Genetic variants of EBI3, tumor Epstein-Barr virus, and human cytomegalovirus status in HPV-negative oral cancer

Abstract

Oral squamous cell carcinoma (OSCC), a malignancy with high recurrence rate and poor survival, may be influenced by immune-related genetic variations and oncogenic viruses. Objective: This study evaluated the clinical relevance of EBI3 polymorphisms, along with tumor Epstein–Barr virus (EBV) and Human Cytomegalovirus (HCMV) status, in prognostically adverse HPV-negative OSCCs. Methodology: EBI3 (rs4740, rs4905, rs428253) genotyping was performed by qPCR in 95 HPV-negative OSCC patients and 108 age-and sex-matched controls. Tumor HPV, EBV, and HCMV status were assessed by qPCR. EBV viral load was calculated by exponential approach and a relative estimate of EBV copies per 105 cells. Associations with overall survival (OS) and recurrence-free survival (RFS) were evaluated by Kaplan-Meier and Cox regression analyses. Results: EBV-positive tumors showed a significant association with increasing nodal stage (P=0.020). EBV viral load stratification (negative, low, high) presented a non-significant trend toward association with advanced tumor stage (P=0.060). Notably, EBI3 rs428253 predicted worse OS in EBV-positive patients, whereas rs4740 and rs4905 variants were associated with advanced tumor stage (P=0.024 and P=0.018). rs4740 and rs4905 variants were inversely associated with OSCC risk in dominant and overdominant models. Analysis detected HCMV in 7.4% of tumors but was not clinically relevant. Conclusions: EBI3 genetic variants and EBV status may have prognostic relevance in HPV-negative OSCC. EBV may interact with the host genetics to influence nodal metastases and outcomes, suggesting a potential EBV-EBI3 axis, which warrants further investigation. Future precision oncology approaches may incorporate host and viral genetic markers to identify and stratify high-risk HPV-negative OSCC patients.