Survival In Renal Cell Carcinoma Research Articles

BUB1B Overexpression Is an Independent Prognostic Marker and Associated with CD44, p53, and PD-L1 in Renal Cell Carcinoma

Introduction: BUB1 mitotic checkpoint serine/threonine kinase B encoded by BUB1B gene is a member of the spindle assembly checkpoint family. Several reports have demonstrated that overexpression of BUB1B is associated with cancer progression and prognosis. Objective: This study aims to clarify the expression and function of BUB1B in renal cell carcinoma (RCC). Methods: The expression of BUB1B was determined using immunohistochemistry and bioinformatics analysis in RCC. The effects of BUB1B knockdown on cell growth and invasion were evaluated. We analyzed the interaction between BUB1B, cancer stem cell markers, p53, and PD-L1 in RCC. Results: In 121 cases of RCC, immunohistochemistry showed that 30 (25%) of the RCC cases were positive for BUB1B. High BUB1B expression was significantly correlated with high nuclear grade, T stage, and M stage. A Kaplan-Meier analysis showed that the high expression of BUB1B was associated with poor overall survival after nephrectomy. High BUB1B expression was associated with CD44, p53, and PD-L1 in RCC. Knockdown of BUB1B suppressed cell growth and invasion in RCC cell lines. Knockdown of BUB1B also suppressed the expression of CD44 and increased the expression of phospho-p53 (Ser15). In silico analysis showed that BUB1B was associated with inflamed CD8+, exhausted T-cell signature, IFN-γ signature, and the response to nivolumab. Conclusion: These results suggest that BUB1B plays an oncogenic role and may be a promising predictive biomarker for survival in RCC.

Statin use and the overall survival of renal cell carcinoma: A meta-analysis.

Statins are commonly prescribed drugs that reduce cholesterol levels and the risk of cardiovascular and cerebrovascular events. Clinical studies have shown that statins also possess cancer-preventive properties. Two studies have reported that statins also possess cancer-preventive properties; however, whether statins improve the prognosis of patients with renal cell carcinoma is still unclear. In this study, we used meta-analysis to evaluate the association between statin use and overall survival risk in patients with renal cell carcinoma. Published studies on statin-treated renal cell carcinoma were retrieved from PubMed, Embase, The Cochrane Library, China National Knowledge Infrastructure and Wanfang databases from inception to July 2019. The relevant data were extracted and a meta-analysis was performed using Cochrane Review Manager (RevMan 5.3) software. Data from five studies, which reported on 5,299 patients, were analysed. The application of statins showed no effects on the overall survival of patients with renal cell carcinoma compared with the control group (OR = 1.07, 95% CI:0.77 to 1.49, P = 0.68). The findings of this meta-analysis suggest that statin application does not affect the overall survival of patients with renal cell carcinoma.

Clinicopathological characteristics and oncological outcomes of patients with renal cell carcinoma.

Although certain characteristics of renal cell carcinoma (RCC) seen in Sri lanka are different to the developed world and incidence is rising, no data on oncological outcome and patient survival are avaialble. A hospital-based cohort study was done in a tertiary referral centre over a period of eight years (2012-2019). A total of 285 newly diagnosed RCC had a mean follow-up period of 28.3 months. Radical nephrectomy was performed in 189 patients while 91 patients had partial nephrectomy. Clear cell RCC which was seen in 231 (81.1%) patients while papillary RCC was seen in 43 (15.1%). There were 54 deaths during the follow-up. The 30-day postoperative mortality was 2.1%. Thirty (10.5%) patients developed metastases while three patients developed local recurrences. The overall five -year survival rate was 72.8% (95%CI=65.9-80.5). Five-year survival of papillary RCC (60.5%) was lower than clear cell RCC (74.1%). Tumour stage, presence of metastases and histological grade of the tumour influenced the survival. Gender (p= 0.3), histological type (p= 0.5) or type of surgery (p=0.2) had no statistically significant effect on survival.

BRD4 inhibition sensitizes renal cell carcinoma cells to the PI3K/mTOR dual inhibitor VS-5584.

