Aljuhani Thamer Abdulhamid, Shaik Noor Ahmad, Alqawas Rahaf Talal, Bokhary Rana Y, Al-Mutadares Mahmood, Al Mahdi Hadiah Bassam, Al-Rayes Nuha, El-Harouni Ashraf AbdulRahman, Elango Ramu, Banaganapalli Babajan, Awan Zuhier Ahmad
Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia.
Front Pharmacol. 2024 Nov 20;15:1498295. doi: 10.3389/fphar.2024.1498295. eCollection 2024.
Colorectal cancer (CRC) is the leading cancer among Saudis, and mutations in , , and genes are therapeutically significant due to their association with pathways critical for cell cycle regulation. This study evaluates the prevalence and frequency of somatic mutations in these actionable genes in Saudi CRC patients and assesses their pathogenicity with bioinformatics methods.
The study employed the TruSight Tumor 15 next-generation sequencing (NGS) panel on 86 colorectal cancer (CRC) samples to detect somatic mutations in , , and genes. Bioinformatic analyses of NGS sequences included variant annotation with ANNOVAR, pathogenicity prediction, variant reclassification with CancerVar, and extensive structural analysis. Additionally, molecular docking assessed the binding of Encorafenib to wild-type and mutant proteins, providing insights into the therapeutic relevance of pathogenic variants.
Out of 86 tumor samples, 40 (46.5%) harbored somatic mutations within actionable genes (: 2.3%, : 43%, : 2.3%). Fourteen missense variants were identified (: n = 1, : n = 11, : n = 2). Variants with strong clinical significance included V600E (2.32%) and G12D (18.60%). Variants with potential clinical significance included several and an mutation, while variants of unknown significance included E49K and R102Q. One variant was novel: R102Q, and two were rare: E49K and G138E. We further extended the CancerVar prediction capability by adding new pathogenicity prediction tools. Molecular docking demonstrated that Encorafenib inhibits the V600E variant BRAF protein less effectively compared to its wild-type counterpart.
Overall, this study highlights the importance of comprehensive molecular screening and bioinformatics in understanding the mutational landscape of CRC in the Saudi population, ultimately improving targeted drug treatments.
结直肠癌（CRC）是沙特人群中最主要的癌症，并且 、 和 基因的突变因其与细胞周期调控关键通路的关联而具有重要治疗意义。本研究评估沙特CRC患者中这些可操作基因的体细胞突变的患病率和频率，并使用生物信息学方法评估其致病性。
本研究对86例结直肠癌（CRC）样本采用TruSight肿瘤15下一代测序（NGS） panel来检测 、 和 基因中的体细胞突变。对NGS序列的生物信息学分析包括使用ANNOVAR进行变异注释、致病性预测、使用CancerVar进行变异重新分类以及广泛的结构分析。此外，分子对接评估了恩考芬尼与野生型和突变型 蛋白的结合，从而深入了解致病性变异的治疗相关性。
在86个肿瘤样本中，40个（46.5%）在可操作基因中存在体细胞突变（ ：2.3%， ：43%， ：2.3%）。鉴定出14个错义变异（ ：n = 1， ：n = 11， ：n = 2）。具有强临床意义的变异包括 V600E（2.32%）和 G12D（18.60%）。具有潜在临床意义的变异包括几个 和一个 突变，而意义未明的变异包括 E49K和 R102Q。一个变异是新的： R102Q，两个是罕见的： E49K和G138E。我们通过添加新的致病性预测工具进一步扩展了CancerVar的预测能力。分子对接表明，与野生型对应物相比，恩考芬尼对V600E变异BRAF蛋白的抑制作用较弱。
总体而言，本研究强调了全面分子筛查和生物信息学在了解沙特人群CRC突变谱方面的重要性，最终改善靶向药物治疗。
