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Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low-risk clear cell renal cell carcinoma.

ABSTRACT: BACKGROUND:The majority of patients diagnosed with clear cell renal cell carcinoma (ccRCC) have low-risk disease with a < 10% chance of ccRCC-specific death. DNA sequencing revealed that mutations in BAP1 (BRCA1 associated protein-1) occur in 5% to 15% of ccRCC cases and are associated with poor outcomes. The vast majority of BAP1 mutations abolish protein expression. In this study, we used a highly sensitive and specific immunohistochemistry (IHC) assay to test whether BAP1 expression is an independent marker of ccRCC-specific survival, particularly in patients with low-risk disease. METHODS:BAP1 expression was assessed, using IHC, in 1479 patients who underwent nephrectomy to treat clinically localized ccRCC. A centralized pathologist dichotomized patients as either BAP1-positive or BAP1-negative. The authors employed Kaplan-Meier and Cox regression models to associate BAP1 expression with cancer-specific survival. RESULTS:A total of 10.5% of tumors were BAP1-negative, 84.8% of tumors were BAP1-positive, and 4.6% of tumors had ambiguous staining for BAP1. Patients with BAP1-negative tumors have an increased risk of ccRCC-related death (hazard ratio [HR]?= 3.06; 95% confidence interval [CI]?= 2.28-4.10; P = 6.77 × 10(-14) ). BAP1 expression remained an independent marker of prognosis after adjusting for the UCLA integrated staging system (UISS) (HR = 1.67; 95% CI = 1.24-2.25; P

SUBMITTER: Joseph RW

PROVIDER: S-EPMC4075029 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low-risk clear cell renal cell carcinoma.

Joseph Richard W RW Kapur Payal P Serie Daniel J DJ Eckel-Passow Jeanette E JE Parasramka Mansi M Ho Thai T Cheville John C JC Frenkel Eugene E Rakheja Dinesh D Brugarolas James J Parker Alexander A

Cancer 20131230 7

<h4>Background</h4>The majority of patients diagnosed with clear cell renal cell carcinoma (ccRCC) have low-risk disease with a < 10% chance of ccRCC-specific death. DNA sequencing revealed that mutations in BAP1 (BRCA1 associated protein-1) occur in 5% to 15% of ccRCC cases and are associated with poor outcomes. The vast majority of BAP1 mutations abolish protein expression. In this study, we used a highly sensitive and specific immunohistochemistry (IHC) assay to test whether BAP1 expression i ...[more]

PMID: 24382589

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Project description:ObjectiveClear cell renal cell carcinoma (ccRCC) is a malignant renal tumor that is highly prone to metastasis and recurrence. The exact pathogenesis of this cancer is still not well understood. This study aimed to identify novel hub genes in renal clear cell carcinoma and determine their diagnostic and prognostic value.MethodsIntersection genes were obtained from multiple databases, and protein-protein interaction analysis and functional enrichment analysis were performed to identify key pathways related to the intersection genes. Hub genes were identified using the cytoHubba plugin in Cytoscape. GEPIA and UALCAN were utilized to observe differences in mRNA and protein expression of hub genes between KIRC and adjacent normal tissues. The Wilcoxon rank sum test was used to analyze hub gene levels between paired KIRC and matched non-cancer samples. IHC results were obtained from the HPA online database, and according to the median gene expression level, they were divided into a high-expression group and a low-expression group. The correlation of these groups with the prognosis of KIRC patients was analyzed. Logistic regression and the Wilcoxon rank sum test were used to test the relationship between SLC34A1 level and clinicopathological features. The diagnostic value of SLC34A1 was evaluated by drawing the receiver operating characteristic (ROC) curve and calculating the area under the curve (AUC). Cox regression analysis was used to analyze the relationship between clinicopathological features, SLC34A1 expression, and KIRC survival rate. LinkedOmics was used to obtain the genes most related to SLC34A1 and their functional enrichment. Genetic mutations and methylation levels of SLC34A1 in KIRC were obtained from the cBioPortal website and the MethSurv website, respectively.ResultsFifty-eight ccRCC differential genes were identified from six datasets, and they were mainly enriched in 10 functional items and 4 pathways. A total of 5 hub genes were identified. According to the GEPIA database analysis, low expression of SLC34A1, CASR, and ALDOB in tumors led to poor prognosis. Low expression of SLC34A1 mRNA was found to be related to clinicopathological features of patients. SLC34A1 expression in normal tissues could accurately identify tumors (AUC 0.776). SLC34A1 was also found to be an independent predictor of ccRCC in univariate and multivariate Cox analyses. The mutation rate of the SLC34A1 gene was 13%. Eight of the 10 DNA methylated CpG sites were associated with the prognosis of ccRCC. SLC34A1 expression in ccRCC was positively correlated with B cells, eosinophils, neutrophils, T cells, TFH, and Th17 cells, and negatively correlated with Tem, Tgd, and Th2 cells.ConclusionThe expression level of SLC34A1 in KIRC samples was found to be decreased, which predicted a decreased survival rate of KIRC. SLC34A1 may serve as a molecular prognostic marker and therapeutic target for KIRC patients.

Project description:Clear cell renal cell carcinoma (ccRCC) accounts for approximately 4/5 of all kidney cancers. Accumulation of minor changes in the cellular homeostasis may be one cause of ccRCC. Therefore, we downloaded the RNA sequencing and survival data of the kidney renal cell carcinoma (KIRC) cohort from the Cancer Genome Atlas (TCGA) database. After the univariate and multivariate Cox regression analyses, 19 kidney-specific differentially expressed genes (DEGs) were found. Solute Carrier Family 22 Member 12 (SLC22A12) resulted in an independent prognostic predictor for both overall survival (OS) and disease-free survival (DFS). SLC22A12 expression was lower in tumoral tissue compared to normal tissue. Moreover, patients in the SLC22A12 low expression group had a higher pathological stage and worse survival than the high expression group. Additionally, qRT-PCR assay, immunoblotting test (IBT), and immunohistochemical (IHC) analyses of cancer tissues/cells and the corresponding normal controls verified that SLC22A12 is downregulated in ccRCC. Receiver operator characteristic (ROC) curves showed that the low expression level of SLC22A12 could be a good diagnostic marker for ccRCC (AUC=0.7258; p <0.0001). Gene set enrichment analysis (GSEA) showed that SLC22A12 expression levels are related to metabolism, cell cycle, and tumor-related signaling pathways. GO and KEGG analyses revealed that SLC22A12 transports multiple organic compounds, ions, and hormones and participates in the extracellular structure organization. Furthermore, SLC22A12 over-expression in vitro inhibited the proliferation, migration, and invasion of renal cancer cells by regulating PI3K/Akt pathways. Such effects were reversed when knocking out SLC22A12. In summary, as a transporter for many vital metabolites, SLC22A12 may affect tumor cell survival through its impacts on the mentioned metabolites. In conclusion, this study uncovered that SLC22A12 is a promising prognostic and diagnostic biomarker for ccRCC.

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Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low-risk clear cell renal cell carcinoma.

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Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low-risk clear cell renal cell carcinoma.

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