Activation of the PI3K/AKT/mTOR pathway promotes the progression of renal cell carcinoma (RCC). This study tested the anti-RCC cell activity of the PI3K/mTOR dual inhibitor, VS-5584. We show that VS-5584 inhibited PI3K/AKT/mTORC1/2 activation in established (786-O and A498 lines) and primary RCC cells, thereby suppressing cell survival, proliferation, migration and cell cycle progression. VS-5584 induced significant apoptosis in RCC cells. A daily single oral dose of VS-5584 (20 mg/kg) significantly inhibited 786-O tumor growth in vivo. VS-5584 treatment of 786-O tumor xenografts and RCC cells resulted in feedback upregulation of bromodomain-containing protein 4 (BRD4). Furthermore, BRD4 inhibition (by JQ1 and CPI203), knockdown or complete knockout potentiated VS-5584-induced RCC cell death and apoptosis. Conversely, forced overexpression of BRD4 attenuated the cytotoxicity of VS-5584 in 786-O cells. Collectively, VS-5584 potently inhibits RCC cell proliferation and survival. Its anti-tumor activity is further enhanced by the targeted inhibition of BRD4.

MBD2 Correlates with a Poor Prognosis and Tumor Progression in Renal Cell Carcinoma.

PurposeDNA methylation plays an important role in regulating gene expression. Methyl-CpG-binding domain (MBD) proteins recognize and bind to methylated DNA, which mediate gene silencing by the interaction with deacetylases and histone methyltransferases. MBD2 has been reported in various human cancers; however, its clinical implication and potential regulatory role in renal cell carcinoma (RCC) have not been elaborated.Materials and MethodsIn the study, we estimated the expression and prognostic value of MBD2 in RCC cell lines and tissues by Western blotting and immunohistochemistry. The associations of MBD2 expression and pathological characters and survival in RCC patients were performed using χ2 and Kaplan–Meier survival analysis, respectively. Univariate and multivariable Cox regression analyses suggested the independent predictors in RCC prognosis. The functional role of MBD2 in RCC progression was assessed by in vitro cell experiments. In addition, we identified the MBD2-mediated alterations of protein-related proliferation and EMT markers in RCC cells after MBD2 overexpression and knockdown.ResultsWe found that the protein levels of MBD2 were upregulated in RCC cells and tissues. High MBD2 expression was related to TNM stage and predicted poorer survival in RCC. Enforced expression of MBD2 significantly promoted the proliferation, cycle progress, invasion and migration of RCC cells in vitro. However, downregulating MBD2 remarkably weakened the above cell functions. Mechanistically, the promotive effect of MBD2 overexpression may be regulated by its effects onp21, p53 and Cyclin D1 expression and EMT process.ConclusionThese results indicated that MBD2confers an oncogenic function in the malignant progression of RCC. MBD2 could be served as a meaningful prognostic biomarker and a latent therapeutic target in RCC patients.

Renal Cell Carcinoma: Predicting DNA Methylation Subtyping and Its Consequences on Overall Survival With Computed Tomography Imaging Characteristics.

The aim of the study was to investigate associations between computed tomography (CT) imaging characteristics, DNA methylation subtyping, and overall survival in renal cell carcinomas. Survival curves were calculated using the Kaplan-Meier analysis. The CT data from 212 patients generated with The Cancer Imaging Archive (TCIA) were reviewed. Identified were 70 (33.0%) M1 subtype, 17 (8.0%) M2 subtype, and 125 (59.0%) M3 subtype. Univariate and multivariate analyses were performed using the logistic regression model. Patients with M1 subtype had the shortest median overall survival (P < 0.001). On univariate analysis, long axis of 70 mm, intratumoral calcifications, enhancement, long axis > median, short axis > median, and intratumoral vascularity were associated with a significantly higher incidence of M1 subtype (P < 0.05). Short axis ≤ median, absence of necrosis, absence of intratumoral vascularity, and nodular enhancement were associated with M2 subtype (P < 0.05). Short axis ≤ median, long axis ≤ median, long axis of less than 70 mm, and necrosis were associated with a significantly higher incidence of M3 subtype (P < 0.05). On multivariate logistic regression analysis, long axis of greater than 70 mm (odds ratio [OR] = 2.452, P = 0.004; 95% confidence interval [CI] = 1.332-4.514) and necrosis (OR = 4.758, P = 0.041, 95% CI = 1.065-21.250) were associated with M1 subtype (area under the curve [AUC] = 0. 664). Necrosis (OR = 0.047, P < 0.001, 95% CI = 0.012-0.178) and enhancement (OR = 0.083, P = 0.024, 95% CI = 0.010-0.716) were associated with M2 subtype (AUC = 0.909). Long axis > median (OR = 0.303, P < 0.001, 95% CI = 0.164-0.561) and necrosis (OR = 3.256, P = 0.003, 95% CI = 1.617-10.303) were associated with M3 subtype (AUC = 0. 664). The shortest survival was observed in patients with M1 subtype. This preliminary radiogenomics analysis of renal cell carcinoma demonstrated associations between CT imaging characteristic and DNA methylation subtyping.

