Related Experiment Video
Updated: May 9, 2026
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Cooperation and antagonism among cancer genes: the renal cancer paradigm
Samuel Peña-Llopis1, Alana Christie, Xian-Jin Xie
1Departments of Internal Medicine, Developmental Biology, and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Abstract:
It is poorly understood how driver mutations in cancer genes work together to promote tumor development. Renal cell carcinoma (RCC) offers a unique opportunity to study complex relationships among cancer genes. The four most commonly mutated genes in RCC of clear-cell type (the most common type) are two-hit tumor suppressor genes, and they cluster in a 43-Mb region on chromosome 3p that is deleted in approximately 90% of tumors: VHL (mutated in ∼80%), PBRM1 (∼50%), BAP1 (∼15%), and SETD2 (∼15%). Meta-analyses that we conducted show that mutations in PBRM1 and SETD2 co-occur in tumors at a frequency higher than expected by chance alone, indicating that these mutations may cooperate in tumorigenesis. In contrast, consistent with our previous results, mutations in PBRM1 and BAP1 tend to be mutually exclusive. Mutation exclusivity analyses (often confounded by lack of statistical power) raise the possibility of functional redundancy. However, mutation exclusivity may indicate negative genetic interactions, as proposed herein for PBRM1 and BAP1, and mutations in these genes define RCC with different pathologic features, gene expression profiles, and outcomes. Negative genetic interactions among cancer genes point toward broader context dependencies of cancer gene action beyond tissue dependencies. An enhanced understanding of cancer gene dependencies may help to unravel vulnerabilities that can be exploited therapeutically.
Insights
Driver mutations in renal cell carcinoma (RCC) genes like VHL, PBRM1, BAP1, and SETD2 cooperate or interact negatively. Understanding these complex genetic interactions in RCC can reveal therapeutic vulnerabilities.
Area of Science:
- Oncology
- Cancer Genomics
- Molecular Biology
Background:
- The interplay between driver mutations in cancer genes is not well understood.
- Renal cell carcinoma (RCC), particularly clear-cell type, presents a model for studying these complex genetic relationships.
- Four key genes (VHL, PBRM1, BAP1, SETD2) are frequently mutated and located in a deleted region on chromosome 3p in RCC.
Purpose of the Study:
- To investigate the co-occurrence and mutual exclusivity of mutations in key RCC driver genes.
- To explore the functional implications of genetic interactions between cancer genes.
- To identify potential therapeutic vulnerabilities arising from these dependencies.
Main Methods:
- Utilized meta-analyses to assess the co-occurrence frequency of mutations in PBRM1 and SETD2.
- Performed mutation exclusivity analyses for genes including PBRM1 and BAP1.
- Correlated genetic interactions with pathological features, gene expression profiles, and patient outcomes in RCC.
Main Results:
- Mutations in PBRM1 and SETD2 co-occur more frequently than expected by chance, suggesting cooperative roles in tumorigenesis.
- Mutations in PBRM1 and BAP1 are mutually exclusive, indicating potential negative genetic interactions.
- These genetic interactions correlate with distinct pathological features, gene expression patterns, and clinical outcomes in RCC.
Conclusions:
- Co-occurrence and mutual exclusivity of driver mutations reveal complex genetic interactions in RCC.
- Negative genetic interactions, such as between PBRM1 and BAP1, highlight context dependencies in cancer gene function.
- Understanding these gene dependencies may uncover novel therapeutic strategies for renal cell carcinoma.
More Related Videos
12:22The Use of Reverse Phase Protein Arrays (RPPA) to Explore Protein Expression Variation within Individual Renal Cell Cancers
Published on: January 22, 2013
05:36Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
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