High expression of H2AX/γ-H2AX is associated with distinct biological pathway alterations and shorter survival in oropharyngeal squamous cell carcinoma.

Background: The histone gene H2AX and its phosphorylated protein γ-H2AX play a crucial role in the DNA damage response. This study investigates the expression of H2AX mRNA and its phosphorylated γ-H2AX protein in oropharyngeal squamous cell carcinoma (OPSCC), its association with distinct biological pathway alterations and its potential as a biomarker.

Materials And Methods: Expression of H2AX mRNA in 76 OPSCC from The Cancer Genome Atlas (TCGA) cohort was analyzed. Patients were stratified into H2AX- and H2AX OPSCC based on a survival-associated cutoff. Differentially expressed genes were identified using DESeq2, followed by pathway enrichment analyses. Immunohistochemical staining of γ-H2AX protein expression was performed on an independent cohort of 209 OPSCC, followed by survival and Cox regression analyses.

Results: High H2AX mRNA expression was a significant prognostic factor associated with shorter OS in the TCGA OPSCC cohort (HR 4.77, p = 0.04). In H2AX tumors, differential gene expression analysis revealed upregulation of genes regulating DNA repair and cell cycle (CDK1, CCNB1, ZWINT). High γ-H2AX protein expression was significantly associated with HPV-negative OPSCC (p = 0.005), and remained an independent predictor of poor survival in the total OPSCC cohort (HR 2.24, p = 0.03) and particularly in HPV-negative patients (HR 3.67, p = 0.007).

Conclusion: H2AX/γ-H2AX expression is a potential prognostic biomarker in OPSCC, with elevated levels indicating poor survival, especially in HPV-negative cases. These findings suggest distinct molecular behaviors in OPSCC based on H2AX expression and highlight the need for further investigation into its therapeutic implications.