Re: Impact of Hospital Nephrectomy Volume on Intermediate- to Long-Term Survival in Renal Cell Carcinoma.

No AccessJournal of UrologyUrological Survey1 Nov 2020Re: Impact of Hospital Nephrectomy Volume on Intermediate- to Long-Term Survival in Renal Cell Carcinoma M. Pilar LagunaMD, PhD M. Pilar LagunaM. Pilar Laguna More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001259AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Re: Impact of Hospital Nephrectomy Volume on Intermediate- to Long-Term Survival in Renal Cell Carcinoma." The Journal of Urology, 204(5), pp. 1092–1093 Suggested Reading : Impact of surgical factors on robotic partial nephrectomy outcomes: comprehensive systematic review and meta-analysis. J Urol 2018; 200: 258. Link, Google Scholar : Trends in regionalization of inpatient care for urological malignancies, 1988 to 2002. J Urol 2007; 178: 2103. Link, Google Scholar : Hospital volume is a determinant of postoperative complications, blood transfusion and length of stay after radical or partial nephrectomy. J Urol 2012; 187: 405. Link, Google Scholar : Trends in renal surgery: robotic technology is associated with increased use of partial nephrectomy. J Urol 2013; 189: 1229. Link, Google Scholar : Volume-outcome relationships in the treatment of renal tumors. J Urol 2012; 187: 1984. Link, Google Scholar : National trends in the use of partial nephrectomy: a rising tide that has not lifted all boats. J Urol 2012; 187: 816. Link, Google Scholar : The impact of provider volume on outcomes from urological cancer therapy. J Urol 2005; 174: 432. Link, Google Scholar : Differential use of partial nephrectomy for intermediate and high complexity tumors may explain variability in reported utilization rates. J Urol 2013; 189: 2047. Link, Google Scholar : Contemporary trends in nephrectomy for renal cell carcinoma in the United States: results from a population based cohort. J Urol 2011; 186: 1779. Link, Google Scholar : Increasing use of kidney sparing approaches for localized renal tumors in a community based health system: impact on renal functional outcomes. J Urol 2011; 186: 1229. Link, Google Scholar : When partial nephrectomy is unsuccessful: understanding the reasons for conversion from robotic partial to radical nephrectomy at a tertiary referral center. J Urol 2017; 198: 30. Link, Google Scholar : Hospital surgical volume and associated postoperative complications of pediatric urological surgery in the United States. J Urol 2015; 194: 506. Link, Google Scholar © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 204Issue 5November 2020Page: 1092-1093 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information M. Pilar Laguna More articles by this author Expand All Advertisement PDF DownloadLoading ...

Serum tumour associated trypsin inhibitor, as a biomarker for survival in renal cell carcinoma

Objective Tumour associated trypsin inhibitor (TATI) is a peptide that is a marker for several tumours. TATI may also behave as an acute phase reactant in severe inflammatory disease. Overexpression of TATI predicts an unfavourable outcome for many cancers. This study aimed to evaluate the prognostic value of pre- and postoperative concentration of TATI in serum (S-TATI) of patients with renal cell carcinoma (RCC). Materials and methods S-TATI was determined by time resolved immunofluorometric assay in preoperative and postoperative samples that were collected from 132 RCC patients, who underwent partial or complete nephrectomy in Helsinki University Hospital from May 2005 to July 2010. Results Preoperative S-TATI was significantly associated with tumour stage, lymph-node involvement, metastatic stage, Chronic Kidney Disease Stage (CKD grade), and preoperative C-reactive protein level (p < 0.05). Postoperative S-TATI was significantly associated only with CKD grade (p < 0.001). Multivariate Cox regression analysis of postoperative S-TATI, as a continuous variable, was an independent prognostic factor for overall survival (HR = 1.01, 95% CI = 1.00−1.01, p = 0.03) and cancer-specific survival (CSS) (HR = 1.01, 95% CI = 1.00−1.02, p = 0.004). Conclusions Our data suggest that elevated postoperative S-TATI may be associated with adverse prognosis in RCC patients.

