Review of Prognostic Expression Markers for Clear Cell Renal Cell Carcinoma.
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ABSTRACT:
SUBMITTER: Petitprez F
PROVIDER: S-EPMC8113694 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Epithelial-to-mesenchymal transition (EMT) is important in tumor invasiveness and metastasis. We aimed to determine prognostic value of six key EMT markers (CDH1, CDH2, SNAI1, SNAI2, VIM, TWIST1) in clear cell renal cell carcinoma (ccRCC). A total of 533 ccRCC patients with RNASeq data from The Cancer Genome Atlas (TCGA) cohort were included for analysis. Gene expression of these EMT markers was compared between tumor and normal tissues based on Oncomine database and TCGA cohort. Their correlations with progression-free survival (PFS) and overall survival (OS) were also examined in both TCGA cohort and FUSCC (Fudan University Shanghai Cancer Center) cohort. Cox proportional hazards regression model and Kaplan-Meier plot were used to assess the relative factors. Functional enrichment analyses were utilized to describe biologic function annotations and significantly involved hallmarks pathways of each gene. We found that Epithelial marker, CDH1 expression was lower, while mesenchymal markers (CDH2, SNAI1, VIM, TWIST1) expression was higher in ccRCC primary tumors. In the TCGA cohort, we found that patients with higher expression of VIM, TWIST1 or lower expression of CDH1 had worse prognosis. Further, in the FUSCC cohort, we confirmed the predictive ability of mesenchymal markers and epithelial marker expression in PFS and OS of ccRCC patients. After generating Cox regression models, EMT markers (CDH1, SNAI1, VIM, and TWIST1) were independent prognostic factors of both PFS and OS in ccRCC patients. Our preliminary EMT prediction model can facilitate further screening of EMT biomarkers and cast a better understanding of EMT gene function in ccRCC.
| S-EPMC6977664 | biostudies-literature
Project description:BACKGROUND:Growing evidence has demonstrated immune reactivity as a confirmed important carcinogenesis and therapy efficacy for clear cell renal cell carcinoma (ccRCC). Aquaporin 9 (AQP9) is involved in many immune-related signals; however, its role in ccRCC remains to be elucidated. This study investigated AQP9 expression in tumor tissues and defined the prognostic value in ccRCC patients. METHODS:A total of 913 ccRCC patients with available RNA-sequence data from the Cancer Genome Atlas (TCGA) database and Fudan University Shanghai Cancer Center (FUSCC) were consecutively recruited in analyses. Differential transcriptional and proteome expression profiles were obtained and validated using multiple datasets. A partial likelihood test from Cox regression analysis was developed to address the influence of independent factors on progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method and log-rank test were performed to assess survival. Receiver operating characteristic (ROC) curves were used to describe binary classifier value of AQP9 using area under the curve (AUC) score. Functional enrichment analyses and immune infiltration analysis were used to describe significantly involved hallmark pathways of hub genes. RESULTS:Significantly elevated transcriptional and proteomic AQP9 expressions were found in ccRCC samples. Increased AQP9 mRNA expression was significantly associated with advanced clinicopathological parameters and correlated with shorter PFS and OS in TCGA and FUSCC cohorts (p?<?0.001). ROC curves suggested the significant diagnostic and prognostic ability of AQP9 (PFS, AUC?=?0.823; OS, AUC?=?0.828). Functional annotations indicated that AQP9 is involved in the most significant hallmarks including complement, coagulation, IL6/JAK-STAT3, inflammatory response and TNF-alpha signaling pathways. CONCLUSION:Our study revealed that elevated AQP9 expression was significantly correlated with aggressive progression, poor survival and immune infiltrations in ccRCC patients, and we validated its prognostic value in a real-world cohort. These data suggest that AQP9 may act as an oncogene and a promising prognostic marker in ccRCC.
| S-EPMC6842264 | biostudies-literature
Project description:BACKGROUND: The aim of this study was to determine whether Src family kinases (SFK) are expressed in renal cell cancer and to assess their prognostic significance. METHODS: mRNA expression levels were investigated for the 8 SFK members by quantitative real-time PCR in 19 clear cell cancer tissue samples. Immunohistochemical staining was utilised to assess expression of Src kinase, dephosphorylated Src kinase at Y(530) (SrcY(530)), phosphorylated Src at Y(419) (SrcY(419)) and the downstream focal adhesion kinase (FAK) marker at the Y(861) site (FAK Y(861)) in a cohort of 57 clear cell renal cancer specimens. Expression was assessed using the weighted histoscore method. RESULTS: Src, Lyn, Hck, Fgr and Fyn were the most highly expressed in renal cancer. All members were more highly expressed in T2 disease, and furthermore expression levels between T2 and T3 disease showed a significant decrease for Lck, Lyn, Fyn, Blk and Yes (P=0.032). Assessment of membrane, cytoplasm and nuclear expression of Src kinase, SrcY(530) and SrcY(419) were not significantly associated with cancer-specific survival. High expression of cytoplasmic FAK Y(861) was associated with decreased cancer-specific survival (P=0.001). On multivariate analysis, cytoplasmic FAK Y(861) was independently associated with cancer-specific survival (hazard ratio 3.35, 95% CI 1.40-7.98, P=0.006). CONCLUSION: We have reported that all SFK members are expressed in renal cell carcinoma. The SFK members had their highest levels of expression before the disease no longer being organ confined. We hypothesise that these SFK members are upregulated before the cancer spreading out-with the organ and given that Src itself is not associated with cancer-specific survival but the presence of FAK Y(861), a downstream marker for SFK member activity is associated with decreased cancer-specific survival, we hypothesise that another SFK member is associated with decreased cancer-specific survival in renal cell cancer.
