poor overall survival (OS) outcome in patients with ccRCC (HR = 1.71, 95%CI = 1.40–2.01 in up-regulated subgroup; HR = 0.53, 95% CI = 0.25–0.80 in down-regulated subgroup). The overexpression of PVT1 was significantly associated with poor OS in ccRCC (HR = 1.51, 95% CI = 1.02–2.00). Meanwhile, up-regulation of LUCAT1 was significantly related to worse OS in ccRCC patients (HR = 1.51, 95% CI = 1.01–2.00).Conclusions:These results suggest that lncRNAs could be used to predict unfavorable prognosis and function as potential prognostic biomarkers in ccRCC.

Three novel hub genes and their clinical significance in clear cell renal cell carcinoma.

Purpose. To investigate the association of biomarkers correlated with clinical stages and survival of clear cell renal cell carcinoma (ccRCC).Methods. The GSE36895 dataset was downloaded and differentially expressed or methylated genes were analyzed. Hub genes were identified with weighted gene co-expression network analysis (WGCNA) and protein-protein interaction network (PPI), and validated with TCGA database and our own tissues. The biological processes of hub genes were further explored by functional enrichment analysis. Survival analyses were also performed. The underlying mechanisms for ccRCC development were detected with Gene set enrichment analyses.Results. A total of 1624 differentially expressed genes were analyzed by WGCNA and 6 co-expressed gene modules were identified. Three hub genes (EHHADH, ACADM and AGXT2) were met the criterion of both WGCNA and PPI networks analysis, which showed highest negative association with pathological T stage (r = - 0.45, p = 0.01) and tumor grade (r = - 0.45, p = 0.01). The downregulation of these hub genes was validated with using both TCGA database and samples harvested at our institute The biological processes that hub genes involved, such as metabolic process (p = 9.63E - 09), oxidation-reduction process (p = 1.05E - 08) and oxidoreductase activity (p = 1.72E - 04), were revealed. Survival analysis showed a higher expression or lower methylation of these hub genes, a longer survival of ccRCC patients. ccRCC samples with higher expression of hub genes were enriched in gene sets correlated with signaling like biosynthesis of unsaturated fatty acids, butanoate metabolism, and PPAR signaling pathway.Conclusions. We identified three novel tumor suppressors associated with pathological T stage and overall survival of ccRCC. They might be potential as individualized therapeutic targets and diagnostic biomarkers for ccRCC.

Overexpression of G6PD Represents a Potential Prognostic Factor in Clear Cell Renal Cell Carcinoma.

Glucose-6-phosphate dehydrogenase (G6PD) participates in glucose metabolism and it acts as the rate-limiting enzyme of the pentose phosphate pathway (PPP). Recently, G6PD dysregulation has been found in a variety of human cancers. Through analyzing published data in The Cancer Genome Atlas (TCGA), our pilot study indicated that G6PD mRNA expression was significantly higher in advanced Fuhrman grade in clear cell renal cell carcinoma (ccRCC). These clues promoted us to further evaluate the expression profile of G6PD and its prognostic impact in patients with ccRCC. In this study, G6PD expression levels were analyzed in 149 human ccRCC and normal tissues using immunohistochemistry. The results showed that compared with that in the normal renal samples, G6PD was found highly expressed in 51.0% of ccRCC (p<0.05). High expression of G6PD was significantly correlated to tumor extent, lymph node metastasis, Fuhrman grade, and TNM stage of ccRCC (all p<0.05). Moreover, positive G6PD expression was associated with poorer overall survival in ccRCC (p<0.001). In Cox regression analyses, high expression of G6PD also could be an independent prognostic factor for overall survival in ccRCC (p=0.007). This study suggests that overexpression of G6PD is associated with advanced disease status and therefore may become an important prognosticator for poor outcomes in ccRCC, as well as a potential therapeutic target for developing effective treatment modalities.

Identification and validation of soluble carrier family expression signature for predicting poor outcome of renal cell carcinoma.

