Prognostic Marker For ccRCC Research Articles

MiR-10b is a prognostic marker in clear cell renal cell carcinoma

AimsClear cell renal cell carcinoma (ccRCC) is the most common adult kidney cancer. It is an aggressive tumour with unpredictable outcome. The currently used clinical parameters are not always accurate...

Expression and prognostic significance of zinc fingers and homeoboxes family members in renal cell carcinoma.

Zinc fingers and homeoboxes (ZHX) is a transcription repressor family that contains three members; ZHX1, ZHX2, and ZHX3. Although ZHX family members have been associated with the progression of cancer, their values as prognostic factors in cancer patients have been poorly examined. Renal cell carcinoma (RCC) is a highly heterogeneous, aggressive cancer that responds variably to treatment. Thus, prognostic molecular markers are required to evaluate disease progression and to improve the survival. In clear cell RCC (ccRCC), ZHX1 and ZHX3 expression were found to be down-regulated but ZHX2 was up-regulated, and the expressions of ZHX1 and ZHX3 were significantly associated with pathological stage. Furthermore, Kaplan-Meier and multivariate regression analysis showed that reduction in the mRNA expression of ZHX1 was associated with poorer survival. Taken together, the present study shows loss of ZHX1 is correlated with ccRCC progression and suggests it is an independent prognostic marker in ccRCC.

MiR-19a correlates with poor prognosis of clear cell renal cell carcinoma patients via promoting cell proliferation and suppressing PTEN/SMAD4 expression

MicroRNAs (miRNAs) were reported to be involved in the development of clear cell renal cell carcinoma (ccRCC). However, the study on miRNAs in ccRCC is far from complete. The present study identified miRNAs which could act as potential novel prognostic markers for ccRCC, and analyzed its possible mechanism. We found that miR-19a correlated with poor prognosis of ccRCC patients via promoting cell proliferation and suppressing PTEN/SMAD4 expression. Both the microarray screening result and TCGA KIRC dataset analysis showed that miR-19a was significantly upregulated in ccRCC tissues, and further analysis of TCGA data revealed that the upregulated level of miR-19a was strongly associated with advanced T stage and poor prognosis of ccRCC patients. Consistent with clinical observations, miR-19a overexpression significantly promoted ccRCC cell proliferation invitro. To further explore the mechanism by which miR-19a correlated with cell proliferation and poor prognosis of ccRCC, we performed gene set enrichment analysis (GSEA) for target genes of miR-19a in ccRCC patients. Result indicated that the key target genes of miR-19a included SMAD4 and PTEN. In ccRCC tissues, expression levels of SMAD4 and PTEN were negatively correlated with expression level of miR-19a, revealing that miR-19a suppressed the expression of SMAD4 and PTEN in ccRCC patients. miR-19a overexpression significantly suppressed the expression of SMAD4 and PTEN invitro, further verifying that SMAD4 and PTEN were the target genes of miR-19a in ccRCC cells. Our results elucidated the tumor promoting role of miR-19a and established miR-19a as a potential novel prognostic marker for ccRCC.

MicroRNA-194 is a Marker for Good Prognosis in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent adult kidney cancer. Prognostic markers are needed to guide patient management toward aggressive versus more conservative approaches, especially for small tumors ≤4 cm. miR‐194 was reported to be downregulated in several cancers and is involved in epithelial to mesenchymal transition. We evaluated miR‐194 as a prognostic marker in ccRCC. In a cohort of 234 patients with primary ccRCC, we correlated miR‐194 expression level with multiple clinicopathological features including disease‐free and overall survival, tumor size, clinical stage, and histological grade. Our results shows a stepwise decrease in miR‐194 expression from normal kidney to primary ccRCC (P = 0.0032) and a subsequent decrease from primary to metastatic lesions. Additionally, patients with higher miR‐194 expression has significantly longer disease‐free survival (P = 0.041) and overall survival (P = 0.031) compared to those with lower expression. In multivariate analysis, miR‐194‐positive tumors retain significance in disease‐free survival and overall survival, suggesting miR‐194 is an independent marker for good prognosis in ccRCC. Moreover, miR‐194 is a marker for good prognosis for patients with small renal masses (P = 0.014). These findings were validated on an independent data set from The Cancer Genome Atlas. We also compared miR‐194 expression between RCC subtypes. ccRCC had the highest levels, whereas chromophobe RCC and oncocytoma had comparable lower levels. Target prediction coupled with pathway analysis show that miR‐194 is predicted to target key molecules and pathways involved in RCC progression. miR‐194 represents a prognostic biomarker in ccRCC.

