Evaluating the association of missense mutations in cyclin E1 and MYC genes with breast cancer using computational analysis

Abstract

MYC gene is a central regulator of the cell cycle and mutations in MYC can initiate the positive-feedback loop of cyclin E1. However, mutational analysis of cyclin E1 and MYC in previous studies has not been considered yet. Therefore, we have accessed a plethora of computational approaches to validate the structural and functional impact of cyclin E1 and MYC mutations and their association with breast cancer. The missense mutations were collected from the COSMIC database. Initially, the most pathogenic mutations were classified using PolyPhen, Sift, FTHMM, SNP&Go and PANTHER tools, which categorize 7/10 and 6/11 mutations of cyclin E1 and MYC as most pathogenic respectively. These filtered mutations were found to be evolutionarily conserved by ConSurf and HOPE and might also disrupt molecular mechanisms assorted by MutPred2. The structural analysis, interatomic interactions, and protein interactome analysis via i-TASSEER, Swiss modelling, Missense3D and DynaMut have confirmed that L161P, H162Q and H306N of cyclin E1 and N26S, I131N and K404N of MYC are most pathogenic to the protein structure. The wild-type and mutant structures docked with their degradation and regulatory proteins by pyDockWeb and ClusPro were evaluated to quantify their binding affinity. PPI-Affinity has shown cyclin E1H306N-CDK2 energy decrease by 0.2 kcal/mol, and PRODIGY has shown cyclin E1H162Q-CDK2 and cyclin E1H306N-CDK2 have lowered the ΔG as compared to wild-type complex (<−8.5 kcal/mol). Whereas each mutant-complex of MYC has dropped the ΔG as compared to the wild-type complex. Similarly, PPI-Affinity and PRODIGY have shown an average increase of ΔG with degradation proteins. S25L and H306N of cyclin E1 decrease binding affinity with Cul-3 and Fbw7. While N26S, I131N, S207L, I277M and K404N of MYC cause a decrease in affinity for p107, β-TrCP, and Pak2. In conclusion, these mutations might change the structure and function of proteins and result in halting their degradation and onset of breast cancer.