Structural prediction,whole exome sequencing and molecular dynamics simulation confirms p.G118D somatic mutation of PIK3CA as functionally important in breast cancer patients |
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Institution: | 1. Departments of Urology, Tulane University School of Medicine, New Orleans, LA;2. Departments of Pathology, Tulane University School of Medicine, New Orleans, LA;1. Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India;2. Department of Neuroscience Technology, College of Applied Medical Sciences, Imam Abdulrahman Bin Faisal University, Jubail, Saudi Arabia;3. Department of Biomedical Sciences, College of Health and Sciences, QU Health, Qatar University, Doha, Qatar;1. Circulating Biomarkers Laboratory, Faculty of Medical Sciences, Rio de Janeiro State University, Rio de Janeiro 20550-170, Brazil;2. Graduate Program in Medical Sciences, Rio de Janeiro State University, Rio de Janeiro 20550-170, Brazil;3. Americas Medical City, Barra da Tijuca, Rio de Janeiro 22775-001, Brazil;4. BIOARRAY Therapeutics Inc., Farmington 06032, USA;5. Micro-Imagem Laboratory, Rio de Janeiro 22060-000, Brazil;6. Laboratory of Functional Genomics and Bioinformatics, PTDIS/FIOCRUZ, Rio de Janeiro 21040-900, Brazil;7. Kennedy Faculty, Belo Horizonte, Minas Gerais 31535-040, Brazil |
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Abstract: | To understand the structural and functional importance of PIK3CA somatic mutations, whole exome sequencing, molecular dynamics simulation techniques in combination with in silico prediction algorithms such as SIFT, PolyPhen, Provean and CADD were employed. Twenty out of eighty missense somatic mutations in PIK3CA gene were found to be pathogenic by all the four algorithms. Most recurrent mutations found were known hotspot PIK3CA mutations with known clinical significance like p.E545 K, p.E545A, p.E545 G and p.C420R. A missense mutation p.G118D was found to be recurrently mutated in 5 cases. Interestingly, this mutation was observed in one of the patients who underwent whole exome sequencing and was completely absent from the controls. To see the effect of this mutation on the structure of PIK3CA protein, molecular dynamics simulation was performed. By molecular dynamics approach, we have shown that p.G118D mutation deviated from the native structure which was supported by the decrease in the number of hydrogen bonds, difference in hydrogen bond distance and angle, difference in root mean square deviation between the native and the mutant structures. |
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Keywords: | Somatic mutation Whole exome sequencing Molecular dynamics SIFT CADD |
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