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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
TP53 mutations, expression and interaction networks in human cancers
Xiaosheng Wang1, Qingrong Sun2
1Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
Abstract:
Although the associations of p53 dysfunction, p53 interaction networks and oncogenesis have been widely explored, a systematic analysis of TP53 mutations and its related interaction networks in various types of human cancers is lacking. Our study explored the associations of TP53 mutations, gene expression, clinical outcomes, and TP53 interaction networks across 33 cancer types using data from The Cancer Genome Atlas (TCGA). We show that TP53 is the most frequently mutated gene in a number of cancers, and its mutations appear to be early events in cancer initiation. We identified genes potentially repressed by p53, and genes whose expression correlates significantly with TP53 expression. These gene products may be especially important nodes in p53 interaction networks in human cancers. This study shows that while TP53-truncating mutations often result in decreased TP53 expression, other non-truncating TP53 mutations result in increased TP53 expression in some cancers. Survival analyses in a number of cancers show that patients with TP53 mutations are more likely to have worse prognoses than TP53-wildtype patients, and that elevated TP53 expression often leads to poor clinical outcomes. We identified a set of candidate synthetic lethal (SL) genes for TP53, and validated some of these SL interactions using data from the Cancer Cell Line Project. These predicted SL genes are promising candidates for experimental validation and the development of personalized therapeutics for patients with TP53-mutated cancers.
Insights
TP53 mutations are common in many cancers and linked to poor outcomes. This study analyzes TP53 networks and identifies potential therapeutic targets for TP53-mutated cancers.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- TP53 mutations are frequent in human cancers.
- Understanding TP53's role in oncogenesis and its interaction networks is crucial.
- A systematic analysis across diverse cancer types is needed.
Purpose of the Study:
- To systematically analyze TP53 mutations, gene expression, clinical outcomes, and interaction networks in 33 cancer types.
- To identify genes regulated by p53 and those correlated with TP53 expression.
- To discover synthetic lethal partners of TP53 for targeted therapy development.
Main Methods:
- Utilized The Cancer Genome Atlas (TCGA) data for comprehensive analysis.
- Examined TP53 mutation status, gene expression, and clinical data across 33 cancer types.
- Performed survival analyses and leveraged the Cancer Cell Line Project for validation.
Main Results:
- TP53 is the most frequently mutated gene in several cancers, often an early event.
- Identified genes repressed by p53 and genes with expression correlating to TP53 levels.
- TP53-truncating mutations typically decrease TP53 expression; non-truncating mutations can increase it.
- TP53 mutations and elevated TP53 expression correlate with worse patient prognoses.
- Identified and validated candidate synthetic lethal genes for TP53.
Conclusions:
- TP53 mutations significantly impact cancer development and patient outcomes.
- p53 interaction networks offer insights into cancer biology.
- Candidate synthetic lethal genes represent promising therapeutic targets for TP53-mutated cancers.
- This research supports the development of personalized therapies.
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