Our recent study demonstrated that
cancer cells with compromised
glutathione homeostasis, including reduced expression of the
glutathione reductase (GSR) gene, were selectively killed by inhibition of
thioredoxin reductase. The human GSR gene is located on chromosome 8p, a region often lost in lung and other
cancers. However, whether GSR is altered in primary
lung cancer remains unknown. To analyze alterations of GSR in
lung cancer, we performed fluorescence in situ hybridization with probes for GSR and the chromosome 8 centromere (CEP8) in 45 surgical specimens of primary
lung cancer, including 24
lung adenocarcinomas, 10
squamous cell carcinomas, 8 neuroendocrine
cancers, and 3 small cell
lung cancers. Twenty-five surgically resected normal lung tissue specimens from these
lung cancer patients were used as a controls. The signal ratio of GSR to CEP8 per cell was used to identify gain or loss of GSR. GSR loss was detected in 6 of 24 (25%)
adenocarcinoma specimens and 5 of 10 (50%)
squamous cell carcinoma specimens, but not in neuroendocrine
cancer or
small cell lung cancer specimens. We also found that 19 of 45 (42%) specimens had chromosome 8
aneuploidy (more or less than 2 signals for CEP8), including 8 with both
aneuploidy and GSR deletion. Chromosome 8
aneuploidy was detected in all types of
lung cancer analyzed. Univariate and multivariable logistic regression analyses indicated that male patients had an increased risk of GSR deletion (hazard ratio [HR] = 4.77, 95% confidence interval [CI] = 1.00-22.86, P = 0.051), and patients who had undergone preoperative
radiation therapy or had a self-reported history of cigarette smoking had an increased risk of chromosome 8
aneuploidy (preoperative radiation: HR = 18.63, 95% CI = 0.90-384.17, P = 0.058; smoking: HR = 7.59, 95% CI = 0.86-66.75, P = 0.068), although the p values did not reach significance. Because GSR deficiency and chromosome 8
aneuploidy have implications in targeted
therapy and/or
immunotherapy for
cancer, they might serve as predictive
biomarkers for precision
therapy of
lung cancers.