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The Use of Reverse Phase Protein Arrays RPPA to Explore Protein Expression Variation within Individual Renal Cell Cancers
Published on: January 22, 2013
Classification of Clear Cell Renal Cell Carcinoma based on Tumor Suppressor Genomic Profiling
Weimin Zhong1, Fengling Zhang1, Chaoqun Huang1
1The Fifth Hospital of Xiamen, Xiamen 361101, Fujian Province, China.
Abstract:
Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of malignancy in adults. However, the clinical significance of tumor suppressor genes (TSG) is largely elusive. Herein, the expression profile TSGs and its clinical response in ccRCC were investigated. A total of 603 ccRCC samples from two cohorts (TCGA and ICGC) were retrieved in this study. Three molecular subtypes (C1, C2, and C3) were identified based on the TSGs expression profile in the TCGA dataset. Through Weighted Gene Correlation Network Analysis (WGCNA), six modules associated with three subtypes were identified. Pathway enrichment for the modules revealed that crucial pathways including p53 signaling and immune-related pathways were significantly enriched. We further focused on the relationship between immune infiltration level and subtypes, and found that subtype C1 was associated with higher immune infiltration level, subtype C2 was corresponding with medium immune infiltration level, whereas subtype C3 was correlated with lower immune infiltration level. Interestingly, C2 have a better survival outcome, while C1 and C3 showed a poor prognosis. Considering their survival difference, we then performed a differentially expression analysis between C2 and C1&3, and a total of 99 differentially expressed tumor suppressor genes (DETSGs) were identified. According to these DETSGs, 59 potential compounds with 28 mechanisms of action (MOA) were predicted using the Connectivity Map (CMap) database. Among these compounds, leflunomide, naftopidil, and ribavirin were the most prospective compounds for the treatment of ccRCC. In addition, we found that subtype C2 is more sensitive to sorafenib and sunitinib drugs, and C2 have more likelihood to be responded to immunotherapy. In summary, the three subtypes hinged on the tumor suppressor gene expression for ccRCC might contribute to understanding the underlying molecular mechanisms of ccRCC. Also, its potential compounds might offer guidelines for developing a novel treatment strategy of ccRCC.
Insights
Clear cell renal cell carcinoma (ccRCC) subtypes were identified based on tumor suppressor gene expression. Subtype C2 shows better survival and potential drug sensitivity, offering new treatment strategies for ccRCC.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Clear cell renal cell carcinoma (ccRCC) is the most common adult kidney cancer.
- The clinical role of tumor suppressor genes (TSGs) in ccRCC remains unclear.
- Understanding ccRCC molecular subtypes is crucial for targeted therapies.
Purpose of the Study:
- To investigate the expression profile of TSGs in ccRCC.
- To identify molecular subtypes based on TSG expression.
- To explore the clinical significance and therapeutic potential of these subtypes.
Main Methods:
- Analysis of 603 ccRCC samples from TCGA and ICGC cohorts.
- Weighted Gene Correlation Network Analysis (WGCNA) to identify gene modules.
- Pathway enrichment analysis and immune infiltration assessment.
- Differential gene expression analysis and drug compound prediction using CMap database.
Main Results:
- Three molecular subtypes (C1, C2, C3) were identified based on TSG expression.
- Subtypes correlate with distinct immune infiltration levels and prognoses.
- Subtype C2 exhibits better survival and sensitivity to targeted therapies and immunotherapy.
- 99 differentially expressed TSGs were identified, leading to the prediction of 59 potential therapeutic compounds.
Conclusions:
- TSG-based molecular subtypes provide insights into ccRCC heterogeneity.
- Subtype C2 represents a group with favorable prognosis and therapeutic potential.
- Identified compounds like leflunomide, naftopidil, and ribavirin warrant further investigation for ccRCC treatment.
- These findings may guide novel therapeutic strategies for ccRCC.
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