The soluble carrier (SLC) family plays an important role in cell metabolism. The purpose of the current study was to screen SLCs as potential prognostic factors in clear cell renal cell carcinoma (ccRCC). A total of 509 patients with ccRCC from The Cancer Genome Atlas (TCGA) cohort were enrolled in this study. The expression profile of SLCs was obtained from the TCGA RNAseq database. Metadata of the TCGA cohort, including age, sex, TNM stage, tumor grade, American Joint Committee on Cancer stage, laterality, and overall survival, were collected. Univariate and multivariate Cox proportional hazards regression models were used to analyze the relative factors. Prognosis-associated genes were further validated in a Fudan University Shanghai Cancer Center (FUSCC) cohort consisting of 178 patients. Among a total of 364 SLC transporters, 61 were independent predictors of ccRCC patient overall survival. Among the 61 SLC transporters, 26 were significantly downregulated and 23 were significantly upregulated in tumor tissues compared with non-malignant kidney tissues. Analyses of two open source, RNA expression data sets on sunitinib response revealed that SLC10A2 was downregulated in tyrosine kinase inhibitor-resistant samples. We validated SLC10A2 expression in the FUSCC cohort and showed that SLC10A2 expression was an independent prognostic predictor of overall survival of ccRCC (hazard ratio=0.432, 95% CI: 0.204-0.915). Our results identified a number of associations of SLC gene expression with prognosis of ccRCC patients, indicating that these genes may represent possible oncogenes that could serve as therapeutic targets of ccRCC.

Cooperative Effect of miR-141-3p and miR-145-5p in the Regulation of Targets in Clear Cell Renal Cell Carcinoma.

BackgroundDue to the poor prognosis for advanced renal cell carcinoma (RCC), there is an urgent need for new therapeutic targets and for prognostic markers to identify high risk tumors. MicroRNAs (miRNAs) are frequently dysregulated in tumors, play a crucial role during carcinogenesis and therefore might be promising new biomarkers. In previous studies, we identified miR-141-3p and miR-145-5p to be downregulated in clear cell RCC (ccRCC). Our objective was to investigate the functional association of these miRNAs, focusing on the cooperative regulation of new specific targets and their role in ccRCC progression.MethodsThe effect of miR-141-3p and miR-145-5p on cell migration was examined by overexpression in 786-O cells. New targets of both miRNAs were identified by miRWalk, validated in 786-O and ACHN cells and additionally characterized in ccRCC tissue on mRNA and protein level.ResultsIn functional analysis, a tumor suppressive effect of miR-141-3p and miR-145-5p by decreasing migration and invasion of RCC cells could be shown. Furthermore, co-overexpression of the miRNAs seemed to result in an increased inhibition of cell migration. Both miRNAs were recognized as post-transcriptional regulators of the targets EAPP, HS6ST2, LOX, TGFB2 and VRK2. Additionally, they showed a cooperative effect again as demonstrated by a significantly increased inhibition of HS6ST2 and LOX expression after simultaneous overexpression of both miRNAs. In ccRCC tissue, LOX mRNA expression was strongly increased compared to normal tissue, allowing also to distinguish between non-metastatic and already metastasized primary tumors. Finally, in subsequent tissue microarray analysis LOX protein expression showed a prognostic relevance for the overall survival of ccRCC patients.ConclusionThese results illustrate a jointly strengthening effect of the dysregulated miR-141-3p and miR-145-5p in various tumor associated processes. Focusing on the cooperative effect of miRNAs provides new opportunities for the development of therapeutic strategies and offers novel prognostic and diagnostic capabilities.

MP71-08 SELECT CONCURRENT CHROMOSOME 3P MUTATIONS PREDICT WORSE OVERALL AND RECURRENCE-FREE SURVIVAL IN CLEAR CELL RENAL CARCINOMA IN THE CANCER GENOME ATLAS

