Novel MicroRNA Binding Site SNPs and the Risk of Clear Cell Renal Cell Carcinoma (ccRCC): A Case-Control Study

2020 ◽  
Vol 20 ◽  
Author(s):  
Irina R. Gilyazova ◽  
Narasimha M. Beeraka ◽  
Elizaveta A. Klimentova ◽  
Kirill V. Bulygin ◽  
Vladimir N. Nikolenko ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Binding Site ◽  
Binding Sites ◽  
Renal Cell ◽  
Control Group ◽  
Allelic Discrimination ◽  
Cell Renal Cell Carcinoma ◽  
Risk Of Death ◽  
Tsc1 Gene

Background: Renal cell carcinoma represents 3% of all adult malignancies. MicroRNAs exhibit specific functions in various biological processes through their interaction with cellular mRNA involved in apoptosis and cell cycle control. Recent studies have reported the potential association of single-nucleotide polymorphisms (SNPs) in miRNA-binding sites of VHL-HIF1α pathway genes with renal cancer development and progression. Objective: The objective of this study is to investigate SNPs invoking an alteration in the nature of interaction with miRNA binding sites of VHL-HIF1α pathway genes. Patients & Methods: Total 450 cases of histologically and clinically verified ccRCC and 490 controls were included in our study. Genotyping was performed using a TaqMan PCR allelic discrimination method. Kaplan-Meier method of statistical analysis was implemented to analyze the overall patient survival rate. Results : Polymorphism rs10491534 in TSC1 gene was significantly associated with risk of developing advanced ccRCC. Allele G of rs1642742 in VHL gene was significantly prevalent in ccRCC compared with control group aged 55 and older (OR = 1.5566; CI [1.1532-2.1019]). Results from the dominant model combining individuals with AG or AA genotype showed that the A allele bearers of CDCP1 rs6773576 exhibited higher risk of death compared to GG carriers (HR 3.93, 95% CI 1.76-17.21, log-rank P = 0.0033). Conclusion: The present study delineated the association of miRNA binding site variants in VHL-HIF1α pathway genes with the ccRCC risk, which may affect clinical outcome.

Effect of EH domain containing protein 2 on the biological behavior of clear cell renal cell carcinoma

2019 ◽  
Vol 38 (8) ◽  
pp. 927-937 ◽  
Author(s):  
C Liu ◽  
S Liu ◽  
L Wang ◽  
Y Wang ◽  
Y Li ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Western Blot ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Control Group ◽  
Cell Renal Cell Carcinoma ◽  
Invasion And Migration ◽  
Eh Domain ◽  
And Migration

To investigate the effects of EH domain containing protein 2 (EHD2) on clear cell renal cell carcinoma (ccRCC) and provide new insights for the clinical treatment of rental cancer. Forty patients (26 males and 14 females, 62.4 ± 5.7 years old) with ccRCC were selected from January 2015 to December 2016 to serve as research subjects in this study. The EHD2 protein expression in the tumor tissues and adjacent healthy tissues of ccRCC patients were detected by Western Blot assay. The cells of ccRCC cell lines RLC-310 and 786-O were divided into normal control group (control), no-load control group (pLV), EHD2 overexpression group (pLV-EHD2), and EHD2 interference group (pLV-siEHD2). The expression levels of EHD2 protein in each group of cells were detected by western blot. The cell proliferation was detected by Cell Counting Kit-8 (CCK-8) assay. Wound healing assay was performed to check the cell migration ability. Transwell invasion assay was used to detect the cell invasion ability. Cell apoptosis was detected by flow cytometry. The expression level of EHD2 was significantly increased in pLV-EHD2 group and decreased in pLV-siEHD2 group compared with control group and pLV-siEHD2 group, indicating the successfully established EHD2 overexpression cell line and EHD2 RNA interference cell line. EHD2 overexpression enhanced the proliferation, invasion, and migration but inhibited the apoptosis of ccRCC cells, while EHD2 interference showed opposite functions. EHD2 interference can inhibit the development of ccRCC by inhibiting the proliferation, invasion, and migration, and EHD2 can potentially serve as a molecular target for the clinical treatment of ccRCC.

