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Updated: Jun 19, 2026
The Use of Reverse Phase Protein Arrays RPPA to Explore Protein Expression Variation within Individual Renal Cell Cancers
Published on: January 22, 2013
Abstract:
Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1). We surveyed more than 400 tumours using different genomic platforms and identified 19 significantly mutated genes. The PI(3)K/AKT pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 (also known as MIR21) and GRB10. Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment.
Insights
Clear cell renal cell carcinoma (ccRCC) involves genetic changes in oxygen sensing and chromatin. Metabolic shifts in aggressive ccRCC offer new therapeutic targets.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Clear cell renal cell carcinoma (ccRCC) is characterized by genetic alterations in key cellular pathways.
- Genes involved in oxygen sensing (e.g., VHL) and chromatin maintenance (e.g., PBRM1) are frequently mutated in ccRCC.
Purpose of the Study:
- To comprehensively survey genetic mutations in ccRCC.
- To identify potential therapeutic targets by analyzing pathway alterations and metabolic shifts.
Main Methods:
- Genomic profiling of over 400 ccRCC tumors using diverse platforms.
- Integrative analysis of genetic mutations, DNA methylation, and protein expression.
Main Results:
- Identified 19 significantly mutated genes, including recurrent mutations in the PI(3)K/AKT pathway.
- Linked widespread DNA hypomethylation to SETD2 mutations and SWI/SNF complex mutations to broad pathway effects.
- Observed metabolic reprogramming in aggressive ccRCC, including TCA cycle downregulation and pentose phosphate pathway upregulation.
Conclusions:
- Genetic alterations in ccRCC impact cellular metabolism, chromatin state, and signaling pathways.
- Metabolic remodeling is a recurrent feature correlating with tumor stage and severity.
- These findings provide novel insights into ccRCC pathogenesis and potential therapeutic strategies.
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