Recognizing the Continuous Nature of Expression Heterogeneity and Clinical Outcomes in Clear Cell Renal Cell Carcinoma

414 Background: While mutations in PBRM1 (~40%) and BAP1(~10%) are associated with clinical outcomes and pathologic features in clear cell renal cell carcinoma (ccRCC), the impact of protein expression of these genes remains unknown. Herein, we quantify PBRM1/BAP1 protein expression in a large cohort of patients with localized ccRCC and associate expression with cancer-specific survival (CSS) and pathologic features. Methods: We utilized the Mayo Clinic Renal Registry and identified 1,416 patients who underwent nephrectomy to treat clinically localized ccRCC between 1/3/1990 and 4/14/2009. We used immunohistochemistry (IHC) to detect PBRM1/BAP1 expression, and a central pathologist blinded to the outcomes scored tumors as either positive or negative. Tumors with heterogeneous or equivocal staining were excluded from this analysis. We generated Cox proportional hazard regression models for associations with ccRCC-SS, and we employed Mann-Whitney U tests for associations with pathologic features. Results: Of the 1,416 samples, 1,232 (87%) were PBRM1/BAP1 positive or negative, 163 (11%) had heterogeneous staining, and 21 (1%) could not be assessed. The distribution and association of PBRM1/BAP1 phenotypes with clinical outcomes are listed in the table below. PBRM1+/BAP1+ tumors have the best CSS, and PBRM1-/BAP1- have the worst. In addition, PBRM1/BAP1 expression strongly associated with the tumor size, stage, grade, and tumor necrosis (p<0.0001). Conclusions: This study is the first and largest to quantify PRBM1/BAP1 protein expression in ccRCC tumors. We were able to quantify PBRM1/BAP1 through IHC in the vast majority of tumors (87%), and PRBM1/BAP1 expression strongly associates with both CSS and pathologic tumor characteristics. Our data confirms our previous findings of the importance of PRBM1/BAP1 in the molecular pathogenesis of ccRCC. [Table: see text]

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Fumarate hydratase expression in localized, radically-resected clear cell renal cell carcinoma and its association with clinical outcomes.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.620 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 620-620

Author(s):

Giovanni FucÃ ◽

Claudio Vernieri ◽

Simona Massa ◽

Alessia Bertolotti ◽

Giovanna Garzone ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Clinical Outcomes ◽

Relapse Rate ◽

Renal Cell ◽

Clear Cell ◽

Fumarate Hydratase ◽

Cell Renal Cell Carcinoma ◽

Fuhrman Grade ◽

Tubular Cells

620 Background: Prognostic stratification of localized clear cell renal cell carcinoma (lccRCC) mainly relies on clinical characteristics and TNM staging system, while biological biomarkers are currently lacking. We previously showed that reduced expression of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) was associated with better clinical outcomes in patients (pts) with metastatic ccRCC. In the present study we aimed at assessing the association between intratumor FH expression and clinical outcomes in pts with radically-resected lccRCC. Methods: Pts with radically-resected lccRCC and available formalin-fixed, paraffin-embedded (FFPE) primary (renal) tumor tissue were included. FH protein expression was assessed by means of immunohistochemistry (IHC) and defined as normal (comparably to non-neoplastic tubular cells) or low (lower than in non-neoplastic tubular cells). Results: Out of 50 pts included, we found a normal FH expression in 20 cases (40%) and a low FH expression in 30 cases (60%). Median age was 57 years (interquartile range 49-68) and 48 pts (96%) had pN0 disease, while 2 pts (4%) had pN1 disease. Low FH expression was associated with pT ( P= .003) but not with sex, age, Fuhrman grade or pN. After a median follow-up of 76.9 months, low FH expression was associated with a lower relapse rate (13% vs 50%; odds ratio for relapse 0.16; 95% confidence interval [CI] 0.04-0.62; P= .005), longer relapse-free survival (RFS) (5-years RFS rate 90% vs 50%; HR 0.20; 95% CI 0.06-0.63; P= .006) and a trend toward a better overall survival (OS) (5-years OS rate 100% vs 77.3%; HR 0.14; 95% CI 0.02-1.23; P= .07) when compared with normal FH expression. In the multivariable model including other characteristics associated with RFS, low FH expression confirmed an independent association with RFS (adjusted HR 0.25; 95% CI 0.06-0.91; P= .03). Conclusions: In our study, low intratumor FH, as detected by IHC, was associated with lower relapse rate, better RFS and a trend toward a better OS in patients with lccRCC when compared with normal FH levels. The role of FH expression as a prognostic biomarker in this setting warrants further investigation.

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Role of Inflammatory Related Gene Expression in Clear Cell Renal Cell Carcinoma Development and Clinical Outcomes

The Journal of Urology ◽

10.1016/j.juro.2011.06.049 ◽

2011 ◽

Vol 186 (5) ◽

pp. 2071-2077 ◽

Cited By ~ 21

Author(s):

Weiqi Tan ◽

Michelle A.T. Hildebrandt ◽

Xia Pu ◽

Maosheng Huang ◽

Jie Lin ◽

...