Association of topoisomerase II expression and cancer-specific death in patients with surgically resected clear cell renal cell carcinoma.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 446-446 ◽  
Author(s):  
Faithlore Patrice Gardner ◽  
Richard Wayne Joseph ◽  
Daniel Serie ◽  
Tracy W. Hilton ◽  
Mansi Parasramka ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Cancer Specific Survival ◽  
Risk Of Death ◽  
Pathologic Features ◽  
Increased Risk ◽  
Risk Of Cancer

446 Background: Despite the development of prognostic algorithms based on clinico-pathologic features, the ability to identify aggressive forms of clear cell renal cell carcinoma (ccRCC) remains suboptimal. Topoisomerase IIA (TOP2a) is a biomarker of DNA replication and a target for antineoplastic agents. Herein, we evaluate the association of TOP2a expression in ccRCC tumors with pathologic features of aggressiveness and risk of cancer-specific death. Methods: We identified 947 patients who underwent nephrectomy to treat clinically localized ccRCC between January 16, 1990, and September 27, 2006. TOP2a expression was assessed using IHC and scored as number of positive cells per mm2. We evaluated TOP2a expression using a continuous variable and tertile categories. For associations with pathologic features, we employed Kruskal-Wallis tests and for associations with cancer-specific survival, we generated Cox proportional hazard regression models. Results: HigherTOP2a expression is associated with later stage, higher grade and higher Mayo SSIGN score (all p < 0.001). The risk of death from RCC increases with increasing TOP2a expression (p trend < 0.0001). Compared to patients in the lowest tertile, those patients with tumors in the highest tertile of TOP2a expression were at increased risk of RCC death (HR=2.31 95% CI 1.64-3.25; p < 0.0001). Interestingly, among those patients with low risk disease (SSIGN score 0-3; ~95% 10 year survival), those with high TOP2a were at increased risk of RCC death (HR=3.09 95% CI 1.29-7.40; p = 0.01). Conclusions: Higher TOP2a expression is associated with more aggressive pathologic features and increased risk of cancer-specific death among patients undergoing surgery for localized ccRCC. If confirmed, these data support further inquiry for TOP2a as a prognostic and predictive biomarker for ccRCC patients.

scholarly journals SNP-SNP Interaction in Genes Encoding PD-1/PD-L1 Axis as a Potential Risk Factor for Clear Cell Renal Cell Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3521
Author(s):  
Marta Wagner ◽  
Krzysztof Tupikowski ◽  
Monika Jasek ◽  
Anna Tomkiewicz ◽  
Agata Witkowicz ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Immune Surveillance ◽  
Nucleotide Polymorphisms ◽  
Allelic Discrimination ◽  
Cell Renal Cell Carcinoma ◽  
Genes Encoding ◽  
Snp Interaction

PD-1/PD-L1 axis plays an important role in maintaining homeostasis and prevention from autoimmunity; however, in the tumor microenvironment, PD-1/PD-L1 interaction is responsible for the evasion of immune surveillance by tumor cells. We therefore hypothesized that single nucleotide polymorphisms (SNPs) in genes encoding PD-1 and PD-L1 molecules are associated with the development and outcome of renal cell carcinoma (RCC). Here we genotyped nine polymorphisms: five of PDCD1: rs36084323G>A, rs11568821G>A, rs2227981C>T, rs10204525G>A, rs7421861T>C and four of PD-L1: rs822335C>T, rs4143815G>C, rs4742098A>G, rs10815225G>C in 237 RCC patients (including 208 with clear cell RCC (ccRCC)) and 256 controls, with application of allelic discrimination method with use of TaqMan Assays. Interestingly, we found the SNP-SNP interaction between rs10815225 and rs7421861 polymorphisms associated with ccRCC risk. The rs7421861 TC genotype decreased the risk of ccRCC development compared to TT and CC genotypes in the group of rs10815225 GC + CC individuals (OR = 0.21, CI95% = 0.08; 0.54). While possessing of rs10815225 GC or CC genotype increased susceptibility to ccRCC when compared to rs10815225 GG genotype in individuals with rs7421861 TT or CC genotype (OR = 2.40, CI95% = 1.25; 4.61). In conclusion, genetic variants in PDCD1 and PD-L1 genes, especially taken together as SNP-SNP interactions, can be considered to be ccRCC risk factors.

Survival trends of men and women with metastatic clear cell renal cell carcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4566-4566
Author(s):  
Claud Grigg ◽  
Sally Trufan ◽  
Peter E Clark ◽  
Stephen Boyd Riggs ◽  
Jason Zhu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Clinical Stage ◽  
Tumor Biology ◽  
Cell Renal Cell Carcinoma ◽  
Risk Of Death ◽  
Increased Risk

