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Published on: August 4, 2019
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Comprehensive classification of TP53 somatic missense variants based on their impact on p53 structural stability
Benjamin Tam1, Philip Naderev P Lagniton1, Mariano Da Luz1
1Faculty of Health Sciences, University of Macau, University Avenue, Taipa, Macau SAR 999078, China.
Briefings in Bioinformatics
|August 14, 2024
Summary
Predicting the impact of somatic missense variants on protein stability can now be achieved using the Ramachandran Plot-Molecular Dynamics Simulations (RP-MDS) method, aiding cancer research.
Area of Science:
- Genetics and Genomics
- Molecular Biology
- Bioinformatics
Background:
- Somatic variations, particularly missense variants, are implicated in human diseases like cancer.
- The functional consequences of many somatic variants remain undetermined, hindering clinical applications.
- Previous work established the Ramachandran Plot-Molecular Dynamics Simulations (RP-MDS) method for predicting germline missense variant effects on protein stability.
Purpose of the Study:
- To test the hypothesis that the RP-MDS method, developed for germline variants, can predict the functional impact of somatic missense variants.
- To assess the applicability of RP-MDS for analyzing somatic variants in cancer-related genes, using TP53 as a model.
Main Methods:
- Applied the RP-MDS method to analyze 397 somatic missense variants in the TP53 gene.
- Evaluated the predicted impact of variants on p53 protein structure stability.
- Validated RP-MDS predictions using a p53-p21 promoter-green fluorescent protein (GFP) reporter gene assay.
Main Results:
- RP-MDS predicted 195 out of 397 (49.1%) somatic TP53 missense variants as deleterious due to significant disruption of p53 protein structure.
- Experimental validation using a reporter gene assay largely supported the RP-MDS predictions.
- Demonstrated a strong correlation between predicted structural instability and functional deleteriousness for somatic missense variants.
Conclusions:
- The RP-MDS method is effective in predicting the functional impact of somatic missense variants.
- Assessing effects on protein structural stability is a viable approach for identifying deleterious somatic variants.
- This method holds potential for advancing the clinical interpretation of somatic variation data in cancer.
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