DNA damage marker γH2AX is a potential predictive marker for progression of epithelial dysplasia of the oral cavity

Abstract

Aims

To evaluate the relationships between immunohistochemical markers related to cellular senescence, cell proliferation and histological grade of epithelial dysplasia of the oral cavity (OD). In addition, the predictive value of these markers for progression of OD was assessed.

Methods

Retrospective immunohistochemical analyses were performed on 86 formalin fixed and paraffin embedded specimens of OD and oral squamous cell carcinoma (OSCC) for Ki67, γH2AX, p53, p16, H3K9me3 and CycD1. Three separate areas representing the highest severity of OD on each slide were digitally annotated by two independent pathologists. Mean automated histoscores of the selected markers were generated and compared to that of age-matched healthy controls (n=24). Follow-up data of OD was retrieved and anonymised by a clinical team member and linked using unique participant identifiers. The median follow-up was 10.9 years (interquartile range: 10.1-11.5).

Results

Ki67 (p<0.0001), γH2AX (p=0.03) and p53 (p=0.04) were significantly increased with higher histological grade of OD. γH2AX (p=0.03), but not histological grade of OD (p=0.73), was prospectively associated with disease progression. Using the median histoscore for γH2AX (median histoscore = 17) as a cut-off, histoscore≥17 was associated with an increased risk of disease progression (HR=3.15, 95%CI 1.41-7.39, p=0.0064).

Conclusions

Although proliferation marker Ki67, DNA damage/checkpoint markers γH2AX and p53 were increased in higher grade of OD, only γH2AX was predictive of disease progression. These observations may reflect the role of DNA replicative stress in the transformation from OD to OSCC. Larger studies should evaluate whether γH2AX can be used as a predictive marker of OD

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