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Integrative Computational Analysis of TP53 Exon 5-6 Mutations in Oral Cavity, Prostate, and Breast Cancers in a
Mouhamed Mbaye1, Fatimata Mbaye2, Mbacke Sembene2
1Pharmaceutical Biophysics Laboratory, Department of Pharmacy, Faculty of Medicine, Pharmacy and Odontology, Cheikh Anta Diop University, Dakar BP. 5005, Senegal.
Abstract:
Background/Objectives: The tumor suppressor gene TP53 is one of the most frequently mutated genes in human cancers, with alterations predominantly affecting its DNA-binding domain (DBD). However, the mutational landscape and functional consequences of TP53 variants remain poorly characterized in African populations. This study aimed to characterize mutations in exons 5-6 of TP53 in oral cavity cancer (OCC), prostate cancer (PC), and breast cancer (BC) in a Senegalese population, and to assess their structural effects, functional consequences, and impact on protein-protein interactions with BCL-2. Methods: Seventy-eight archived tumor DNA samples from Senegalese patients with OCC, PC, and BC were analyzed. Variants were annotated using COSMIC and dbSNP databases. Functional impact was evaluated with PolyPhen-2. Structural stability changes (ΔΔG) were predicted using FoldX, conformational dynamics (ΔΔSvib) were assessed with ENCoM, and effects on the p53-BCL-2 interaction were analyzed using DDMut-PPI. Statistical analyses were also performed. Results: BC exhibited the highest TP53 mutation frequency, whereas OCC showed greater mutational diversity. Exon-level analysis revealed a significant enrichment of exon 6 mutations in BC. Structural analyses indicated that exon 5 mutations across all cancers and mutations in OCC were predominantly destabilizing and associated with loss-of-function effects. In contrast, recurrent exon 6 mutations in PC and BC, particularly V217L and V218M, were predicted to stabilize the p53 structure. Conformational dynamics differences between exons were significant only in PC. All analyzed mutations were predicted to stabilize the p53-BCL-2 interaction. Conclusions: This integrative in silico study identified cancer and exon-specific TP53 mutation patterns in a Senegalese population, highlighting exon 6 as a context-dependent hotspot with potential oncogenic implication in PC and BC. Despite its computational nature, the study provides valuable insights that merit further investigation.
Insights
TP53 mutations in Senegalese oral, prostate, and breast cancers show distinct patterns. Exon 6 mutations in prostate and breast cancers may stabilize the TP53 protein, impacting BCL-2 interactions.
Area of Science:
- Genomics and Bioinformatics
- Cancer Research
- Molecular Biology
Background:
- The tumor suppressor gene TP53 is frequently mutated in human cancers, particularly in its DNA-binding domain.
- The mutational landscape and functional impact of TP53 variants are understudied in African populations.
- Understanding TP53 alterations is crucial for cancer research and therapeutic development.
Purpose of the Study:
- To characterize TP53 mutations in exons 5-6 in oral cavity cancer (OCC), prostate cancer (PC), and breast cancer (BC) in a Senegalese population.
- To assess the structural effects, functional consequences, and impact on p53-BCL-2 interactions of these TP53 variants.
- To investigate cancer and exon-specific mutation patterns and their potential oncogenic implications.
Main Methods:
- Analysis of 78 archived tumor DNA samples from Senegalese patients with OCC, PC, and BC.
- Variant annotation using COSMIC and dbSNP databases.
- In silico evaluation of functional impact (PolyPhen-2), structural stability (FoldX), conformational dynamics (ENCoM), and p53-BCL-2 interaction (DDMut-PPI).
Main Results:
- Breast cancer (BC) showed the highest TP53 mutation frequency; oral cavity cancer (OCC) exhibited greater mutational diversity.
- Exon 5 mutations were predominantly destabilizing and loss-of-function across cancers; exon 6 mutations in PC and BC (e.g., V217L, V218M) were predicted to stabilize the p53 structure.
- All analyzed mutations were predicted to stabilize the p53-BCL-2 interaction, with significant conformational dynamics differences observed in PC.
Conclusions:
- Identified cancer and exon-specific TP53 mutation patterns in a Senegalese population.
- Exon 6 emerges as a context-dependent hotspot with potential oncogenic roles in PC and BC.
- The study provides valuable in silico insights into TP53 variant impacts, warranting further experimental investigation.
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