Abstract
Clinical trials have suggested a protective effect of selenium supplementation on the risk of esophageal cancer, which may be mediated through the antioxidant activity of selenoenzymes. We investigated whether serum selenium concentrations, selenoenzyme activity, oxidative stress and genetic variation in selenoenzymes were associated with the risk of neoplastic progression to esophageal adenocarcinoma (EA) and two intermediate endpoints, aneuploidy and tetraploidy. In this prospective cohort study, during an average follow-up of 7.3 years, 47 EA cases, 41 aneuploidy cases and 51 tetraploidy cases accrued among 361 participants from the Seattle Barrett's Esophagus Research Study who were free of EA at the time of blood draw and had at least one follow-up visit. Development to EA was assessed histologically and aneuploidy and tetraploidy by DNA content flow cytometry. Serum selenium concentrations were measured using atomic absorption spectrometry, activity of glutathione peroxidase (GPX) 1 and GPX3 by substrate-specific coupled test procedures, selenoprotein P (SEPP1) concentrations and protein carbonyl content by ELISA method and malondialdehyde concentrations by HPLC. Genetic variants in GPX1-4 and SEPP1 were genotyped. Serum selenium was not associated with the risk of neoplastic progression to EA, aneuploidy or tetraploidy (P for trend = 0.25 to 0.85). SEPP1 concentrations were positively associated with the risk of EA [hazard ratio (HR) = 3.95, 95% confidence intervals (CI) = 1.42–10.97 comparing the third tertile with the first] and with aneuploidy (HR = 6.53, 95% CI = 1.31–32.58), but not selenoenzyme activity or oxidative stress markers. No genetic variants, overall, were associated with the risk of neoplastic progression to EA (global p = 0.12–0.69). Our results do not support a protective effect of selenium on risk of neoplastic progression to EA. Our study is the first to report positive associations of plasma SEPP1 concentrations with the risk of EA and aneuploidy, which warrants further investigation.
Highlights
Results from a few clinical trials and observational studies support a protective effect of selenium on the risk of esophageal cancer [1,2,3,4,5]
Because selenium exerts its antioxidant property through selenoenzymes, we examined whether the activity of, as well as genetic variations in, selenoenzymes were associated with the risk of progression
The proton pump inhibitor or H2 blocker medication was used by almost all participants who had not gone through anti-reflux surgery
Summary
Results from a few clinical trials and observational studies support a protective effect of selenium on the risk of esophageal cancer [1,2,3,4,5]. Two trials in China found non-significant reduced risks of esophageal cancer (primarily squamous cell carcinoma) with supplementation of selenium in combination with other micronutrients for more than five years [1,2,3]. Case-cohort analysis within one of these trials found a statistically significant 44% lower risk of esophageal cancer among supplemented participants whose pre-trial serum selenium concentrations were in the highest (.82 mg/L) rather than the lowest (,60 mg/L) quartile [4]. Two small case-control studies showed an inverse association between serum selenium concentrations and the risk of esophageal cancer, but the lower selenium status observed may have been caused by the disease [6,7]. The only previous study of genetic variants in selenoenzymes and risk of esophageal adenocarcinoma (EA) reported null finding [8]
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