Enhancer of Zeste Homolog 2 Expression Is Associated With Metastasis and Adverse Clinical Outcome in Clear Cell Renal Cell Carcinoma: A Comparative Study and Review of the Literature

Context.—Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase mediating chromatin condensation and epigenetic modulation, is overexpressed in various human carcinomas and is associated with adverse clinicopathologic characteristics and biologic behavior. The expression of EZH2 in renal cell carcinomas (RCCs) has not been fully characterized yet. Objective.—To evaluate the prognostic role of EZH2 in RCC by analyzing the immunohistochemical staining pattern of the marker in relation to pathologic features and clinical outcome. Design.—We correlated the immunolabeling of EZH2 with multiple clinicopathologic features, including Fuhrman nuclear grade, pathologic stage, metastatic status, and clinical outcome in 223 clear cell RCCs (CRCCs) and 21 papillary RCCs, by using tissue microarrays of primary and metastatic cases. Results.—Most CRCCs (75%) showed positive EZH2 staining, with most primary tumors showing focal staining in comparison to nonfocal staining in metastatic cases. In primary tumors, EZH2 expression was associated with higher nuclear grade and lower pathologic stage. Metastatic tumors showed a higher number of positive cases (81% versus 67%) and a more diffuse and more intense pattern of staining than primary CRCCs. For the 22 locally advanced primary tumors (T3/4) and 43 metastatic RCCs, patients who experienced RCC-related deaths significantly overexpressed the marker in comparison to patients who did not experience RCC-related mortality. Conclusions.—By showing that EZH2 expression is associated with increased metastatic potential and a worse clinical outcome, this study suggests that EZH2 can serve as a prognostic biomarker for RCC, thus confirming it as a key molecule driving oncogenesis and metastasis.

Download Full-text

Immune classification of clear cell renal cell carcinoma

Scientific Reports ◽

10.1038/s41598-021-83767-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sumeyye Su ◽

Shaya Akbarinejad ◽

Leili Shahriyari

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Renal Cell ◽

Cd4 T Cells ◽

Immune Cell ◽

Clear Cell ◽

P Value ◽

Cell Type ◽

Primary Tumors ◽

Immune Cell Type

AbstractSince the outcome of treatments, particularly immunotherapeutic interventions, depends on the tumor immune micro-environment (TIM), several experimental and computational tools such as flow cytometry, immunohistochemistry, and digital cytometry have been developed and utilized to classify TIM variations. In this project, we identify immune pattern of clear cell renal cell carcinomas (ccRCC) by estimating the percentage of each immune cell type in 526 renal tumors using the new powerful technique of digital cytometry. The results, which are in agreement with the results of a large-scale mass cytometry analysis, show that the most frequent immune cell types in ccRCC tumors are CD8+ T-cells, macrophages, and CD4+ T-cells. Saliently, unsupervised clustering of ccRCC primary tumors based on their relative number of immune cells indicates the existence of four distinct groups of ccRCC tumors. Tumors in the first group consist of approximately the same numbers of macrophages and CD8+ T-cells and and a slightly smaller number of CD4+ T cells than CD8+ T cells, while tumors in the second group have a significantly high number of macrophages compared to any other immune cell type (P-value $$<0.01$$ < 0.01 ). The third group of ccRCC tumors have a significantly higher number of CD8+ T-cells than any other immune cell type (P-value $$<0.01$$ < 0.01 ), while tumors in the group 4 have approximately the same numbers of macrophages and CD4+ T-cells and a significantly smaller number of CD8+ T-cells than CD4+ T-cells (P-value $$<0.01$$ < 0.01 ). Moreover, there is a high positive correlation between the expression levels of IFNG and PDCD1 and the percentage of CD8+ T-cells, and higher stage and grade of tumors have a substantially higher percentage of CD8+ T-cells. Furthermore, the primary tumors of patients, who are tumor free at the last time of follow up, have a significantly higher percentage of mast cells (P-value $$<0.01$$ < 0.01 ) compared to the patients with tumors for all groups of tumors except group 3.

Download Full-text

Preoperative Predicting the WHO/ISUP Nuclear Grade of Clear Cell Renal Cell Carcinoma by Computed Tomography-Based Radiomics Features

Journal of Personalized Medicine ◽

10.3390/jpm11010008 ◽

2020 ◽

Vol 11 (1) ◽

pp. 8

Author(s):

Claudia-Gabriela Moldovanu ◽

Bianca Boca ◽

Andrei Lebovici ◽

Attila Tamas-Szora ◽

Diana Sorina Feier ◽

...

