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Updated: Apr 29, 2026
Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
Molecular genetics of clear-cell renal cell carcinoma
1From the Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX. james.brugarolas@utsouthwestern.edu.
Abstract:
Renal cell carcinoma of clear-cell type (ccRCC) is an enigmatic tumor type, characterized by frequent inactivation of the VHL gene (infrequently mutated in other tumor types), responsiveness to angiogenesis inhibitors, and resistance to both chemotherapy and conventional radiation therapy. ccRCC tumors exhibit substantial mutation heterogeneity. Recent studies using massively parallel sequencing technologies have implicated several novel driver genes. In VHL wild-type tumors, mutations were discovered in TCEB1, which encodes Elongin C, a protein that binds to VHL and is required for its function. Several additional tumor suppressor genes have been identified near the VHL gene, within a region that is frequently deleted in ccRCC on chromosome 3p: SETD2, BAP1, and PBRM1. Mutations in BAP1 and PBRM1 are largely mutually exclusive and are associated with different tumor biology and patient outcomes. In addition, the mTORC1 pathway is deregulated by mutations in MTOR, TSC1, PIK3CA, and PTEN in approximately 20% of ccRCCs. Mutations in TSC1, and possibly other genes, may predict for sensitivity to mTORC1 inhibitors. These discoveries provide insight into ccRCC development and set the foundation for the first molecular genetic classification of the disease, paving the way for subtype-specific therapies.
Insights
Clear-cell renal cell carcinoma (ccRCC) has diverse genetic mutations, including in VHL, TCEB1, SETD2, BAP1, and PBRM1. These genetic insights are crucial for developing targeted therapies for ccRCC subtypes.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Clear-cell renal cell carcinoma (ccRCC) is a complex cancer with unique genetic features, including frequent VHL gene inactivation.
- ccRCC shows resistance to traditional treatments but responds to angiogenesis inhibitors, suggesting specific molecular pathways are involved.
- Tumor heterogeneity and recent discoveries of novel driver genes highlight the need for a deeper understanding of ccRCC's genetic landscape.
Purpose of the Study:
- To identify and characterize novel driver genes and molecular pathways implicated in ccRCC development.
- To explore the genetic alterations in VHL wild-type ccRCC tumors.
- To lay the groundwork for a molecular genetic classification of ccRCC to enable subtype-specific therapies.
Main Methods:
- Massively parallel sequencing technologies were employed to analyze ccRCC tumor genomes.
- Specific genes, including TCEB1, SETD2, BAP1, PBRM1, MTOR, TSC1, PIK3CA, and PTEN, were investigated for mutations.
- Analysis focused on mutations in VHL wild-type tumors and alterations within the chromosome 3p deletion region.
Main Results:
- Mutations in TCEB1 were identified in VHL wild-type ccRCC tumors.
- Several tumor suppressor genes (SETD2, BAP1, PBRM1) located on chromosome 3p were found to be frequently deleted or mutated.
- Mutations in BAP1 and PBRM1 were largely mutually exclusive and linked to distinct tumor characteristics and patient outcomes.
- The mTORC1 pathway was found to be deregulated in about 20% of ccRCCs due to mutations in MTOR, TSC1, PIK3CA, and PTEN.
- Mutations in TSC1 may predict response to mTORC1 inhibitors.
Conclusions:
- Genetic alterations in ccRCC are diverse and involve multiple novel driver genes and pathways.
- The identification of specific mutations provides insights into ccRCC pathogenesis.
- These findings support the development of a molecular genetic classification system for ccRCC, paving the way for personalized treatment strategies.
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