HPV status determines prognostic gene expression methylation and immune infiltration in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) continues to be a deadly cancer with heterogeneous molecular characteristics and poor survival outcomes, particularly in HPV- patients. This study aimed to identify key overexpressed genes that drive HNSCC progression, evaluate their prognostic value, and explore associations with HPV status, promoter methylation, and changes in the immune microenvironment. Using bioinformatics tools (UALCAN, HPA, TISIDB), we analyzed TCGA-HNSC data to evaluate gene expression, survival correlations, HPV subgroup differences, promoter methylation, and immune infiltration patterns. Statistical significance was defined as p < 0.05. Among the top 50 overexpressed genes in HNSCC, eight (LAMC2, CDKN2A, MFAP2, CTHRC1, CXCL13, FST, SPP1, PLAU) exhibited significant survival associations (p < 0.05). HPV- tumors demonstrated marked upregulation of LAMC2, CTHRC1, FST, SPP1, and PLAU, alongside downregulation of CDKN2A and CXCL13. Promoter hypomethylation in tumor tissues correlated with overexpression of LAMC2, CTHRC1, CXCL13, FST, SPP1, and PLAU, whereas CDKN2A showed hypermethylation. Immune infiltration analysis revealed strong correlations between these genes and immunosuppressive Tregs or cytotoxic T-cell depletion. This study identifies eight prognostic biomarkers in HNSCC linked to HPV-driven heterogeneity. These genes could be potential targets for therapy in combination with immunotherapy and epigenetic regulators, helping to overcome tumor resistance in HNSCC with different HPV status.