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology I1 Apr 2016MP71-08 SELECT CONCURRENT CHROMOSOME 3P MUTATIONS PREDICT WORSE OVERALL AND RECURRENCE-FREE SURVIVAL IN CLEAR CELL RENAL CARCINOMA IN THE CANCER GENOME ATLAS Christopher Keith, John Petros, Michael Rossi, and Rebecca Arnold Christopher KeithChristopher Keith More articles by this author , John PetrosJohn Petros More articles by this author , Michael RossiMichael Rossi More articles by this author , and Rebecca ArnoldRebecca Arnold More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1454AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In clear cell renal cell carcinoma (ccRCC), mutations in BAP1 and, in some cohorts, PBRM1 are associated with worse survival, while VHL and SETD2 mutations do not independently predict poor prognosis. While studies have analyzed prognostic impact of independent mutations on these chromosome 3p (chr 3p) genes, the prognostic significance of co-existing mutations in these near-neighboring genes is unknown. METHODS The Cancer Genome Atlas (TCGA) ccRCC database was probed for mutations in VHL, BAP1, SETD2, and PBRM1. Kaplan-Meier survival log-rank and Cox multivariate analysis were performed. RESULTS Of the 418 patients with ccRCC in TCGA, at least one of the four chr 3p genes was mutated in 74% of cases. Co-existing somatic mutations in VHL and BAP1 (n=16), VHL and SETD2 (n=9), or PBRM1 and SETD2 and/or BAP1 (n=13) compared to all other cases was associated with worse recurrence-free (1.83 vs. 6.0 years; p=0.0004) and overall survival (2.42 vs. 7.13 years; p<0.0001). The survival difference remained significant after controlling for total mutational burden (p<0.0001), BAP1 mutations (p=0.014), and PBRM1 mutations (p<0.0001). On multivariate analysis, high-risk chromosome 3p status was associated with significantly decreased recurrence-free survival and overall survival. Interestingly, the deleterious effects of BAP1 in the ccRCC TCGA cohort are negated when the group with only coexisting VHL or PBRM1 mutations is excluded (p=0.83). When comparing the high-risk BAP1 group to all other cases with BAP1 alterations, there is a significant difference in survival (2.42 vs. 5.38 years; p=0.01). CONCLUSIONS Concurrent mutations in VHL and BAP1, VHL and SETD2, or PBRM with SETD2 and/or BAP1 are associated with significantly decreased recurrence-free and overall survival in ccRCC in the TCGA. In addition, the deleterious effect of BAP1 mutations in TCGA is dependent on concurrent chr 3p mutations. Such information may be useful in risk stratification of patients with ccRCC. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e918 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Christopher Keith More articles by this author John Petros More articles by this author Michael Rossi More articles by this author Rebecca Arnold More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

ITGA2B and ITGA8 are predictive of prognosis in clear cell renal cell carcinoma patients.

Integrins play an important role in cancer growth and metastasis. This study aimed at determining the predictive ability of integrins and associated genes identified through molecular network in clear cell renal cell carcinoma. A total of 525 patients with ccRCC from The Cancer Genome Atlas (TCGA) cohorts were collected in this study. The expression profile of integrins and related genes were obtained from the TCGA RNAseq database. Clinicopathological characteristics, including age, gender, tumor size, tumor node metastasis (TNM), tumor grade, stage, laterality, and overall survival were collected. Cox proportional hazards regression model as well as Kaplan-Meier curve were used to assess the relative factors. Genes of integrin family that showed certain correlations with overall survival (OS) were further validated in the Fudan University Shanghai Cancer Center (FUSCC) cohort. In the TCGA cohort, after Cox proportional hazards analysis, ITGA2B (hazards ratio (HR) = 1.232, 95% CI 1.097 to 1.383) and ITGA8 (HR = 0.804, 95% CI 0.696 to 0.930) were shown predictive of ccRCC prognosis. Low ITGA8 expression was associated with poor prognosis for OS (log-rank test, p < 0.0001), while high level of ITGA2B expression was correlated with poor prognosis for OS (log-rank test, p < 0.0001). This finding was validated in FUSCC cohort (log-rank test, all p < 0.05). As a result, low ITGA8 expression was associated with poor prognosis for OS (log-rank test, p = 0.0053), while high level of ITGA2B expression was correlated with poor prognosis for OS (log-rank test, p < 0.0001). Plus, low ITGA8 expression was associated with poor prognosis for disease-free survival (DFS) in the TCGA cohort (log-rank test, p < 0.0001). In the gene cluster network analysis, GIT1 and SHC1 associated with ITGA2B and ITGA8 were identified as independent predictive factors of overall survival of ccRCC. ITGA2B, ITGA8, GIT1, and SHC1 were identified as independent prognostic factors of overall survival of ccRCC. This method may act as a tool to reveal more prognostic-associated genes in ccRCC.

Upregulation of long non-coding RNA MALAT1 correlates with tumor progression and poor prognosis in clear cell renal cell carcinoma.

