在这项研究中，我们首次报告了普什图族患者的突变谱、致病性及其与不同临床病理和社会遗传因素的关联。通过全外显子组测序 (WES) 分析了来自乳腺癌 (BC) 组织的总共 19 个浸润性导管癌 (IDC) FFPE 块和 6 个正常 FFPE 块。在癌症相关基因（即 ATM、CHEK2、PALB2 和 XRCC2）中发现了各种体细胞和种系突变。在总共18个突变中，14个是体细胞突变，4个是种系突变。 ATM基因突变数量最多（11/18），其次是CHEK2（3/18）、PALB2（3/18）和XRCC2（1/18）。除1个移码缺失外，其他17个突变均为非同义单核苷酸变异（SNV）。 SIFT 预测显示 7/18 (38.8%) 突变是有害的。 PolyPhen-2 和 MutationTaster 分别确定 5/18 (27.7%) 突变可能具有破坏性，10/18 (55.5%) 突变可能导致疾病。 PALB2 p.Q559R (6/19; 31.5%)、XRCC2 p.R188H (5/19; 26.31%) 和 ATM p.D1853N (4/19; 21.05%) 等突变是反复发生的突变，建议具有生物标志物潜在的。使用 GeneMANIA 和 STRING 进行蛋白质网络预测。 ISPRED-SEQ 指出了三个相互作用位点突变，这些突变被进一步用于分子动力学模拟。在所有三种突变蛋白中观察到回转半径平均增加，揭示了它们的折叠行为受到干扰。获得的 SNV 进一步与肿瘤临床病理状态相关的各种参数相关。发现三个突变位置（ATM p.D1853N、CHEK2 p.M314I 和 PALB2 p.T1029S）高度保守。最后，从野生型和突变型蛋白中筛选出两种药物：恶拉戈利 (DrugBank ID：DB11979) 和 LTS0102038（一种三萜类化合物，从抗癌药用植物 Fagonia indica 中分离出来）。相比之下，与突变体相比，正常 ATM 与这两种化合物的相互作用次数较多。版权所有 © 2024 Ahmad、Ali、Khalil、Ali、Khan、Khan、Ahmed、Basharat、Alorini 和 Mehmood。

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., ATM, CHEK2, PALB2, and XRCC2. Among a total of 18 mutations, 14 mutations were somatic and 4 were germline. The ATM gene exhibited the maximum number of mutations (11/18), followed by CHEK2 (3/18), PALB2 (3/18), and XRCC2 (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 PALB2 p.Q559R (6/19; 31.5%), XRCC2 p.R188H (5/19; 26.31%), and ATM p.D1853N (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 (ATM p. D1853N, CHEK2 p.M314I, and PALB2 p.T1029S) 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 Fagonia indica). Comparatively, a higher number of interactions were noted for normal ATM with both compounds, as compared to mutants.Copyright © 2024 Ahmad, Ali, Khalil, Ali, Khan, Khan, Ahmed, Basharat, Alorini and Mehmood.