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Histopathology. 2017 Oct;71(4):522-528. doi: 10.1111/his.13260. Epub 2017 Jul 21.

DNA damage marker phosphorylated histone H2AX is a potential predictive marker for progression of epithelial dysplasia of the oral cavity.

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Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
Queen Elizabeth University Hospital, Glasgow, UK.
Academic Unit of Oral and Maxillofacial Pathology, The University of Sheffield, Sheffield, UK.
Cancer Research UK Beatson Institute, Glasgow, UK.
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.



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


Retrospective immunohistochemical analyses were performed on 86 formalin-fixed paraffin-embedded specimens of OD and oral squamous cell carcinoma (OSCC) for Ki67, phosphorylated histone H2AX (γH2AX), p53, p16, trimethyl-histone H3 (Lys9) (H3K9me3) and cyclin D1 (CycD1). Three separate areas representing the highest severity of OD on each slide were annotated digitally 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 were retrieved and anonymized 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). Ki67 (P < 0.0001), γH2AX (P = 0.03) and p53 (P = 0.04) were increased significantly with higher histological grade of OD. γH2AX (P = 0.03), but not histological grade of OD (P = 0.73), was associated prospectively 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 [hazard ratio (HR) = 3.15, 95% confidence interval (CI): 1.41-7.39, P = 0.0064].


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.


biomarkers; carcinoma in situ; cellular senescence; immunohistochemistry; neoplasm; oral cavity

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