AUTHOR=Ahmad Hilal , Ali Asif , Khalil Ali Talha , Ali Roshan , Khan Ishaq , Khan Mah Muneer , Ahmed Ibrar , Basharat Zarrin , Alorini Mohammed , Mehmood Amna 

TITLE=Clinico-genomic findings, molecular docking, and mutational spectrum in an understudied population with breast cancer patients from KP, Pakistan

JOURNAL=Frontiers in Genetics

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2024.1383284

DOI=10.3389/fgene.2024.1383284

ISSN=1664-8021

ABSTRACT=<p>In this study, we report the mutational profiles, pathogenicity, and their association with different clinicopathologic and sociogenetic factors in patients with Pashtun ethnicity for the first time. A total of 19 FFPE blocks of invasive ductal carcinoma (IDC) from the Breast Cancer (BC) tissue and 6 normal FFPE blocks were analyzed by whole-exome sequencing (WES). Various somatic and germline mutations were identified in cancer-related genes, i.e., <italic>ATM</italic>, <italic>CHEK2</italic>, <italic>PALB2</italic>, and <italic>XRCC2</italic>. Among a total of 18 mutations, 14 mutations were somatic and 4 were germline. The <italic>ATM</italic> gene exhibited the maximum number of mutations (11/18), followed by <italic>CHEK2</italic> (3/18), <italic>PALB2</italic> (3/18), and <italic>XRCC2</italic> (1/18). Except one frameshift deletion, all other 17 mutations were nonsynonymous single-nucleotide variants (SNVs). SIFT prediction revealed 7/18 (38.8%) mutations as deleterious. PolyPhen-2 and MutationTaster identified 5/18 (27.7%) mutations as probably damaging and 10/18 (55.5%) mutations as disease-causing, respectively. Mutations like <italic>PALB2 p.Q559R</italic> (6/19; 31.5%), <italic>XRCC2 p.R188H</italic> (5/19; 26.31%), and <italic>ATM p.D1853N</italic> (4/19; 21.05%) were recurrent mutations and proposed to have a biomarker potential. The protein network prediction was performed using GeneMANIA and STRING. ISPRED-SEQ indicated three interaction site mutations which were further used for molecular dynamic simulation. An average increase in the radius of gyration was observed in all three mutated proteins revealing their perturbed folding behavior. Obtained SNVs were further correlated with various parameters related to the clinicopathological status of the tumors. Three mutation positions (<italic>ATM</italic><italic>p. D1853N</italic>, <italic>CHEK2 p.M314I</italic>, and <italic>PALB2 p.T1029S</italic>) were found to be highly conserved. Finally, the wild- and mutant-type proteins were screened for two drugs: elagolix (DrugBank ID: DB11979) and LTS0102038 (a triterpenoid, isolated from the anticancer medicinal plant <italic>Fagonia indica</italic>). Comparatively, a higher number of interactions were noted for normal <italic>ATM</italic> with both compounds, as compared to mutants.</p>