PMID- 31699039
OWN - NLM
STAT- MEDLINE
DCOM- 20200214
LR  - 20200309
IS  - 1471-2350 (Electronic)
IS  - 1471-2350 (Linking)
VI  - 20
IP  - 1
DP  - 2019 Nov 7
TI  - Screening and computational analysis of colorectal associated non-synonymous 
      polymorphism in CTNNB1 gene in Pakistani population.
PG  - 171
LID - 10.1186/s12881-019-0911-y [doi]
LID - 171
AB  - BACKGROUND: Colorectal cancer (CRC) is categorized by alteration of vital 
      pathways such as beta-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. METHODS: 200 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 CTNNB1(WT) and 
      mutant S33F and T41A were performed to evaluate the stability, folding, 
      conformational changes and dynamic behaviors of CTNNB1 protein. RESULTS: Sequence 
      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 beta-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). 
      CONCLUSION: Present 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.
FAU - Razak, Suhail
AU  - Razak S
AUID- ORCID: 0000-0003-2167-8630
AD  - Reproductive physiology lab, Department of Animal Sciences Quaid-i-Azam 
      University, Islamabad, Pakistan. ruhail12345@yahoo.com.
AD  - Department of Community Health Sciences, College of Applied Medical Sciences, 
      King Saud University, Riyadh, Saudi Arabia. ruhail12345@yahoo.com.
FAU - Bibi, Nousheen
AU  - Bibi N
AD  - Department of Bioinformatics, Shaheed Benazir Bhutto Women University, Peshawar, 
      Khyber Pakhtunkhwa, Pakistan.
FAU - Dar, Javid Ahmad
AU  - Dar JA
AD  - College of Science, King Saud University, Riyadh, Saudi Arabia.
FAU - Afsar, Tayyaba
AU  - Afsar T
AD  - Department of Community Health Sciences, College of Applied Medical Sciences, 
      King Saud University, Riyadh, Saudi Arabia.
FAU - Almajwal, Ali
AU  - Almajwal A
AD  - Department of Community Health Sciences, College of Applied Medical Sciences, 
      King Saud University, Riyadh, Saudi Arabia.
FAU - Parveen, Zahida
AU  - Parveen Z
AD  - Faculty of Biological Sciences Quaid-I-Azam University Islamabad and University 
      of Iceland, 101, Reykjavik, Iceland.
FAU - Jahan, Sarwat
AU  - Jahan S
AD  - Reproductive physiology lab, Department of Animal Sciences Quaid-i-Azam 
      University, Islamabad, Pakistan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191107
PL  - England
TA  - BMC Med Genet
JT  - BMC medical genetics
JID - 100968552
RN  - 0 (CTNNB1 protein, human)
RN  - 0 (beta Catenin)
SB  - IM
EIN - BMC Med Genet. 2020 Feb 24;21(1):39. PMID: 32093642
MH  - Adult
MH  - Colorectal Neoplasms/*genetics
MH  - Crystallography, X-Ray
MH  - Female
MH  - Genetic Predisposition to Disease
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Molecular Dynamics Simulation
MH  - *Mutation
MH  - Pakistan
MH  - *Polymorphism, Genetic
MH  - Protein Conformation
MH  - beta Catenin/chemistry/*genetics
PMC - PMC6836551
OTO - NOTNLM
OT  - And protein expression
OT  - CTNNB1
OT  - Colorectal cancer
OT  - DNA
OT  - Immunohistochemistry
OT  - Molecular modeling
COIS- The authors declare that they have no competing interest.
EDAT- 2019/11/09 06:00
MHDA- 2020/02/15 06:00
PMCR- 2019/11/07
CRDT- 2019/11/09 06:00
PHST- 2019/01/08 00:00 [received]
PHST- 2019/10/24 00:00 [accepted]
PHST- 2019/11/09 06:00 [entrez]
PHST- 2019/11/09 06:00 [pubmed]
PHST- 2020/02/15 06:00 [medline]
PHST- 2019/11/07 00:00 [pmc-release]
AID - 10.1186/s12881-019-0911-y [pii]
AID - 911 [pii]
AID - 10.1186/s12881-019-0911-y [doi]
PST - epublish
SO  - BMC Med Genet. 2019 Nov 7;20(1):171. doi: 10.1186/s12881-019-0911-y.