PMID- 38024667
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231201
IS  - 2470-1343 (Electronic)
IS  - 2470-1343 (Linking)
VI  - 8
IP  - 45
DP  - 2023 Nov 14
TI  - Mutational Landscape and In-Silico Analysis of TP53, PIK3CA, and PTEN in Patients 
      with Breast Cancer from Khyber Pakhtunkhwa.
PG  - 43318-43331
LID - 10.1021/acsomega.3c07472 [doi]
AB  - Herein, we report the mutational spectrum of three breast cancer candidate genes 
      (TP53, PIK3CA, and PTEN) using WES for identifying potential biomarkers. The WES 
      data were thoroughly analyzed using SAMtools for variant calling and 
      identification of the mutations. Various bioinformatic tools (SIFT, PolyPhen-2, 
      Mutation Taster, ISPRED-SEQ, SAAFEQ-SEQ, ConSurf, PROCHECK etc.) were used to 
      determine the pathogenicity and nature of the SNVs. Selected interaction site 
      (IS) mutations were visualized in PyMOL after building 3D structures in 
      Swiss-Model. Ramachandran plots were generated by using the PROCHECK server. The 
      selected IS mutations were subjected to molecular dynamic simulation (MDS) 
      studies using Gromacs 4.5. STRING and GeneMANIA were used for the prediction of 
      gene-gene interactions and pathways. Our results revealed that the luminal A 
      molecular subtype of the breast cancer was most common, whereas a high percentage 
      of was Her2 negatives. Moreover, the somatic mutations were more common as 
      compared to the germline mutations in TP53, PIK3CA, and PTEN. 20% of the 
      identified mutations are reported for the first time from Khyber Pakhtunkhwa. In 
      the enrolled cohort, 23 mutations were nonsynonymous SNVs. The frequency of 
      mutations was the highest in PIK3CA, followed by TP53 and PTEN. A total of 13 
      mutations were found to be highly pathogenic. Four novel mutations were 
      identified on PIK3CA and one each on PTEN and TP53. SAAFEQ-SEQ predicted the 
      destabilizing effect for all mutations. ISPRED-SEQ predicted 9 IS mutations (6 on 
      TP53 and 3 on PIK3CA), whereas no IS mutation was predicted on PTEN. The TP53 IS 
      mutations were TP53(R43H), TP53(Y73X), TP53(K93Q), TP53(K93R), TP53(D149E), and 
      TP53(Q199X); whereas for PIK3CA, the IS mutations were PIK3CA(L156V), 
      PIK3CA(M610K), and PIK3CA(H1047R). Analysis from the ConSurf Web server revealed 
      five SNVs with a highly conserved status (conservation score 9) across TP53 and 
      PTEN. TP53(P33R) was found predominant in the grade 3 tumors, whereas 
      PTEN(p.C65S) was distributed on ER+, ER-, PR+, PR-, Her2+, and Her2- patients. 
      TP53(p.P33R) mutation was found to be recurring in the 14/19 (73.6%) patients 
      and, therefore, can be considered as a potential biomarker. Finally, these 
      mutations were studied in the context of their potential association with 
      different hormonal and social factors.
CI  - (c) 2023 The Authors. Published by American Chemical Society.
FAU - Ahmad, Hilal
AU  - Ahmad H
AD  - Institute of Basic Medical Sciences Khyber Medical University, Khyber Medical 
      University, Phase V, Peshawar 25000, Pakistan.
FAU - Ali, Asif
AU  - Ali A
AD  - Institute of Basic Medical Sciences Khyber Medical University, Khyber Medical 
      University, Phase V, Peshawar, Peshawar 25000, Pakistan.
AD  - College of Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates.
AD  - School of Medicine, University of Glasgow, Glasgow G12 8QQ, U.K.
FAU - Ali, Roshan
AU  - Ali R
AD  - Institute of Basic Medical Sciences Khyber Medical University, Khyber Medical 
      University, Phase V, Peshawar 25000, Pakistan.
FAU - Khalil, Ali Talha
AU  - Khalil AT
AUID- ORCID: 0000-0002-9848-8723
AD  - Department of Pathology, Lady Reading Hospital Medical Teaching Institution 
      (LRH-MTI), Peshawar, Khyber Pakhtunkhwa 25000, Pakistan.
FAU - Khan, Ishaq
AU  - Khan I
AD  - Institute of Basic Medical Sciences Khyber Medical University, Khyber Medical 
      University, Phase V, Peshawar 25000, Pakistan.
FAU - Khan, Mah Muneer
AU  - Khan MM
AUID- ORCID: 0000-0001-7862-2721
AD  - General Surgery, Khyber Teaching Hospital Medical Teaching Institute, Peshawar 
      25000, Pakistan.
FAU - Alorini, Mohammed
AU  - Alorini M
AD  - Department of Basic Medical Sciences, Unaizah College of Medicine and Medical 
      Sciences, Qassim University, Unaizah, 56219, Saudi Arabia.
LA  - eng
PT  - Journal Article
DEP - 20231102
PL  - United States
TA  - ACS Omega
JT  - ACS omega
JID - 101691658
PMC - PMC10652387
COIS- The authors declare no competing financial interest.
EDAT- 2023/11/29 18:42
MHDA- 2023/11/29 18:43
PMCR- 2023/11/02
CRDT- 2023/11/29 16:14
PHST- 2023/09/27 00:00 [received]
PHST- 2023/10/10 00:00 [revised]
PHST- 2023/10/11 00:00 [accepted]
PHST- 2023/11/29 18:43 [medline]
PHST- 2023/11/29 18:42 [pubmed]
PHST- 2023/11/29 16:14 [entrez]
PHST- 2023/11/02 00:00 [pmc-release]
AID - 10.1021/acsomega.3c07472 [doi]
PST - epublish
SO  - ACS Omega. 2023 Nov 2;8(45):43318-43331. doi: 10.1021/acsomega.3c07472. 
      eCollection 2023 Nov 14.