4566 Background: Clear cell renal cell carcinoma (ccRCC) is nearly twice as common in men as in women, and women with non-metastatic RCC have a better prognosis than men. The etiology for these disparities is not known, though sex-specific differences in risk factor prevalence and tumor biology have been reported. The differential impact of systemic therapies, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), on prognosis in women and men with metastatic ccRCC is not defined. Methods: Clinicopathologic features and survival of patients with clinical stage IV ccRCC were obtained from the National Cancer Database (NCDB). Patients were grouped by date of metastatic diagnosis into three eras that correspond to major advances in systemic therapy: 2004-2005 (pre-TKI), 2006-2014 (TKI), and 2015-2016 (ICI). Uni- and multi-variable chi-square, logistic regression, and survival analyses were used for comparisons. Survival differences were assessed using Kaplan-Meier curves. Results: 15,025 male and 7,100 female patients with metastatic ccRCC were identified. Demographic features were similar between cohorts though females were slightly older (median 64.8 vs 62.7 mo, p < 0.0001), more likely to be black (6.5% vs 6.0%, p = 0.0119) or receiving Medicare benefits (46.4% vs 39.9%, p < 0.0001). In the combined cohort, median overall survival (OS) was higher in patients diagnosed in the ICI vs TKI (23.0 vs 16.5 mo) and pre-TKI eras (14.4 mo, log-rank p < 0.0001). Compared with men of the same age groups, OS was inferior for women age 50-64 yr (median 18.4 vs 21.1mo, p = 0.0084) and > 64 yr (15.3 vs 12.6mo, p = 0.0001), but not < 50 yr (20.3 vs 21.7mo, p = 0.6290). In the ICI era, median OS improved by a lesser absolute but similar relative amount for women compared to men (+5.6mo [+39%] and +7.2mo [+41%]), respectively). After controlling for age, race, Charlson-Deyo score, initial treatment modality, and insurance and socioeconomic status, women remained at increased risk of death in both the ICI era (HR 1.12 [95% CI 1.04-1.22], p = 0.004) and the TKI era (HR 1.08 [1.04-1.12], p < 0.001). Conclusions: Women with metastatic ccRCC have a worse prognosis than men which is not explained by demographic differences. This disparity is observed in both the TKI and ICI eras. This finding contrasts with previous studies suggesting women with localized RCC have a favorable prognosis compared with men. Further investigation into the sex-specific biology of metastatic ccRCC is warranted.

scholarly journals Patient Characteristics and Survival Outcomes of Non-Metastatic, Non-Clear Cell Renal Cell Carcinoma

2022 ◽  
Vol 11 ◽  
Author(s):  
Josiah An ◽  
Vignesh T. Packiam ◽  
Adithya Chennamadhavuni ◽  
Jordan Richards ◽  
Jayanshu Jain ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Collecting Duct ◽  
Oncologic Outcomes ◽  
Survival Outcomes ◽  
Cell Renal Cell Carcinoma ◽  
Risk Of Death

BackgroundNon-clear cell renal cell carcinoma (ccRCC) includes histologically and molecularly distinct subtypes such as papillary, chromophobe, collecting duct, and sarcomatoid RCC, with an incidence ranging from 20% to 25%. Oncologic outcomes and the role of adjuvant systemic therapy [vascular endothelial growth factor inhibitor (VEGFi) or immunotherapy] for non-ccRCC are not well-described.ObjectiveTo assess the incidence and survival outcomes of non-ccRCC subtypes in comparison to ccRCC.MethodsThe National Cancer Database was utilized to identify patients with non-metastatic RCC (T1–T4, N0–N1) between 2004 and 2015. The non-ccRCC cohort was further stratified by histologic subtype: papillary, chromophobe, sarcomatoid, and collecting duct RCC. Multivariable Cox regression models were used to compare overall survival (OS).ResultsThe 5-year OS for chromophobe, papillary, clear cell, collecting duct, and sarcomatoid RCC was 91%, 82%, 81%, 44%, and 40%, respectively. After adjusting for clinicopathologic and treatment characteristics, there was no significant difference in OS between papillary RCC and ccRCC (p = 0.17). Patients with collecting duct and sarcomatoid subtypes were at over two times increased risk of death compared to patients with clear cell (p &lt; 0.01 and p &lt; 0.01, respectively). Conversely, patients with chromophobe RCC were at 36% decreased risk of death compared to ccRCC (p &lt; 0.01).ConclusionsThis hospital-based analysis confirms that collecting duct and sarcomatoid histologic subtypes are uncommon and associated with poor survival after surgery when compared to the other RCC subtypes. Further studies are needed to evaluate the role of neoadjuvant and adjuvant systemic therapies in these subtypes to improve oncologic outcomes.

scholarly journals Quantitative proteomics identifies secreted diagnostic biomarkers as well as tumor-dependent prognostic targets for clear cell Renal Cell Carcinoma

2021 ◽  
Author(s):  
Aydanur Senturk ◽  
Ayse Tugce Sahin ◽  
Ayse Armutlu ◽  
Murat Can Kiremit ◽  
Omer Acar ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Quantitative Proteomics ◽  
Clear Cell ◽  
Expression Profiles ◽  
Cell Renal Cell Carcinoma ◽  
Risk Of Death ◽  
Proteomics Approach ◽  
Approved Drugs

