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

Su Ir Lyu; Caroline Fretter; Hans Nikolaus Caspar Eckel; Karl Knipper; Anne Maria Schultheis; Reinhard Büttner; Alexander Quaas; Jens Peter Klussmann; Adrian Georg Simon

doi:10.1016/j.oraloncology.2024.107171

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

Oral Oncol. 2025 Jan 4:161:107171. doi: 10.1016/j.oraloncology.2024.107171. Online ahead of print.

Authors

Su Ir Lyu¹, Caroline Fretter², Hans Nikolaus Caspar Eckel³, Karl Knipper⁴, Anne Maria Schultheis⁵, Reinhard Büttner⁶, Alexander Quaas⁷, Jens Peter Klussmann⁸, Adrian Georg Simon⁹

Affiliations

¹ Institute of Pathology, University Hospital of Cologne, University Cologne, Faculty of Medicine, Kerpener Strasse 62, 50937 Cologne, Germany. Electronic address: [email protected].
² Institute of Pathology, University Hospital of Cologne, University Cologne, Faculty of Medicine, Kerpener Strasse 62, 50937 Cologne, Germany; Department of Internal Medicine, Lee Health Hospital, Florida State University College of Medicine at Cape Coral, 636 Del Prado Boulevard, Cape Coral, FL 33990, USA. Electronic address: [email protected].
³ Department of Otorhinolaryngology/Head and Neck Surgery, University Hospital of Cologne, University Cologne, Faculty of Medicine, Kerpener Strasse 62, 50973 Cologne, Germany. Electronic address: [email protected].
⁴ Department of General, Visceral and Cancer Surgery, University of Cologne, University Cologne, Faculty of Medicine, Kerpener Strasse 62, 50973 Cologne, Germany. Electronic address: [email protected].
⁵ Institute for Surgical Pathology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg im Breisgau, Germany. Electronic address: [email protected].
⁶ Institute of Pathology, University Hospital of Cologne, University Cologne, Faculty of Medicine, Kerpener Strasse 62, 50937 Cologne, Germany. Electronic address: [email protected].
⁷ Institute of Pathology, University Hospital of Cologne, University Cologne, Faculty of Medicine, Kerpener Strasse 62, 50937 Cologne, Germany. Electronic address: [email protected].
⁸ Department of Otorhinolaryngology/Head and Neck Surgery, University Hospital of Cologne, University Cologne, Faculty of Medicine, Kerpener Strasse 62, 50973 Cologne, Germany. Electronic address: [email protected].
⁹ Institute of Pathology, University Hospital of Cologne, University Cologne, Faculty of Medicine, Kerpener Strasse 62, 50937 Cologne, Germany. Electronic address: [email protected].

PMID: 39756240
DOI: 10.1016/j.oraloncology.2024.107171

Abstract

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^high- and H2AX^low 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^high 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.

Keywords: Biomarker; H2AX; HPV; Head and neck cancer; OPSCC; Oropharyngeal squamous cell carcinoma; γ-H2AX.