The influence of venous tumor thrombus combined with bland thrombus on the surgical treatment and prognosis of renal cell carcinoma patients.

ObjectiveTo describe the clinical characteristics of renal cell carcinoma (RCC) with venous tumor thrombus (VTT) and bland thrombus (BT), and to evaluate the influence of BT on surgical treatment and cancer‐specific survival (CSS) of RCC with VTT.MethodsWe retrospectively reviewed clinical data of 123 patients with RCC and VTT, who underwent surgical treatment in our center between February 2015 and May 2018. Patients were divided into the BT group (21 patients) and non‐BT group (102 patients). Chi‐square and Mann‐Whitney U test were used for categorical and continuous variables respectively. Univariable log‐rank tests and multivariable Cox regressions were conducted to evaluate the prognostic significance of each variable. Kaplan‐Meier plots were performed to evaluate the influence of BT.ResultsIn the delayed phase of enhanced magnetic resonance imaging (MRI), BT and VTT had difference. Patients were divided according to the relative position of BT: proximal end BT (one patients), contralateral renal vein BT (two patients), distal end BT (12 patients), and multiple BT (six patients). The average length of BT was 8.4 ± 5.8 cm (range: 0.6‐20.0 cm). Patients with BT had longer operative time (P = .001), more surgical blood loss (P = .004), higher proportion of open surgery (P = .006), more postoperative complications (P = .011). BT (hazard ratio [HR] = 3.323, P = .007) were independent risk factors for poor prognosis.ConclusionsIn the delayed phase of enhanced MRI, BT showed no obvious enhancement, while VTT usually showed enhancement. This was an important basis for preoperative imaging diagnosis of BT. The presence of BT increases the difficulty of surgery, and is correlated with adverse survival outcomes in patients with RCC and VTT.

Outcome of renal cell carcinoma in patients on dialysis compared to non-dialysis patients.

To investigate the impact of hemodialysis on survival in renal cell carcinoma (RCC) patients. We studied 388 patients who underwent radical or partial nephrectomy for RCC at Toranomon Hospital from 2005 to 2013. Survival curves were drawn according to the Kaplan-Meier method and compared with the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model to assess the prognostic influence of hemodialysis on cancer-specific survival. Of the 388 patients, 66 were on hemodialysis and 322 were not on dialysis. In the hemodialysis patients, incidental diagnosis of RCC was less frequent than in the non-dialysis patients. In addition, RCC was more likely to be multicentric (41% vs 1.2%), bilateral (14% vs 0.6%), and papillary (18% vs 7%) in hemodialysis patients. Moreover, tumors were smaller, the stage was lower, and the Fuhrman nuclear grade was higher in the patients on hemodialysis. The 5-year cancer-specific survival rate was 82.8% for hemodialysis patients and 93.5% for nondialysis patients. Multivariate analysis indicated that hemodialysis, stage, and Fuhrman nuclear grade were independent prognostic factors for RCC. This study suggested that hemodialysis was an independent prognostic factor for cancer-specific survival in RCC patients, along with the tumor stage and Fuhrman nuclear grade.

An evaluation of the role of tumor load in cytoreductive nephrectomy.

New radiological tools can accurately provide preoperative three-dimensional spatial assessment of metastatic renal cell carcinoma (RCC). We aimed to determine whether the distribution, volume, shape, and fraction of RCC resected in a cytoreductive nephrectomy associates with survival. We retrospectively reviewed 560 patients undergoing cytoreductive nephrectomy, performing a comprehensive volumetric analysis in eligible patients of all detectable primary and metastatic RCC prior to surgery. We used Cox regression analysis to determine the association between the volume, shape, fraction resected, and distribution of RCC and overall survival (OS). There were 62 patients eligible for volumetric analysis, with similar baseline characteristics to the entire cohort, and median survivor followup was 34 months. Larger primary tumors were less spherical, but not associated with different metastatic patterns. Increased primary tumor volume and tumor size, but not the fraction of tumor resected, were associated with inferior survival. The rank of tumors based on unidimensional size did not completely correspond to the rank by primary tumor volume, however, both measurements yielded similar concordance for predicted OS. Larger tumor volume was not associated with a longer postoperative time off treatment. Primary tumor volume was significant for predicting OS, while the fraction of disease resected did not appear to impact patient outcomes. Although rich in detail, our study is potentially limited by selection bias. Future temporal studies may help elucidate whether the primary tumor shape is associated with tumor growth kinetics.