AbstractClear cell Renal Cell Carcinoma (ccRCC) is the third most common and most malignant urological cancer, with a 5-year survival rate of 10% for patients with advanced tumors. Here, we identified 10,160 unique proteins by in-depth quantitative proteomics, of which 955 proteins were significantly regulated between tumor and normal adjacent tissues. We verified 4 putatively secreted biomarker candidates, namely PLOD2, FERMT3, SPARC and SIRPα, as highly expressed proteins that are not affected by intra- and inter-tumor heterogeneity. Moreover, SPARC displayed a significant increase in urine samples of ccRCC patients, making it a promising marker for clinical screening assays. Furthermore, based on molecular expression profiles, we propose a biomarker panel for the robust classification of ccRCC tumors into two main clusters, which significantly differed in patient outcome with an almost three times higher risk of death for cluster 1 tumors compared to cluster 2 tumors. Moreover, among the most significant clustering proteins, 13 were targets of repurposed inhibitory FDA-approved drugs. Our rigorous proteomics approach identified promising diagnostic and tumor-discriminative biomarker candidates which can serve as therapeutic targets for the treatment of ccRCC.

Association of topoisomerase II expression and cancer-specific death in patients with surgically resected clear cell renal cell carcinoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15539-e15539
Author(s):  
Faithlore Patrice Gardner ◽  
Richard Wayne Joseph ◽  
Daniel Serie ◽  
Tracy W. Hilton ◽  
Mansi Parasramka ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Cancer Specific Survival ◽  
Risk Of Death ◽  
Pathologic Features ◽  
Increased Risk ◽  
Risk Of Cancer

e15539 Background: Despite the development of prognostic algorithms based on clinico-pathologic features, the ability to identify aggressive forms of clear cell renal cell carcinoma (ccRCC) remains suboptimal. Topoisomerase IIA (TOP2a) is a biomarker of DNA replication and a target for antineoplastic agents. Herein, we evaluate the association of TOP2a expression in ccRCC tumors with pathologic features of aggressiveness and risk of cancer-specific death. Methods: We identified 1,380 patients who underwent nephrectomy to treat clinically localized ccRCC between 1/16/1990 and 4/14/2009. TOP2a expression was assessed using IHC and scored as number of positive cells per mm2. We evaluated TOP2a expression using a continuous variable and tertile categories. For associations with pathologic features we employed Kruskal-Wallis tests and for associations with cancer-specific survival we generated Cox proportional hazard regression models. Results: HigherTOP2a expression is associated with later stage, higher grade and higher MayoSSIGN score (all p < 0.001). The risk of death from RCC increases with increasing TOP2a expression (p trend < 0.0001), and this association remained strong after after multivariate adjustment for well-known predictors of RCC aggressiveness. Compared to patients in the lowest tertile, those patients with tumors in the highest tertile of TOP2a expression were at increased risk of RCC death (HR=2.62 95% CI 1.95-3.54; p<0.0001). Interestingly, among those patients with low risk disease (SSIGN score 0-3; ~95% 10 year survival), those with high TOP2a were at increased risk of RCC death (HR=3.48 95% CI 1.56-7.76; p =0.002). Conclusions: Higher TOP2a expression is associated with more aggressive pathologic features and increased risk of cancer-specific death among patients undergoing surgery for localized ccRCC. If confirmed, these data support further inquiry for TOP2a as a prognostic and predictive biomarker for ccRCC patients.

scholarly journals POLR2A Drives Tumor Cell Aggressive in Both VHL and PBRM1 Mutation Renal-Cell Carcinoma

2021 ◽  
Author(s):  
Linyan Chai ◽  
Zhengguo Qiu ◽  
Xiaozhi Zhang ◽  
Rong Li ◽  
Yao Wang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Control Group ◽  
Cell Renal Cell Carcinoma

Abstract Background: Loss of VHL always results in the loss of PBRM1 and causes aggressive clear cell renal cell carcinoma. However, VHL mutation was not significantly associated with worse survival, and PBRM1 modulate the tumor behavior is not clear. Thus, exploration of key molecules promoting the tumor aggressive is urgent in both VHL and PBRM1 RCC patient.Methods and results: POLR2A was screened out by analyzing The Cancer Genome Atlas mutation data. Gene Set Enrichment Analysis results showed that E2F, G2M, and mTOR1 pathways were all altered in response to POLR2A high expression. Furthermore, In vitro, knockdown of POLR2A in 769-P and 786-O cells resulted in cell growth arrest and cell cycle blockade compared to control cells, the mechanism though decreasing cyclin D1-CDK4 axis. In vivo results were confirmed 786-O cells in which POLR2A expression was silenced, exhibited tumor growth inhibited compared to control group.Conclusions: POLR2A was the key protein after VHL and PBRM1 mutations in RCC, inhibition of POLR2A crippled cell viability and proliferation in vivo and in vitro, We anticipate POLR2A represents a novel candidate for RCC treatment.

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