Keyword(s):

Gene Expression ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Clinical Outcomes ◽

Renal Cell ◽

Clear Cell ◽

Related Gene ◽

Cell Renal Cell Carcinoma

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High mucin-7 expression is an independent predictor of adverse clinical outcomes in patients with clear-cell renal cell carcinoma

Tumor Biology ◽

10.1007/s13277-016-5375-5 ◽

2016 ◽

Vol 37 (11) ◽

pp. 15193-15201 ◽

Cited By ~ 6

Author(s):

SonTung NguyenHoang ◽

Yidong Liu ◽

Le Xu ◽

Yuan Chang ◽

Lin Zhou ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Clinical Outcomes ◽

Renal Cell ◽

Clear Cell ◽

Independent Predictor ◽

Cell Renal Cell Carcinoma

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Identification of CCL4 as an Immune-Related Prognostic Biomarker Associated With Tumor Proliferation and the Tumor Microenvironment in Clear Cell Renal Cell Carcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.694664 ◽

2021 ◽

Vol 11 ◽

Author(s):

Lu Zhang ◽

Mengzhao Zhang ◽

Lu Wang ◽

Jianlong Li ◽

Tao Yang ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Tumor Microenvironment ◽

Cell Carcinoma ◽

Clinical Outcomes ◽

Renal Cell ◽

Clear Cell ◽

Prognostic Biomarker ◽

Tumor Proliferation ◽

Cell Renal Cell Carcinoma ◽

Gene Sets

The last decade has witnessed revolutionary advances taken in immunotherapy for various malignant tumors. However, immune-related molecules and their characteristics in the prediction of clinical outcomes and immunotherapy response in clear cell renal cell carcinoma (ccRCC) remain largely unclear. C-C Motif Chemokine Ligand 4 (CCL4) was extracted from the intersection analysis of common differentially expressed genes (DEGs) of four microarray datasets from the Gene Expression Omnibus database and immune-related gene lists in the ImmPort database using Cytoscape plug-ins and univariate Cox regression analysis. Subsequential analysis revealed that CCL4 was highly expressed in ccRCC patients, and positively correlated with multiple clinicopathological characteristics, such as grade, stage and metastasis, while negatively with overall survival (OS). We performed gene set enrichment analysis (GSEA) and gene set variant analysis (GSVA) with gene sets coexpressed with CCL4, and observed that gene sets positively related to CCL4 were enriched in tumor proliferation and immune-related pathways while metabolic activities in the negatively one. To further explore the correlation between CCL4 and immune-related biological process, the CIBERSORT algorithm, ESTIMATE method, and tumor mutational burden (TMB) score were employed to evaluate the tumor microenvironment (TME) characteristics of each sample and confirmed that high CCL4 expression might give rise to high immune cell infiltration. Moreover, correlation analysis revealed that CCL4 was positively correlated with common immune checkpoint genes, such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and lymphocyte activating 3 (LAG3). Overall, this study demonstrated that CCL4 might serve as a potential immune-related prognostic biomarker to predict clinical outcomes and immunotherapy response in ccRCC. Moreover, CCL4 might contribute to TME modulation, indicating the mechanism CCL4 involved in tumor proliferation and metastasis, which could provide novel therapeutic perceptions for ccRCC patients.

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Linking Gene Mutations to Clinical Outcomes and Response to Therapy in Clear-cell Renal Cell Carcinoma: Ready for Prime Time?

European Urology ◽

10.1016/j.eururo.2016.10.034 ◽

2017 ◽

Vol 71 (3) ◽

pp. 415-416 ◽

Cited By ~ 1

Author(s):

Pavlos Msaouel ◽

Gabriel G. Malouf ◽

Nizar M. Tannir

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Clinical Outcomes ◽

Renal Cell ◽

Clear Cell ◽

Gene Mutations ◽

Response To Therapy ◽

Prime Time ◽

Cell Renal Cell Carcinoma

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Integration of Recurrent Somatic Mutations with Clinical Outcomes: A Pooled Analysis of 1049 Patients with Clear Cell Renal Cell Carcinoma

European Urology Focus ◽

10.1016/j.euf.2016.06.015 ◽

2017 ◽

Vol 3 (4-5) ◽

pp. 421-427 ◽

Cited By ~ 20

Author(s):

Brandon John Manley ◽

Emily C. Zabor ◽

Jozefina Casuscelli ◽

Daniel M. Tennenbaum ◽

Almedina Redzematovic ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Clinical Outcomes ◽

Renal Cell ◽

Somatic Mutations ◽

Clear Cell ◽

Pooled Analysis ◽

Cell Renal Cell Carcinoma

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Loss of DUSP4 Expression as a Prognostic Biomarker in Clear Cell Renal Cell Carcinoma

Diagnostics ◽

10.3390/diagnostics11101939 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1939

Author(s):

Seongsik Bang ◽

Seungyun Jee ◽

Hwangkyu Son ◽

Young Chan Wi ◽

Hyunsung Kim ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Mrna Expression ◽

Clinical Outcomes ◽

Renal Cell ◽

Clear Cell ◽

Negative Regulator ◽

Prognostic Impact ◽

Cell Renal Cell Carcinoma ◽

Potential Biomarker

Dual-specificity protein phosphatase 4 (DUSP4) is a negative regulator of mitogen-activated protein kinases. The prognostic impact of DUSP4 expression in renal cell carcinoma is not well studied. Therefore, we evaluated the clinicopathological implications of DUSP4 expression in clear cell renal cell carcinoma by performing immunohistochemistry (IHC). The clinical outcome according to DUSP4 expression was evaluated through survival analyses, and the association between mRNA expression and prognosis was confirmed by online analysis (Kaplan–Meier plotter). Loss of DUSP4 expression was noted in most histological subtypes of renal cell carcinoma. Loss of DUSP4 expression in clear cell renal cell carcinoma was significantly correlated with old age (p = 0.033), high histologic grade (p < 0.001), tumor necrosis (p < 0.001), and high pT category (p < 0.001). In survival analysis, loss of DUSP4 expression was associated with poor clinical outcomes in cancer-specific survival and recurrence-free survival (p = 0.010 and p = 0.007, respectively). Upon TCGA data analysis, patients with low DUSP4 mRNA expression showed a shorter overall survival (p = 0.023). These results suggest that loss of DUSP4 expression can be used as a potential biomarker for predicting clinical outcomes in clear cell renal cell carcinoma patients.

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