Abstract A004: Introducing single-cell sequencing genomic DNA copy number analysis to study cancer heterogeneity in renal cell carcinoma and its potential benefits in cancer health disparities research

Abstract Renal cell carcinoma (RCC) is one of the most lethal urological malignancies and is responsible for around 80 percent of all primary renal neoplasms. In the US, every year are reported approximately 74,000 new cases and almost 15,000 deaths. It has been reported significant racial disparities in survival for renal cell carcinoma (RCC) between African Americans patients (AA), Hispanics and Caucasians Americans (CA) but more efforts are needed in order to have a high resolution genomic profile of the tumor. Currently, RCC has been characterized by extensive cancer heterogeneity using bulk sequencing. In order to get new insight in the study of RCC cancer heterogeneity, we applied DNA single cell sequencing since it has the potential to improve our understanding of this genetic feature by providing sub-clonal and variant information in high resolution. To this end, we studied cancer heterogeneity applying single cell copy number analysis and clonotype detection in four RCC tumors. 10x Chromium™ Technology was used for processing single cells. This technology provides 100 Kb CNV events, calling clonotypes down to 10 of 1000 cell inputs. The most representative sample resulted with more than 50% of tumor content. Analysis of the tumor cells showed variable median ploidies. In addition, regional copy number was estimated by processing our data in 20 Kb cases of reads. Multiple sub-clones were identified in sample number one where four clusters of sub-clones characterized cancer heterogeneity. By using Fast maximum-likelihood and Bayesian Information Criterion, the clustering process were implemented on the most representative sample to select the optimal clustering solution. This allowed us to provide a better insight of sub-clonal evolution. We detected copy number changes on entire chromosome arms and mutations at variant detection level. For this last, we identified previously reported VHL gene mutations that have been reported in RCC samples as signatures of clinical prognosis. The use of single cell copy number analysis has the potential to uncover and characterize the evolution of hidden sub-clones, highlighting their important uses in cancer health disparities research to identify genomic racial differences in RCC risk and progression of AA, Hispanics and CA patients. Citation Format: Enrique I. Velazquez Villarreal, David W. Craig, John D. Carpten. Introducing single-cell sequencing genomic DNA copy number analysis to study cancer heterogeneity in renal cell carcinoma and its potential benefits in cancer health disparities research [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A004.

Abstract C071: Effect measure modification implication of area of residence in survival disadvantage of black children with renal cell carcinoma

