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Positive Selection Shapes Breast Cancer Tumor Suppressor Genes: Unveiling Insights into BRCA1, BRCA2, and MDC1
Youssef M Fadel1, Marwan Khaled1, Mohamed Emam2,3
1Bioinformatics Group, Center for Informatics Sciences (CIS), Nile University, Giza, Egypt.
Abstract:
Worldwide, breast cancer is the leading cause of death in women with cancers. Given this situation, new approaches to treatment are urgently needed. Tumor Suppressor Genes (TSGs) defects play a crucial role in tumor development, and recent studies propose their reactivation as a promising way for clinical intervention in breast cancer. Here, we performed detailed evolutionary analyses of 241 breast cancer TSGs across 25 mammalian genomes, revealing 28 genes under strong positive selection. These genes exhibit elevated molecular pressure in codons corresponding to amino acids located in crucial protein domains and motifs. Notably, one positively selected site in the BRCA1 C-terminal domain is known for its role in DNA damage response, suggesting potential interference with DNA repair mechanisms. Moreover, the substitution of some other sites found in important key motifs, namely two codons in BRCA2 (752 and 939) localized within the phosphoinositide-3-OH-kinase-related and playing a crucial role in the DNA repair and the DNA damage checkpoints. Our findings could be inspirational to foster future recommendations for drug-targeting sites and further illuminate the function of these proteins. Finally, the code developed in our study is delivered in the Automated tool for positive selection (ATPs) ( https://github.com/APS-P/Automated-Tool-for-Positive-Selection-ATPS-/wiki ) to assist the easy reproducibility and support future evolutionary genomics analyses.
Insights
Evolutionary analysis of 241 breast cancer Tumor Suppressor Genes (TSGs) across 25 mammalian genomes identified 28 genes under positive selection. These genes, including BRCA1 and BRCA2, show critical sites potentially impacting DNA repair and cancer progression.
Area of Science:
- Evolutionary genomics
- Cancer biology
- Molecular evolution
Background:
- Breast cancer is a leading cause of mortality in women globally, necessitating novel therapeutic strategies.
- Defects in Tumor Suppressor Genes (TSGs) are pivotal in tumor development, with reactivation emerging as a potential clinical intervention.
- Understanding the evolutionary pressures on TSGs can offer insights into their function and therapeutic vulnerabilities.
Purpose of the Study:
- To conduct evolutionary analyses of breast cancer-associated TSGs across mammalian genomes.
- To identify genes and specific sites under positive selection, indicating functional adaptation or altered selective pressures.
- To explore the implications of these findings for understanding DNA repair mechanisms and developing targeted therapies.
Main Methods:
- Comparative evolutionary analyses of 241 breast cancer TSGs.
- Examination across 25 mammalian genomes.
- Identification of genes and codons under positive selection using evolutionary metrics.
Main Results:
- Identified 28 breast cancer TSGs under strong positive selection across 25 mammalian genomes.
- Observed elevated molecular pressure on codons within crucial protein domains and motifs of these selected genes.
- Highlighted positively selected sites in BRCA1 and BRCA2, potentially affecting DNA damage response and repair pathways.
Conclusions:
- Evolutionary insights reveal key sites in breast cancer TSGs under significant adaptive pressure.
- Findings suggest potential roles for these selected sites in DNA repair and checkpoint regulation.
- The study provides a foundation for future drug-targeting strategies and a deeper understanding of TSG function in breast cancer.
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