| S-EPMC3426751 | biostudies-other
Project description:To better understand the molecular mechanisms that underlie the tumorigenesis and progression of clear cell renal cell carcinoma (ccRCC), we studied the gene expression profiles of 29 ccRCC tumors obtained from patients with diverse clinical outcomes by using 21,632 cDNA microarrays. We identified gene expression alterations that were both common to most of the ccRCC studied and unique to clinical subsets. There was a significant distinction in gene expression profile between patients with a relatively nonaggressive form of the disease [100% survival after 5 years with the majority (15/17 or 88%) having no clinical evidence of metastasis] versus patients with a relatively aggressive form of the disease (average survival time 25.4 months with a 0% 5-year survival rate). Approximately 40 genes most accurately make this distinction, some of which have previously been implicated in tumorigenesis and metastasis. To test the robustness and potential clinical usefulness of this molecular distinction, we simulated its use as a prognostic tool in the clinical setting. In 96% of the ccRCC cases tested, the prediction was compatible with the clinical outcome, exceeding the accuracy of prediction by staging. These results suggest that two molecularly distinct forms of ccRCC exist and that the integration of expression profile data with clinical parameters could serve to enhance the diagnosis and prognosis of ccRCC. Moreover, the identified genes provide insight into the molecular mechanisms of aggressive ccRCC and suggest intervention strategies.
| S-EPMC55525 | biostudies-literature
Project description:Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of RCC; however, prognostic prediction tools for ccRCC are scant. Developing mRNA or long non-coding RNA (lncRNA)-based risk assessment tools may improve the prognosis in patients with ccRCC. RNA-sequencing and prognostic data from patients with ccRCC were downloaded from The Cancer Genome Atlas and the European Bioinformatics Institute Array database at the National Center for Biotechnology Information. Differentially expressed (DE) RNAs (DERs) and prognostic DERs were screened between less favorable and favorable prognoses using the limma package in R 3.4.1, and analyzed using univariate and multivariate Cox regression analyses, respectively. Risk score models were constructed using optimal combinations of DEmRNAs and DElncRNAs identified using the Least Absolute Shrinkage And Selection Operator Cox regression model of the penalized package. Associations between risk score models and overall survival time were evaluated. Independent prognostic clinical factors were screened using univariate and multivariate Cox regression analyses, and nomogram models were constructed. Gene Ontology biological processes and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted using the clusterProfiler package in R3.4.1. A total of 451 DERs were identified, including 404 mRNAs and 47 lncRNAs, between less favorable and favorable prognoses, and 269 DERs, including 233 mRNAs and 36 lncRNAs, were identified as independent prognostic factors. Optimal combinations including 10 DEmRNAs or 10 DElncRNAs were screened using four risk score models based on the status or expression levels of the 10 DEmRNAs or 10 DElncRNAs. The model based on the expression levels of the 10 DEmRNAs had the highest prognostic power. These prognostic DEmRNAs may be involved in biological processes associated with the inflammatory response, complement and coagulation cascades and neuroactive ligand-receptor interaction pathways. The present validated risk assessment tool based on the expression levels of these 10 DEmRNAs may help to identify patients with ccRCC at a high risk of mortality. These 10 DEmRNAs in optimal combinations may serve as prognostic biomarkers and help to elucidate the pathogenesis of ccRCC.
| S-EPMC7400162 | biostudies-literature
Project description:Clear cell renal cell carcinoma (ccRCC) is the major and aggressive subtype of renal cell carcinoma. It is known to derive its histologic appearance from accumulation of abundant lipids and glycogens. The cell death-inducing DFF45-like effector (CIDE) family has been characterized as the lipid droplet proteins involved in the metabolism of lipid storage droplets. The purpose of this study was to evaluate the expression of CIDE proteins in ccRCC cells and to investigate their prognostic significance. We examined consecutive patients with sporadic ccRCC, who underwent nephrectomy, to measure their mRNA and protein expression of CIDE proteins. We found that Cidec and ADRP expression were significantly up-regulated in ccRCC, compared with normal kidney tissues. Cideb was down-regulated. We also found that Cideb was expressed more in low-grade ccRCC than in high-grade tumors. To further clarify the relationship between Cideb expression and patient prognosis, we evaluated 57 ccRCC patients followed up for 120 months. Reduced ccRCC Cideb expression was associated with a higher Fuhrman nuclear grade. Patients with high Cideb expression had better overall survival rate than those with low expression (p < 0.05). Cideb expression was an independent predictor of survival (p = 0.001). Although the biologic function of Cideb in ccRCC remains unknown, the expression level of Cideb might be a novel predictor of prognosis in ccRCC.