DNA methylation status defines clinicopathological parameters including survival for patients with clear cell renal cell carcinoma (ccRCC).

Epigenetic alterations in the methylome have been associated with tumor development and progression in renal cell carcinoma (RCC). In this study, 45 tumor samples, 12 tumor-free kidney cortex tissues, and 24 peripheral blood samples from patients with clear cell RCC (ccRCC) were analyzed by genome-wide promoter-directed methylation arrays and related to clinicopathological parameters. Unsupervised hierarchical clustering separated the tumors into two distinct methylation groups (clusters A and B), where cluster B had higher average methylation and increased number of hypermethylated CpG sites (CpGs). Furthermore, tumors in cluster B had, compared with cluster A, a larger tumor diameter (p = 0.033), a higher morphologic grade (p < 0.001), a higher tumor-node-metastasis (TNM) stage (p < 0.001), and a worse prognosis (p = 0.005). Higher TNM stage was correlated to an increase in average methylation level (p = 0.003) and number of hypermethylated CpGs (p = 0.003), whereas a number of hypomethylated CpGs were mainly unchanged. However, the predicted age of the tumors based on methylation profile did not correlate with TNM stage, morphological grade, or methylation cluster. Differently methylated (DM) genes (n = 840) in ccRCC samples compared with tumor-free kidney cortex samples were predominantly hypermethylated and a high proportion were identified as polycomb target genes. The DM genes were overrepresented by transcription factors, ligands, and receptors, indicating functional alterations of significance for ccRCC progression. To conclude, increased number of hypermethylated genes was associated with increased TNM stage of the tumors. DNA methylation classification of ccRCC tumor samples at diagnosis can serve as a clinically applicable prognostic marker in ccRCC.

Prognostic significance of two lipid metabolism enzymes, HADHA and ACAT2, in clear cell renal cell carcinoma.

Renal cell carcinoma (RCC) is one of the leading causes of cancer mortality in adults, but there is still no acknowledged biomarker for its prognostic evaluation. Our previous proteomic data had demonstrated the dysregulation of some lipid metabolism enzymes in clear cell RCC (ccRCC). In the present study, we elucidated the expression of two lipid metabolism enzymes, hydroxyl-coenzyme A dehydrogenase, alpha subunit (HADHA) and acetyl-coenzyme A acetyltransferase 2 (ACAT2), using Western blotting analysis, then assessed the prognostic potential of HADHA and ACAT2 using immunohistochemistry (IHC) on a tissue microarray of 145 ccRCC tissues. HADHA and ACAT2 were downregulated in ccRCC (P < 0.05); further IHC analysis revealed that HADHA expression was significantly associated with tumor grade, stage, size, metastasis, and cancer-specific survival (P = 0.004, P < 0.001, P < 0.001, P = 0.049, P < 0.001, respectively) and ACAT2 expression was significantly associated with tumor stage, size, and cancer-specific survival (P < 0.001, P = 0.001, P < 0.001, respectively). In addition, a strong correlation was found between HADHA and ACAT2 expression (R = 0.655, P < 0.001). Further univariate survival analysis demonstrated that high stage, big tumor size, metastasis, and HADHA and ACAT2 down-expression were associated with poorer prognosis on cancer-specific survival (P = 0.007, P = 0.005, P = 0.006, P < 0.001, P = 0.001, respectively), and multivariate analysis revealed that HADHA, stage, and metastasis were identified as independent prognostic factors for cancer-specific survival in patients with ccRCC (P = 0.018, P = 0.046, P = 0.001, respectively). Collectively, these findings indicated that HADHA could serve as a promising prognostic marker in ccRCC, which indicated lipid metabolism abnormality might be involved in ccRCC tumorigenesis.

Low Expression of miR-126 Is a Prognostic Marker for Metastatic Clear Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor with unpredictable behavior. Clinical parameters are not always accurate for predicting prognosis. miR-126 is differentially expressed in many cancers, including RCC, and is down-regulated in metastatic versus primary ccRCC. We assessed the prognostic significance of miR-126 in 264 primary ccRCCs. We also compared its expression in normal kidney, primary and metastatic ccRCC, and RCC subtypes. We validated our results on an independent set of 481 ccRCCs. miR-126 was down-regulated in metastatic versus primary tumors and in tumors of higher stage (P=0.005) or higher grade (P=0.002). miR-126 up-regulation was associated with significantly prolonged disease-free survival (P<0.001) and overall survival (P=0.015). For larger tumors (>4 cm), patients with higher miR-126 expression had significantly longer survival. Restoration of miR-126 expression decreased cellular migration and proliferation in RCC cell lines. The ccRCCs exhibited the highest miR-126 expression, and papillary RCCs exhibited the lowest expression. We identified a number of miR-126 targets and pathways that are involved in carcinogenesis, including the apoptosis signaling pathway. miR-126 is a promising prognostic marker in ccRCC that can distinguish between clear cell and papillary subtypes. In addition, miR-126 has potential therapeutic applications.

