Al-Nakhle Hakeemah, Al-Shahrani Retaj, Al-Ahmadi Jawanah, Al-Madani Wesal, Al-Juhani Rufayda
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taibah University, Al-Madinah Al-Monawarah 42353, Saudi Arabia.
Genes (Basel). 2025 Mar 4;16(3):307. doi: 10.3390/genes16030307.
Programmed cell death protein 1 (PD-1), encoded by the gene, is critical in immune checkpoint regulation and cancer immune evasion. Variants in may alter its function, impacting cancer susceptibility and disease progression. This study evaluates the structural, functional, and regulatory impacts of non-synonymous single-nucleotide polymorphisms (nsSNPs) in the gene, focusing on their pathogenic and oncogenic roles. Computational tools, including PredictSNP1.0, I-Mutant2.0, MUpro, HOPE, MutPred2, Cscape, Cscape-Somatic, GEPIA2, cBioPortal, and STRING, were used to analyze 695 nsSNPs in the PD1 protein. The analysis covered structural impacts, stability changes, regulatory effects, and oncogenic potential, focusing on conserved domains and protein-ligand interactions. The analysis identified 84 deleterious variants, with 45 mapped to conserved regions like the Ig V-set domain essential for ligand-binding interactions. Stability analyses identified 78 destabilizing variants with significant protein instability (ΔΔG values). Ten nsSNPs were identified as potential cancer drivers. Expression profiling showed differential expression in tumor versus normal tissues, correlating with improved survival in skin melanoma but limited value in ovarian cancer. Regulatory SNPs disrupted miRNA-binding sites and transcriptional regulation, affecting expression. STRING analysis revealed key PD-1 protein partners within immune pathways, including PD-L1 and PD-L2. This study highlights the significance of nsSNPs as potential biomarkers for cancer susceptibility, advancing the understanding of PD-1 regulation. Experimental validation and multi-omics integration are crucial to refine these findings and enhance theraputic strategies.
程序性细胞死亡蛋白1（PD-1）由该基因编码，在免疫检查点调节和癌症免疫逃逸中起关键作用。该基因的变异可能会改变其功能，影响癌症易感性和疾病进展。本研究评估了该基因非同义单核苷酸多态性（nsSNPs）的结构、功能和调节影响，重点关注其致病和致癌作用。使用了包括PredictSNP1.0、I-Mutant2.0、MUpro、HOPE、MutPred2、Cscape、Cscape-Somatic、GEPIA2、cBioPortal和STRING在内的计算工具，分析了PD1蛋白中的695个nsSNPs。分析涵盖了结构影响、稳定性变化、调节作用和致癌潜力，重点关注保守结构域和蛋白质-配体相互作用。分析确定了84个有害变异，其中45个映射到保守区域，如对配体结合相互作用至关重要的Ig V-set结构域。稳定性分析确定了78个具有显著蛋白质不稳定性（ΔΔG值）的不稳定变异。10个nsSNPs被确定为潜在的癌症驱动因素。表达谱分析显示肿瘤组织与正常组织中该基因表达存在差异，这与皮肤黑色素瘤患者生存率提高相关，但对卵巢癌的价值有限。调节性SNP破坏了miRNA结合位点和转录调控，影响该基因表达。STRING分析揭示了免疫途径内关键的PD-1蛋白伙伴，包括PD-L1和PD-L2。本研究强调了该基因nsSNPs作为癌症易感性潜在生物标志物的重要性，推进了对PD-1调节的理解。实验验证和多组学整合对于完善这些发现和加强治疗策略至关重要。