| S-EPMC3634988 | biostudies-literature
Project description: Not available
| S-BSST812 | biostudies-other
Project description:ObjectiveTo study the expression of adipophilin (PLIN2), a lipid storage-associated cell protein, in different subtypes of renal cell cancer and to elucidate its prognostic value.Materials and methodsTwo-hundred-seventy-five patients with renal cell carcinoma (RCC) were included in this study. Immunohistochemistry with a polyclonal antibody to adipophilin was used on the tissue microarray (formalin-fixed, paraffin-embedded tissue) for detection of adipophilin. Median follow-up time was 91 (range 1-159) months in the whole cohort and 100 (1-159) months for patients with clear-cell RCC. Additional validation for adipophilin was performed using publicly available gene expression data for clear cell RCC from The Cancer Genome Atlas (TCGA).ResultsAdipophilin expression was detected in 14.3% of papillary RCC, in 0% of chromophobe RCC and in 58.7% of clear-cell RCC in the cytoplasm or at the membrane. Only membrane expression was correlated with other clinical parameters (pT-stage, pN-stage, R-status, sex) and showed a prognostic significance in univariate analysis with regard to overall survival of patients with clear cell subtype (HR 2.90, 95% CI 1.55-5.42, p=0.001), which failed significance on multivariate analysis. mRNA expression of PLIN2 on TCGA data using best selected cut-off was prognostically significant in both univariate (HR 1.76, 95% CI 1.28-2.42, p = 0.0005) and multivariate analyses (HR 1.46, 95% CI 1.05-2.04, p = 0.0257).ConclusionsAdipophilin is a novel and still understudied prognostic biomarker in clear cell renal cell carcinoma which deserves further study.
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Project description:m6A, the main form of mRNA modification, participates in regulating multiple normal and pathological biological events, especially in tumorigenesis. However, there is little known about the association of m6A-related genes with prognosis of clear cell renal cell cancer (ccRCC). Therefore, the prognostic value of m6A-related genes was investigated using Kaplan-Meier curves of overall survival (OS) with the log-rank test and Cox regression analysis. The differential expression of YTHDF2 mRNA in ccRCC and tumor-adjacent normal tissues and associated with clinicopathological characteristics was also analyzed. The alteration of cancer signaling pathways was screened by Gene Set Enrichment Analysis (GSEA). Univariate analysis showed that 15 m6A-related genes (including YTHDF2) were closely related to prognosis. Multivariate analysis further confirmed that YTHDF2 could serve as an independent prognostic factor for the OS of ccRCC patients (P < 0.001). Low-level expression of YTHDF2 had poor prognosis in ccRCC patients with lower tumor-node-metastasis (TNM) stage, age > 61, non-distant metastasis, non-lymph node metastasis, female gender, and higher histological grade (P < 0.05). Moreover, YTHDF2 expression in ccRCC tissues (N = 529) is significantly lower than that of tumor-adjacent normal tissues (N = 72, P = 0.0086). Furthermore, GSEA demonstrated that AKT/mTOR/GSK3 pathway, EIF4 pathway, CHREBP2 pathway, MET pathway, NFAT pathway, FAS pathway, EDG1 pathway, and CTCF pathway are altered in tumors with high YTHDF2 expression. Taken together, our results demonstrated that YTHDF2 (an m6A-related gene) could serve as a potential prognostic biomarker of ccRCC, and targeting epigenetic modification may be a novel therapeutic strategy for the treatment of ccRCC.
| S-EPMC7546891 | biostudies-literature
Project description:Clear cell papillary renal cell carcinoma (CCPRCC) is a low-grade renal neoplasm with morphological characteristics mimicking both clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC). However, despite some overlapping features, their morphological, immunohistochemical, and molecular profiles are distinct. Micro-RNAs (miRNAs) are small noncoding RNAs that play a crucial role in regulating gene expression and are involved in various biological processes, including cancer development. To better understand the biology of this tumor, we aimed to analyze the miRNA expression profile of a set of CCPRCC using microarray and quantitative reverse transcription-polymerase chain reaction. A total of 15 cases diagnosed as CCPRCC were used in this study. Among the most differentially expressed miRNA in CCPRCC, we found miR-210, miR-122, miR-34a, miR-21, miR-34b*, and miR-489 to be up-regulated, whereas miR-4284, miR-1202, miR-135a, miR-1973, and miR-204 were down-regulated compared with normal renal parenchyma. To identify consensus of differentially regulated miRNA between CCPRCC, CCRCC, and PRCC, we additionally determined differential miRNA expression using 2 publically available microarray data sets from the NCBI Gene Expression Omnibus database (GSE41282 and GSE3798). This comparison revealed that the miRNA expression profile of CCPRCC shows some overlapping characteristics between CCRCC and PRCC. Moreover, CCPRCC lacks dysregulation of important miRNAs typically associated with aggressive behavior. In summary, we describe the miRNA expression profile of a relatively infrequent type of renal cancer. Our results may help in understanding the molecular underpinning of this newly recognized entity.
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