Expression of Nucleotide Excision Repair Proteins in Lymphocytes as a Marker of Susceptibility to Squamous Cell Carcinomas of the Head and Neck

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Abstract
The transcript levels of nucleotide excision repair (NER) genes were shown to be associated with risk of squamous cell carcinomas of the head and neck (SCCHN). However, this association may be biased, because the transcript level does not necessarily reflect the level of protein expression. To address this issue, we did a pilot study to test the hypothesis that the expression of six core NER proteins is associated with risk of SCCHN. We obtained cultured lymphocytes from 57 patients with newly diagnosed SCCHN patients and 63 cancer-free controls. We transfected some of the lymphocytes with both damaged and undamaged plasmid DNA and quantified NER protein levels in these lymphocytes using a reverse-phase protein microarray. The relative NER protein levels in the 63 controls were highly correlated with each other (P < 0.001 for all). Compared with the controls, the cases had lower expression levels for all the NER proteins, particularly XPC and XPF, which were reduced by about 25% (P < 0.01). When we used the median expression levels of the NER proteins in the controls as cutoff values, we found that a significantly increased risk of SCCHN was associated with low expression of XPA [odds ratio (OR), 2.99; 95% confidence interval (CI), 1.22-7.47], XPC (OR, 2.46; 95% CI, 1.04-5.87), XPD (OR, 3.02; 95% CI, 1.18-7.76), and XPF (OR, 5.29; 95% CI, 2.01-13.9), but not ERCC1 and XPG, after adjustment for age, sex, ethnicity, smoking, alcohol use, and sample storage time. In a multivariate logistic regression model that included all covariates and NER proteins, however, only low expression of XPF remained a significant risk factor for SCCHN (OR, 11.5; 95% CI, 2.32-56.6). These results suggest that XPF may be a crucial rate-limiting factor in DNA repair and that the reverse-protein microarray assay may be a useful tool for measuring protein markers of susceptibility to cancer.