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EZH2 Expression is increased in BAP1-mutant renal clear cell carcinoma and is related to poor prognosis.

ABSTRACT: Aim: BAP1 is frequently mutated in clear cell renal cell carcinoma (ccRCC) with a definitive role still unclear. Methods: In silico analysis of BAP1-mutant and wild-type gene enrichment and functional annotation in TCGA-KIRC dataset was performed. Target gene was studied based on functional clustering and was knowledge-based. Validation using in-house pathological sections were performed immunohistochemically. In vitro and in vivo studies on target gene were performed. Results: The TCGA ccRCC dataset included 534 ccRCC samples. BAP1 was frequently mutated and more frequently downregulated in ccRCC compared to normal kidney tissue or benign renal tumors. In the analysis between samples with BAP1 mutation (N = 33) and pan-negative (N = 33), we found that cancers with BAP1 mutation was significantly enriched for 14 pathways, of which 3 were DNA repair pathways, in which EZH2 played a role. CcRCC patients with lower BAP1 expression had poor prognosis and showed higher EZH2 expression, which also conferred worsened survival. Genetic and pharmaceutical inhibition of EZH2 not only inhibited BAP1-mutatn ccRCC cell viability and invasion but also abrogated genetic replenishing of BAP1 expression. Validation cohort encompassing 62 ccRCC samples confirmed the worsened phenotype for cases with higher EZH2 expression and significant positive correlation between expressions of EZH2 and BAP1. EZH2 inhibitor also inhibited tumor growth in xenograft mouse model with BAP1-mutated ccRCC cells with unremarkable toxicity. Conclusion: CcRCC with decreased BAP1 level has poor prognosis and is associated with higher EZH2 expression. Inhibition of EZH2 in BAP1-mutated entity holds promise for further investigation.

SUBMITTER: Sun C

PROVIDER: S-EPMC6215999 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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EZH2 Expression is increased in BAP1-mutant renal clear cell carcinoma and is related to poor prognosis.

Sun Chenmin C Zhao Chunchun C Li Shugen S Wang Jianqing J Zhou Qidong Q Sun Jianliang J Ding Qiang Q Liu Min M Ding Guanxiong G

Journal of Cancer 20181001 20

Aim: BAP1 is frequently mutated in clear cell renal cell carcinoma (ccRCC) with a definitive role still unclear. Methods: In silico analysis of BAP1-mutant and wild-type gene enrichment and functional annotation in TCGA-KIRC dataset was performed. Target gene was studied based on functional clustering and was knowledge-based. Validation using in-house pathological sections were performed immunohistochemically. In vitro and in vivo studies on target gene were performed ...[more]

PMID: 30405850

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Project description:BackgroundRunt-related transcription factor 1 (RUNX1) was previously reported to play a dual role in promoting or suppressing tumorigenesis in various malignancies. A public dataset from The Cancer Genome Atlas (TCGA) was used to evaluate the role of RUNX1 in clear cell renal cell carcinoma (ccRCC).MethodsThe Wilcoxon signed-rank test was used to compare the expression of RUNX1 in ccRCC tissues and normal tissues. The Wilcoxon signed-rank test and logistic regression were utilized to investigate the relationship between clinicopathological factors and RUNX1 expression. Additionally, we analysed the differences in prognosis between patients with high and low expression of RUNX1 via the Kaplan-Meier method and Cox regression. Gene set enrichment analysis (GSEA) was performed to explore the mechanisms of RUNX1 in ccRCC.ResultsThe expression of RUNX1 in ccRCC tissues was significantly higher than that in normal tissues. High expression of RUNX1 was significantly associated with gender (p = 0.003), clinical stage (p < 0.001), tissue infiltration (p < 0.001), lymph node metastasis (p = 0.037) and histological grade (p < 0.001). Logistic regression analysis showed that high RUNX1 expression was significantly correlated with gender (OR = 1.71 for male vs. female, p = 0.004), histological grade (OR = 11.61 for grade IV vs. I, p < 0.001), clinical stage (OR = 1.55 for stage III/IV vs. I/II, p = 0.014) and tissue infiltration (OR = 1.54 for positive vs. negative, p = 0.018). Kaplan-Meier survival curves revealed that the prognosis of patients with ccRCC with high RUNX1 expression was worse than that of patients with ccRCC with low RUNX1 expression (p < 0.001). Univariate Cox regression analysis showed that high RUNX1 expression was strongly correlated with poor prognosis (HR = 1.60, 95% CI [1.31-1.97], p < 0.001). In addition, high expression of RUNX1 was an independent prognostic factor for poor overall survival (OS), with an HR of 1.50 (95% CI [1.20-1.87], p < 0.001) in multivariate Cox analysis. GSEA showed that the apoptosis, B cell receptor signalling pathway, calcium signalling pathway, chemokine signalling pathway, JAK/STAT signalling pathway, MAPK signalling pathway, p53 signalling pathway, pathways in cancer, T cell receptor signalling pathway, Toll-like receptor signalling pathway, VEGF signalling pathway, and Wnt signalling pathway were significantly enriched in the RUNX1 high-expression phenotype. In conclusion, RUNX1 can be used as a novel prognostic factor and therapeutic target in ccRCC.

Project description:BackgroundCDC6 (Cell division control protein 6), located at chromosome 17q21.3, plays an important role in the early stage of DNA replication and has unique functions in various malignant tumors. Here, we evaluate the relationship between CDC6 expression and oncology outcomes in patients with clear cell renal cell carcinoma (ccRCC).MethodsA retrospective analysis of 118 ccRCC patients in Affiliated Hospital of Nantong University from 2015 to 2017 was performed. Triplicate tissue microarrays (TMA) were prepared from formalin-fixed and paraffin-embedded specimens. Immunohistochemistry (IHC) was conducted to evaluate the relationship between CDC6 expression and standard pathological features and prognosis. The RNA sequencing data and corresponding clinical information were acquired from the TCGA database. GSEA was used to identify signal pathways related to CDC6. Cox regression analysis was used to assess independent prognostic factors. In addition, the relationship between CDC6 and immunity was also investigated.ResultsThe results of Kaplan-Meier curve indicated that the OS of the patients with high expression of CDC6 was shorter than that of the patients with low CDC6 expression. Integrating the TCGA database and IHC staining, the results showed that CDC6 in ccRCC tissue was obviously up-regulated compared with adjacent normal kidney tissue. The results of Logistic regression analysis demonstrated that ccRCC patients with high expression of CDC6 are more likely to develop advanced disease than ccRCC patients with low CDC6 expression. The results of GSEA showed that the high expression of CDC6 was related to multiple signaling pathways. As for immunity, it was also related to TMB, immune checkpoint molecules, tumor microenvironment and immune infiltration. There were significantly correlations with CDC6 and immune cell infiltration levels and tumor microenvironment. The results of further results of the TCGA database showed that CDC6 was obviously related to immune checkpoint molecules and immune cells.ConclusionsIncreased expression of CDC6 is a potentially prognostic factor of poor prognosis in ccRCC patients.

Dataset Information

EZH2 Expression is increased in BAP1-mutant renal clear cell carcinoma and is related to poor prognosis.

Publications

EZH2 Expression is increased in BAP1-mutant renal clear cell carcinoma and is related to poor prognosis.

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