Abstract
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.