Abstract Purpose: Renal cell carcinoma (RCC) is a rare but severe and aggressive pediatric malignancy. While incidence is uncommon, survival is relatively low with respect to acute lymphocytic leukemia and Wilms' tumor. The incidence of RCC and mortality vary by health variance indicators, namely sex, race, and age. However, data are unavailable on some RCC determinants, such as area of residence. We aimed to assess the temporal trends and survival in pediatric RCC (pRCC). Methods: A retrospective cohort design was utilized to examine the event-free survival of children (0-19 years) with RCC using the Surveillance Epidemiology and End Result Data, 1973-2015. While the time-dependent variable, namely survival in months, was utilized, we assessed the predictors of survival, namely sex, age at diagnosis, education, insurance status, income, and tumor grade. In examining the joint effect of area of residence and race, as an exposure function with time, we used the Cox proportional hazard model, while the annual percent change was assessed using a generalized linear model. Results: Between 1973-2015, there were 174 cases of pRCC, of whom 49 died (28.2%). RCC cumulative incidence tends to increase with advancing age and males (10-14) indicating a 1.6% change between 2000-2015. With respect to area of residence, mortality was higher in urban (46.7%) relative to metropolitan (26.4%). Relative to whites (17.2%), mortality was higher among blacks (47.0%). A sizable survival difference was observed with blacks relative to whites. Compared to whites, blacks were almost three times as likely to die, Hazard Ratio (HR) = 2.90, 95% Confidence Interval (CI) = 1.56-5.31. Survival was associated with sex, with males 21% more likely to die (HR = 1.21, 95% CI 0.69-2.11). Similarly, there was a nexus with age at tumor diagnosis and survival. Although imprecise, children ages 1-4, 5-9, and 10-14 were 72%, 50%, and 21%, respectively, less likely to die compared to children ages 15-19. Tumor grade, education, and income were prognostic in survival, although imprecise. The conjoint effect of area of residence and race illustrated excess risk of dying in urban relative to metropolitan areas. In the metropolitan area, the risk of dying was almost 3 times higher for blacks compared to whites (HR = 2.78, 95% CI 1.45-5.43); in urban areas there was more black survival disadvantage, HR = 4.18, 95% CI 0.84-20.80. After controlling for age, sex, education, and insurance, the risk of dying increased among blacks with RCC in metropolitan areas, a-HR = 3.37, 99% CI 1.35-8.44. Similarly, in the urban areas, after adjustment for age, sex, and insurance, there was an increased risk of dying for blacks compared to whites, a-HR = 8.87, 99% CI 2.77-281.0. Conclusion: Pediatric RCC indicated an increased trend in males and age of diagnosis between 10-14, as well as survival disadvantage of black children. Additionally, area of residence significantly influenced racial differences in mortality. Citation Format: Phatsimo Masire, Arieanna Eaton, Kirk Dabney, Larry Holmes Jr. Effect measure modification implication of area of residence in survival disadvantage of black children with renal cell carcinoma [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C071.

Correlating Transcriptional Networks to Papillary Renal Cell Carcinoma Survival: A Large-Scale Coexpression Analysis and Clinical Validation.

We aimed to investigate the potential mechanisms of progression and identify novel prognosis-related biomarkers for papillary renal cell carcinoma (PRCC) patients. The related data were derived from The Cancer Genome Atlas (TCGA) and then analyzed by weighted gene coexpression network analysis (WGCNA). The correlation between each module and the clinical traits were analyzed by Pearson’s correlation analysis. Pathway analysis was conducted to reveal potential mechanisms. Hub genes within each module were screened by intramodule analysis, and visualized by Cytoscape software. Furthermore, important hub genes were validated in an external dataset and clinical samples. A total of 5,839 differentially expressed genes were identified. By using WGCNA, we identified 21 coregulatory gene clusters based on 289 PRCC samples. We found many modules were significantly associated with clinicopathological characteristics. The gray, pink, light yellow, and salmon modules served as prognosis indicators for PRCC patients. Pathway enrichment analyses found that the hub genes were significantly enriched in the cancer-related pathways. With the external Gene Expression Omnibus (GEO) validation dataset, we found that PCDH12, GPR4, and KIF18A in the pink and yellow modules were continually associated with the survival status of PRCC, and their expressions were positively correlated with pathological grade. Notably, we randomly chose PCDH12 for validation, and the results suggested that the PRCC patients with higher pathological grades (II + III) mostly had higher PCDH12 protein expression levels compared with those patients in grade I. These validated hub genes play critical roles in the prognosis prediction of PRCC and serve as potential biomarkers for future personalized treatment.

Gender impact on renal cell carcinoma survival: A population-based analysis.

e17099 Background: Prior evidence has suggested that females diagnosed with renal cell carcinoma (RCC) present at an earlier stage compared to males, but a survival difference between males and females has been controversial. We aimed to evaluate the impact of gender on RCC survival in the US. Methods: Data of RCC patients diagnosed between 1973 and 2015 in the US was obtained using Surveillance Epidemiology and End Results (SEER) database. We studied the overall and cancer-specific survival of patients diagnosed with RCC in the US according to gender using multivariable covariate-adjusted Cox models and Kaplan-Meier test. Results: We reviewed 155,430 RCC patients, of which 96,656 were males, and 58,774 were females. The median overall survival of female patients was 122 months and was significantly higher than male patients (98 months). Cancer-specific survival showed similar trends with females having significantly higher survival (p-value &lt; 0.001). Adjusted for age, race, stage and grade of cancer, undergoing cancer-targeted surgery, and marital status, female sex was associated with improved overall and cancer-specific survival outcomes; HR = 0.829 (p-value &lt; 0.001), and HR = 0.923 (p-value &lt; 0.001), respectively. Conclusions: Females have a significantly better overall and cancer specific survival compared to males diagnosed with renal cell carcinoma. In previous studies this disparity was attributed to the lower grade and earlier stage of RCC presentation in females, but gender-based disparity persisted in this analysis after adjusting for patient baseline and tumor characteristics. This raises the question of the hormonal effects on the progression of RCC.

