Screening and computational analysis of colorectal associated non-synonymous polymorphism in CTNNB1 gene in Pakistani population View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-11-07

AUTHORS

Suhail Razak, Nousheen Bibi, Javid Ahmad Dar, Tayyaba Afsar, Ali Almajwal, Zahida Parveen, Sarwat Jahan

ABSTRACT

BackgroundColorectal cancer (CRC) is categorized by alteration of vital pathways such as β-catenin (CTNNB1) mutations, WNT signaling activation, tumor protein 53 (TP53) inactivation, BRAF, Adenomatous polyposis coli (APC) inactivation, KRAS, dysregulation of epithelial to mesenchymal transition (EMT) genes, MYC amplification, etc. In the present study an attempt was made to screen CTNNB1 gene in colorectal cancer samples from Pakistani population and investigated the association of CTNNB1 gene mutations in the development of colorectal cancer.Methods200 colorectal tumors approximately of male and female patients with sporadic or familial colorectal tumors and normal tissues were included. DNA was extracted and amplified through polymerase chain reaction (PCR) and subjected to exome sequence analysis. Immunohistochemistry was done to study protein expression. Molecular dynamic (MD) simulations of CTNNB1WT and mutant S33F and T41A were performed to evaluate the stability, folding, conformational changes and dynamic behaviors of CTNNB1 protein.ResultsSequence analysis revealed two activating mutations (S33F and T41A) in exon 3 of CTNNB1 gene involving the transition of C.T and A.G at amino acid position 33 and 41 respectively (p.C33T and p.A41G). Immuno-histochemical staining showed the accumulation of β-catenin protein both in cytoplasm as well as in the nuclei of cancer cells when compared with normal tissue. Further molecular modeling, docking and simulation approaches revealed significant conformational changes in the N-terminus region of normal to mutant CTNNB1 gene critical for binding with Glycogen synthase kinase 3-B (GSK3) and transducin containing protein1 (TrCp1).ConclusionPresent study on Pakistani population revealed an association of two non-synonymous polymorphisms in the CTNNB1 gene with colorectal cancer. These genetic variants led to the accumulation of the CTNNB1, a hallmark of tumor development. Also, analysis of structure to function alterations in CTNNB1 gene is crucial in understanding downstream biological events. More... »

PAGES

171

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s12881-019-0911-y

DOI

http://dx.doi.org/10.1186/s12881-019-0911-y

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https://app.dimensions.ai/details/publication/pub.1122385659

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/31699039


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64 attempt
65 behavior
66 biological events
67 cancer
68 cancer cells
69 cancer samples
70 cells
71 chain reaction
72 changes
73 coli inactivation
74 colorectal cancer
75 colorectal cancer samples
76 colorectal tumors
77 computational analysis
78 conformational changes
79 cytoplasm
80 development
81 docking
82 downstream biological events
83 dynamic behavior
84 dynamics simulations
85 dysregulation
86 events
87 exome sequence analysis
88 exon 3
89 expression
90 familial colorectal tumors
91 female patients
92 folding
93 function alterations
94 gene mutations
95 genes
96 genetic variants
97 glycogen synthase kinase-3
98 hallmark
99 immuno-histochemical staining
100 immunohistochemistry
101 inactivation
102 kinase 3
103 mesenchymal transition (EMT) genes
104 modeling
105 molecular dynamics simulations
106 molecular modeling
107 mutations
108 non-synonymous polymorphisms
109 normal tissues
110 nucleus
111 pathway
112 patients
113 polymerase chain reaction
114 polymorphism
115 population
116 position 33
117 present study
118 protein
119 protein expression
120 protein1
121 reaction
122 region
123 samples
124 screening
125 sequence analysis
126 significant conformational changes
127 simulation approach
128 simulations
129 stability
130 staining
131 structure
132 study
133 synthase kinase-3
134 tissue
135 transducin
136 transition
137 tumor development
138 tumors
139 variants
140 vital pathways
141 β-catenin mutations
142 β-catenin protein
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