Prognostic implication of TIM-3 in clear cell renal cell carcinoma

Clear cell renal carcinoma (ccRCC) is the most common tumor of the kidney.in adults. The prognosis of ccRCC remains unsatisfactory. Recently, T cell immunoglobulin mucin-3 (TIM-3), a novel transmembrane protein, has been implicated in tumor biology. Its role in ccRCC remains unknown. The aim of this study was to investigate the roles of TIM-3 as a prognostic marker in patients with ccRCC.TIM-3 protein expression was determined by immunohistochemistry and Western blot from 137 ccRCC tumor samples and adjacent normal renal tissues. We performed also the cell proliferation assay using 3-(4,5-dimethylthiazol -2yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) and cell invasion assay. The effects of small interfering RNA (siRNA)-mediated knockdown of TIM-3 (TIM-3 siRNA) in two human ccRCC cell lines were evaluated. TIM-3 expression was higher in ccRCC tissue than in the adjacent normal renal tissue (P<0.001). High TIM-3 expression was an independent predictor of both cancer-specific survival and progression-free survival. TIM-3 protein was expressed in both ccRCC cell lines. Knockdown of TIM-3 suppressed the proliferation and invasion capacity of ccRCC cell lines.TIM-3 expression was associated with poor prognosis in ccRCC. Taken together, TIM-3 is a potential prognostic marker in ccRCC.

Increased Expression of Pregnancy Up-Regulated Non-Ubiquitous Calmodulin Kinase Is Associated with Poor Prognosis in Clear Cell Renal Cell Carcinoma

PurposeThe aims of this study were to evaluate the clinical significance and potential prognostic value of pregnancy up-regulated non-ubiquitous calmodulin kinase (PNCK) in clear cell renal cell carcinoma (ccRCC) patients.Materials and MethodsThe expression of PNCK mRNA was determined in 24 paired samples of ccRCCs and adjacent normal tissues using real-time RT-PCR. The expression of PNCK was determined in 248 samples of ccRCCs and 92 paired samples of adjacent normal tissues by immunohistochemical analysis. Statistical analysis was performed to define the relationship between PNCK expression and the clinical features of ccRCC.ResultsThe mRNA level of PNCK was significantly higher in tumorous tissues than in the adjacent non-tumorous tissues (p<0.001). An immunohistochemical analysis of 92 paired tissue specimens showed that PNCK expression was higher in tumorous tissues than in the adjacent non-tumorous tissues (p<0.001). Moreover, there was a significant correlation between the PNCK expression and various clinicopathological parameters such as Fuhrman grade (p = 0.011), tumor size (p<0.001), T stage (p<0.001) and N stage (p = 0.015). Patients with higher PNCK expression had shorter overall survival time than those with lower PNCK expression (p<0.001). Multivariate analysis indicated that PNCK expression was an independent predictor for poor survival of ccRCC patients.ConclusionsTo our knowledge, this is the first study that determines the relationship between PNCK and prognosis in ccRCC. We found that increased PNCK expression is associated with poor prognosis in ccRCC. PNCK may represent a novel prognostic marker for ccRCC.

High expression of FER tyrosine kinase predicts poor prognosis in clear cell renal cell carcinoma

FER tyrosine kinase (FER) has been demonstrated to play a critical role in tumorigenesis and metastasis; however, its potential value as a novel prognostic marker for clear cell renal cell carcinoma (ccRCC) remains unclear. In 48 paired samples of ccRCCs and normal adjacent tissues (ADTs), real-time PCR was used to evaluate the expression of FER mRNA. The expression of FER protein was assessed in 87 ADTs and 206 samples of ccRCC using immunohistochemical methods. Statistical analysis was used to examine the correlations between the expression levels of FER and the clinical characteristics of ccRCC patients. A significant difference was identified between ccRCC tissues and ADTs in the mRNA levels of FER. Immunohistochemistry analyses revealed higher expression of FER protein in 87 ccRCC samples compared to the paired ADTs. In addition, FER protein expression in 206 ccRCC samples was significantly correlated with tumor size, T stage, N classification, metastasis, recurrence and Fuhrman grade, while associations with age and gender were not identifed. The Kaplan-Meier survival analysis showed that patients with high FER levels had a poorer survival outcome compared with those with lower levels. The log-rank test demonstrated that the cumulative survival rates were significantly different between the two groups. The Cox regression analysis indicated that FER expression, N stage and distant metastasis were independent prognostic factors for overall survival of ccRCC patients. Our results indicate that overexpression of FER in tumor tissues predicts a poor prognosis of patients with ccRCC, and FER may serve as a novel prognostic marker for ccRCC.