Leukocyte telomere length and hTERT genetic polymorphism rs2735940 influence the renal cell carcinoma clinical outcome.

Aim: Analysis of the genetic hTERT-1327 C>T (rs2735940) influence on leukocyte telomere length (LTL) and tumor development, progression and overall survival in renal cell carcinoma (RCC) patients. Materials & methods: Using leukocyte DNA of RCC patients and healthy individuals, LTL measurement and allelic discrimination of rs2735940 was performed by real-time PCR. Results: RCC patients showed shorter LTL than healthy individuals and LTL increased with clinical stage. CC+TC genotypes healthy carriers' presented shorter LTL. However, no statistical association between the different genotypes and RCC risk. Nevertheless, CC homozygous presented a reduced time to disease progression and a lower overall survival. The use of hTERT-1327 single nucleotide polymorphism information increased the capacity to predict risk for RCC progression. Conclusion: In fact, in healthy individuals, hTERT-1327 CC+TC genotypes were associated with shorter LTL, and this single nucleotide polymorphism was associated with time to disease progression, being a promising potential prognosis biomarker to be used in the future.

Prognostic and predictive value of immune/stromal-related gene biomarkers in renal cell carcinoma.

Immune/stromal-associated genes may be promising biomarkers for cancer diagnosis and the determination of clinical cancer treatment options. The aim of the present study was to identify prognostic stromal/immune-associated genes in renal cell carcinoma (RCC). RCC gene expression data (885 cases) were obtained from The Cancer Genome Atlas database. Immune/stromal scores were calculated by using the ESTIMATE package in R. Immune/stromal scores were significantly associated with Tumor-Node-Metastasis stage, clinical stage and overall survival rate (P<0.05). There were 419 differentially expressed genes (DEGs) based on immune scores and 738 DEGs based on stromal scores. Among these DEGs, 406 DEGs based on stromal scores and 252 DEGs based on immune scores were significantly associated with overall survival rate (P<0.05). The biological functions of these DEGs were primarily enriched in the ‘immune response’ and ‘regulation of cell migration and proliferation’. These DEGs were observed in a protein-protein interaction network. A LASSO Cox regression model was used to build a prognostic 6 gene-based classifier, including the IL21R, ATP6V1C2, GBP1, P2RY10, GBP4 and TNNC2 genes [area under the curve (AUC) =0.776]. The predictive model which combined this classifier with clinical prognostic factors had a high accuracy in predicting patient survival in RCC (combined AUC =0.899). Taken together, these results demonstrated that there are significant associations between immune/stromal scores and clinicopathological staging. A set of tumor microenvironment-associated genes that have powerful prognostic value in patients with RCC were identified in the present study.

PTEN Is Involved in Sunitinib and Sorafenib Resistance in Renal Cell Carcinoma.

Targeted receptor tyrosine kinase inhibitor (TKI) is a standard treatment in advanced renal cell carcinoma (RCC). However, the role of PTEN in TKI resistance remains poorly understood. We aimed to determine the functional role of PTEN knockout and analyse the predictive significance of PTEN expression for TKI treatment in RCC. We developed PTEN knockout cells in RCC cell lines using the CRISPR-Cas9 system and analysed the effect of PTEN knockout on spheroid formation and resistance to sunitinib and sorafenib. PTEN knockout promoted spheroid formation and decreased sunitinib/sorafenib sensitivity in RCC cell lines. PTEN immunohistochemistry in 74 metastatic RCCs treated with sunitinib and sorafenib revealed negative PTEN expression in 23% of samples. Kaplan-Meier analysis showed a significant association of negative PTEN expression with poor progression-free survival in metastatic RCC treated with sunitinib and sorafenib (p=0.024) or sunitinib alone (p=0.009). PTEN may be a biomarker and therapeutic target in patients with metastatic RCC.