Long noncoding RNAs (lncRNAs) have been investigated as a new class of regulators of cellular processes, such as cell growth, apoptosis, and carcinogenesis. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has recently been identified to be involved in tumorigenesis of several cancers such as lung cancer, pancreatic cancer, and cervical cancer. However, the role of lncRNA MALAT1 in clear cell renal cell carcinoma (ccRCC) remains unclear. Expression levels of lncRNA MALAT1 in ccRCC tissues and renal cancer cell lines were evaluated by quantitative real-time PCR (qRT-PCR), and its association with overall survival of patients was analyzed by statistical analysis. Small interfering RNA (siRNA) was used to suppress MALAT1 expression in renal cancer cells. In vitro assays were conducted to further explore its role in tumor progression. The expression level of MALAT1 was higher in ccRCC tissues and renal cancer cells compared to adjacent non-tumor tissues and normal human proximal tubule epithelial cells HK-2. The ccRCC patients with higher MALAT1 expression had an advanced clinical features and a shorter overall survival time than those with lower MALAT1 expression. And multivariate analysis showed that the status of MALAT1 expression was an independent predictor of overall survival in ccRCC. Additionally, our data indicated that knockdown expression of MALAT1 decreased renal cancer cell proliferation, migration, and invasion. Our data suggested that lncRNA MALAT1 was a novel molecule involved in ccRCC progression, which provided a potential prognostic biomarker and therapeutic target.

TGF-β-activated Kinase-1: A Potential Prognostic Marker for Clear Cell Renal Cell Carcinoma

TGF-β-activated kinase-1 (TAK1) has been found to be over-expressed in a variety of solid malignancies and related to tumor growth. The aim of this study was to evaluate the expression level of TAK1 in clear cell renal cell carcinoma (ccRCC) and assess its value as a novel prognostic marker. TAK1 mRNA was assessed in 51 paired ccRCC tissues and adjacent normal tissues (ADTs) by real-time PCR. Tissue TAK1 protein was also assessed in 91 ADTs and 177 samples of ccRCC immunohistochemically for evaluation of relationships with clinical characteristics. RT-PCR showed that TAK1 RNA level was significantly higher in ccRCC tissues than in the paired ADTs and immunohistochemistry confirmed higher expression of TAK1 protein in ccRCC samples compared with ADTs. TAK1 protein expression in 177 ccRCC samples was significantly correlated with T stage, N classification, metastasis, recurrence and Fuhrman grade, but not age and gender. Patients with low TAK1 levels had a better survival outcome. TAK1 expression and N stage were independent prognosis factors for the overall survival of ccRCC patients. Overexpression of TAK1 predicts a poor prognosis in patients with ccRCC, so that TAK1 may serve as a novel prognostic marker.

Expression of nuclear FIH independently predicts overall survival of clear cell renal cell carcinoma patients

Aim The hypoxia inducible factor (HIF) pathway plays an important role in sporadic clear cell renal cell carcinoma (ccRCC) by stimulating processes of angiogenesis, cell proliferation, cell survival and metastases formation. Herein, we evaluate the significance of upstream proteins directly regulating the HIF pathway; the prolyl hydroxylases domain proteins (PHD)1, 2 and 3 and factor-inhibiting HIF (FIH), as prognostic markers for ccRCC. Methods Immunohistochemical marker expression was examined on a tissue microarray containing tumour tissue derived from 100 patients who underwent nephrectomy for ccRCC. Expression levels of HIF, FIH and PHD1, 2 and 3 were correlated with overall survival (OS) and clinicopathological prognostic factors. Results HIF-1α was positively correlated with HIF-2α ( p < 0.0001), PHD1 ( p = 0.024), PHD2 ( p < 0.0001), PHD3 ( p = 0.004), FIH ( p < 0.0001) and VHL ( p = 0.031). HIF-2α levels were significantly associated with FIH ( p < 0.0001) and PHD2 ( p = 0.0155). Mutations in the VHL gene, expression variations of HIF-1α, HIF-2α and PHD1, 2, 3 did not show a correlation to OS or clinicopathological prognostic factors. Tumour stage, grade, diameter, metastastic disease and intensity of nuclear FIH were significantly correlated to OS in univariable analysis ( p = 0.023). Low nuclear FIH levels remained a strong independent prognostic factor in multivariable analysis ( p = 0.009). Conclusion These results show that low nuclear expression of FIH is a strong independent prognostic factor for a poor overall survival in ccRCC.