Decreased expression of dual-specificity phosphatase 9 is associated with poor prognosis in clear cell renal cell carcinoma

BackgroundThe molecular mechanisms involved in the development and progression of clear cell renal cell carcinomas (ccRCCs) are poorly understood. The objective of this study was to analyze the expression of dual-specificity phosphatase 9 (DUSP-9) and determine its clinical significance in human ccRCCs.MethodsThe expression of DUSP-9 mRNA was determined in 46 paired samples of ccRCCs and adjacent normal tissues by using real-time qPCR. The expression of the DUSP-9 was determined in 211 samples of ccRCCs and 107 paired samples of adjacent normal tissues by immunohistochemical analysis. Statistical analysis was performed to define the relationship between the expression of DUSP-9 and the clinical features of ccRCC.ResultsThe mRNA level of DUSP-9, which was determined by real-time RT-PCR, was found to be significantly lower in tumorous tissues than in the adjacent non-tumorous tissues (p < 0.001). An immunohistochemical analysis of 107 paired tissue specimens showed that the DUSP-9 expression was lower in tumorous tissues than in the adjacent non-tumorous tissues (p < 0.001). Moreover, there was a significant correlation between the DUSP-9 expression in ccRCCs and gender (p = 0.031), tumor size (p = 0.001), pathologic stage (p = 0.001), Fuhrman grade (p = 0.002), T stage (p = 0.001), N classification (p = 0.012), metastasis (p = 0.005), and recurrence (p < 0.001). Patients with lower DUSP-9 expression had shorter overall survival time than those with higher DUSP-9 expression (p < 0.001). Multivariate analysis indicated that low expression of the DUSP-9 was an independent predictor for poor survival of ccRCC patients.ConclusionTo our knowledge, this is the first study that determines the relationship between DUSP-9 expression and prognosis in ccRCC. We found that decreased expression of DUSP-9 is associated with poor prognosis in ccRCC. DUSP-9 may represent a novel and useful prognostic marker for ccRCC.

Diagnostic and prognostic tissuemarkers in clear cell and papillary renal cell carcinoma

Approximately one-third of all Renal Cell Carcinoma (RCC) patients undergoing a nephrectomy face metastatic disease. The availability of novel therapeutics for metastatic patients underscores the importance of identifying patients at risk of recurrence or patients responding well to specific therapies. Unlike clear cell RCC (ccRCC), information on biomarkers for the papillary subtype (pRCC) remains limited. In this review, we identified tissue markers that are differentially expressed between subtypes and may be of diagnostic use. In addition, markers with promising prognostic power for ccRCC and/or pRCC are described and their clinical value is discussed. To identify diagnostic markers that differentiate between pRCC and ccRCC a Pubmed search was performed, limited to original articles published in the English language between 1990 and 2009, using the terms pRCC/papillary RCC/papillary renal cell carcinoma/papillary kidney cancer, biomarker/biomarkers, protein expression, mass spectrometry and immunohistochemistry. Prognostic markers for ccRCC and pRCC were identified using the search terms kidney cancer, renal cell carcinoma, prognostic marker, biomarker and prognosis. Only markers with independent prognostic value in multivariable analysis were included. 25 proteins are differentially expressed between ccRCC and pRCC, reflecting the molecularly distinct nature of these subtypes. 5 of these proteins were externally validated, which shows their diagnostic potential. Whereas 48 biomarkers with independent prognostic power have been identified for ccRCC patients, only CD44, CA9, p53, Ki67 and PCNA have shown prognostic value in multiple studies. Expression of IMP-3 and VEGF-R2 are independent predictors of survival of pRCC patients, although this is shown in single studies. So far 5 validated diagnostic markers are able to differentiate between ccRCC and pRCC. Few independent prognostic markers have been identified for pRCC in single studies, compared to numerous biomarkers identified for the more common ccRCC. Despite the abundance of promising markers for ccRCC, their exact role in clinical decision making still needs to be established through validation studies.

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.