LncRNA 00312 Attenuates Cell Proliferation and Invasion and Promotes Apoptosis in Renal Cell Carcinoma via miR-34a-5p/ASS1 Axis.

Background Previous studies have demonstrated that lncRNAs play functional roles in regulating cancer cell proliferation, invasion, and apoptosis. Recent studies confirmed that lncRNA 00312 has important biological functions in lung and colorectal cancer. However, the role of lncRNA 00312 in renal cell carcinoma (RCC) remains unclear. Our aim was to explore the function of lncRNA 00312 in RCC and its potential molecular mechanism. Methods RCC cell lines A498 and ACHN were used as in vitro models in this study. RT-PCR was performed to determine lncRNA 00312, miR-34a-5p, and ASS1 mRNA expression. Proliferation and invasion were examined by CCK-8 and Transwell assay to confirm the function role of lncRNA 00312. Western blot analysis was used to examine the expression of apoptotic proteins Bax and Bcl-2. Results lncRNA was significantly downregulated in RCC cells such as A498 and ACHN; the expression of lncRNA 00312 in RCC tissues was significantly lower than that in adjacent normal tissues. Patients with low expression of lncRNA 00312 have worse prognosis regarding pathological grade, tumor size, and TNM stage. Overexpression of lncRNA 00312 suppressed A498 and ACHN cell proliferation and invasion, while promoting apoptosis. Our study found that miR-34a-5p had the potential binding site with lncRNA 00312 and revealed the role of miR-34a-5p in RCC. Furthermore, we confirmed that lncRNA 00312 played its role with the participation of ASS1 and miR-34a-5p. Conclusion lncRNA 00312 can inhibit RCC proliferation and invasion and promote apoptosis in vitro by suppressing miR-34a-5p and overexpressing ASS1. Our study demonstrated that the lncRNA 00312/miR-34a-5p/ASS1 axis may play a functional role in the progression of RCC; lncRNA 00312 abundance is a prognostic factor candidate for RCC survival, which provides new insights for RCC clinical treatment.in vitro models in this study. RT-PCR was performed to determine lncRNA 00312, miR-34a-5p, and ASS1 mRNA expression. Proliferation and invasion were examined by CCK-8 and Transwell assay to confirm the function role of lncRNA 00312. Western blot analysis was used to examine the expression of apoptotic proteins Bax and Bcl-2.

Perivascular Neuropilin-1 expression is an independent marker of improved survival in renal cell carcinoma.

Renal cell carcinoma (RCC) treatment has improved in the last decade with the introduction of drugs targeting tumor angiogenesis. However, the 5‐year survival of metastatic disease is still only 10–15%. Here, we explored the prognostic significance of compartment‐specific expression of Neuropilin 1 (NRP1), a co‐receptor for vascular endothelial growth factor (VEGF). NRP1 expression was analyzed in RCC tumor vessels, in perivascular tumor cells, and generally in the tumor cell compartment. Moreover, complex formation between NRP1 and the main VEGF receptor, VEGFR2, was determined. Two RCC tissue microarrays were used; a discovery cohort consisting of 64 patients and a validation cohort of 314 patients. VEGFR2/NRP1 complex formation in cis (on the same cell) and trans (between cells) configurations was determined by in situ proximity ligation assay (PLA), and NRP1 protein expression in three compartments (endothelial cells, perivascular tumor cells, and general tumor cell expression) was determined by immunofluorescent staining. Expression of NRP1 in perivascular tumor cells was explored as a marker for RCC survival in the two RCC cohorts. Results were further validated using a publicly available gene expression dataset of clear cell RCC (ccRCC). We found that VEGFR2/NRP1 trans complexes were detected in 75% of the patient samples. The presence of trans VEGFR2/NRP1 complexes or perivascular NRP1 expression was associated with a reduced tumor vessel density and size. When exploring NRP1 as a biomarker for RCC prognosis, perivascular NRP1 and general tumor cell NRP1 protein expression correlated with improved survival in the two independent cohorts, and significant results were obtained also at the mRNA level using the publicly available ccRCC gene expression dataset. Only perivascular NRP1 expression remained significant in multivariable analysis. Our work shows that perivascular NRP1 expression is an independent marker of improved survival in RCC patients, and reduces tumor vascularization by forming complexes in trans with VEGFR2 in the tumor endothelium. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.