Integrative In Silico Analysis to Identify Functional and Structural Impacts of nsSNPs on Programmed Cell Death Protein 1 (PD-1) Protein and UTRs: Potential Biomarkers for Cancer Susceptibility

<b>Background:</b> Programmed cell death protein 1 (PD-1), encoded by the <i>PDCD1</i> gene, is critical in immune checkpoint regulation and cancer immune evasion. Variants in <i>PDCD1</i> may alter its function, impacting cancer susceptibility and disease progression. <b>Objectives:</b> This study evaluates the structural, functional, and regulatory impacts of non-synonymous single-nucleotide polymorphisms (nsSNPs) in the <i>PDCD1</i> gene, focusing on their pathogenic and oncogenic roles. <b>Methods:</b> 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. <b>Results:</b> 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 <i>PDCD1</i> 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 <i>PDCD1</i> expression. STRING analysis revealed key PD-1 protein partners within immune pathways, including PD-L1 and PD-L2. <b>Conclusions:</b> This study highlights the significance of <i>PDCD1</i> 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.