Keyword(s):

Computed Tomography ◽

Renal Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Predictive Ability ◽

Nuclear Grade ◽

Training Set ◽

Cell Renal Cell Carcinoma ◽

Validation Set ◽

Sensitivity Specificity

Nuclear grade is important for treatment selection and prognosis in patients with clear cell renal cell carcinoma (ccRCC). This study aimed to determine the ability of preoperative four-phase multiphasic multidetector computed tomography (MDCT)-based radiomics features to predict the WHO/ISUP nuclear grade. In all 102 patients with histologically confirmed ccRCC, the training set (n = 62) and validation set (n = 40) were randomly assigned. In both datasets, patients were categorized according to the WHO/ISUP grading system into low-grade ccRCC (grades 1 and 2) and high-grade ccRCC (grades 3 and 4). The feature selection process consisted of three steps, including least absolute shrinkage and selection operator (LASSO) regression analysis, and the radiomics scores were developed using 48 radiomics features (10 in the unenhanced phase, 17 in the corticomedullary (CM) phase, 14 in the nephrographic (NP) phase, and 7 in the excretory phase). The radiomics score (Rad-Score) derived from the CM phase achieved the best predictive ability, with a sensitivity, specificity, and an area under the curve (AUC) of 90.91%, 95.00%, and 0.97 in the training set. In the validation set, the Rad-Score derived from the NP phase achieved the best predictive ability, with a sensitivity, specificity, and an AUC of 72.73%, 85.30%, and 0.84. We constructed a complex model, adding the radiomics score for each of the phases to the clinicoradiological characteristics, and found significantly better performance in the discrimination of the nuclear grades of ccRCCs in all MDCT phases. The highest AUC of 0.99 (95% CI, 0.92–1.00, p < 0.0001) was demonstrated for the CM phase. Our results showed that the MDCT radiomics features may play a role as potential imaging biomarkers to preoperatively predict the WHO/ISUP grade of ccRCCs.

Download Full-text

MET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors

BioMed Research International ◽

10.1155/2015/192406 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Brian Shuch ◽

Ryan Falbo ◽

Fabio Parisi ◽

Adebowale Adeniran ◽

Yuval Kluger ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Predictive Biomarkers ◽

Cell Renal Cell Carcinoma ◽

Primary Tumors ◽

Distant Tissue ◽

Significant Expression ◽

Metastatic Sites

Aims. Inhibitors of the MET pathway hold promise in the treatment for metastatic kidney cancer. Assessment of predictive biomarkers may be necessary for appropriate patient selection. Understanding MET expression in metastases and the correlation to the primary site is important, as distant tissue is not always available.Methods and Results. MET immunofluorescence was performed using automated quantitative analysis and a tissue microarray containing matched nephrectomy and distant metastatic sites from 34 patients with clear cell renal cell carcinoma. Correlations between MET expressions in matched primary and metastatic sites and the extent of heterogeneity were calculated. The mean expression of MET was not significantly different between primary tumors when compared to metastases (P=0.1). MET expression weakly correlated between primary and matched metastatic sites (R=0.5) and a number of cases exhibited very high levels of discordance between these tumors. Heterogeneity within nephrectomy specimens compared to the paired metastatic tissues was not significantly different (P=0.39).Conclusions. We found that MET expression is not significantly different in primary tumors than metastatic sites and only weakly correlates between matched sites. Moderate concordance of MET expression and significant expression heterogeneity may be a barrier to the development of predictive biomarkers using MET targeting agents.

Download Full-text

PARK2andPACRGare commonly downregulated in clear-cell renal cell carcinoma and are associated with aggressive disease and poor clinical outcome

Genes Chromosomes and Cancer ◽

10.1002/gcc.22026 ◽

2012 ◽

Vol 52 (3) ◽

pp. 265-273 ◽

Cited By ~ 18

Author(s):

Marieta I. Toma ◽

Daniela Wuttig ◽

Sandy Kaiser ◽

Alexander Herr ◽

Thomas Weber ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Clinical Outcome ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Poor Clinical Outcome ◽

Cell Renal Cell Carcinoma ◽

Aggressive Disease

Download Full-text

Exceptional Response of Metastatic Chromophobe Renal Cell Carcinoma to Vascular Endothelial Growth Factor (VEGF) Inhibitors: Should Increased VEGF-C Expression Be Used to Guide Treatment?

Case Reports in Urology ◽

10.1155/2019/2479823 ◽

2019 ◽

Vol 2019 ◽

pp. 1-6

Author(s):

Jacob W. Bruinius ◽

Karl J. Dykema ◽

Sabrina L. Noyes ◽

Bin Tean Teh ◽

Brian R. Lane

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Kinase Inhibitor ◽

Clear Cell ◽

Locally Advanced ◽

Chromophobe Renal Cell Carcinoma ◽

Molecular Profile ◽

Vegf Inhibitors ◽

Cell Renal Cell Carcinoma

There is sparse literature demonstrating effective treatments for metastatic chromophobe renal cell carcinoma (ChRCC). The tyrosine kinase inhibitor (TKI) sunitinib selectively inhibits the VEGF pathway and it is a standard care for metastatic clear cell renal cell carcinoma (ccRCC), although data supporting its use in ChRCC is much more limited. A 56-year-old underwent palliative nephrectomy for locally-advanced ChRCC with sarcomatoid differentiation. Tumor gene expression profiling using Affymetrix HG-U133 Plus 2.0 GeneChip platform demonstrated significantly elevated VEGF-C expression compared to normal renal tissue n=12 and other types RCC n=158. Adjuvant sunitinib was used to treat his residual unresectable retroperitoneal lymph nodes. He demonstrated an exceptional response and underwent complete surgical resection four months later. He has been managed with TKIs for nearly nine years with only minimal disease progression. Additional studies exploring treatment options for patients with non-clear cell RCC are needed; in their absence, we would recommend TKIs for patients whose tumors bear a similar molecular profile.

Download Full-text