Selenium, Selenoenzymes, Oxidative Stress and Risk of Neoplastic Progression from Barrett's Esophagus: Results from Biomarkers and Genetic Variants

PLoS ONE

Jun 2012

DOI: 10.1371/journal.pone.0038612

Citations:27

Influential Citations:3

Observational Studies (Human)

Enhanced Details

Methods

Design: Prospective cohort study of Barrett’s esophagus (BE) patients. Participants: 361 BE patients without esophageal adenocarcinoma at blood draw; mostly male (~81%) and Caucasian (~93%); mean age at baseline ~61 years. Follow-up: average 7.3 years. Endpoints: progression to esophageal adenocarcinoma (EA), aneuploidy, and tetraploidy assessed by histology and DNA-content flow cytometry. Biomarker measures: baseline serum selenium; GPX1/GPX3 activities; SEPP1 concentrations; malondialdehyde (MDA) and protein carbonyl content (PCC); SNPs in GPX1-4 and SEPP1 genotyped in a subset (n≈198). Statistical approach: Cox proportional hazards models; time from blood draw to endpoint; covariates included age, sex, waist-to-hip ratio, smoking, NSAID use, and Caucasian ethnicity.

Results

Serum selenium concentration showed no association with risk of EA, aneuploidy, or tetraploidy (HR per 50 mg/L increase: EA 1.16 [0.60–2.28], aneuploidy 1.64 [0.79–3.42], tetraploidy 1.06 [0.54–2.06]; P for trend 0.25–0.85). SEPP1 concentration was positively associated with risk: per 1 mg/L increase, EA HR 1.46 (1.05–2.05); highest SEPP1 tertile vs lowest HR 3.95 (1.42–10.97) for EA and 6.53 (1.31–32.58) for aneuploidy (P for trend = 0.006 and 0.02). GPX1/GPX3 activities and oxidative stress markers (MDA, PCC) were not associated with progression. Two GPX3 SNPs showed nominal associations with EA, but overall gene variation was not significant. Excluding baseline high-grade dysplasia or aneuploidy/tetraploidy did not materially change results. Interpretation: there is no evidence that selenium status protects against progression from BE to EA; SEPP1 may be a biomarker of progression risk and warrants further study. Findings differ from prior cross-sectional studies, possibly due to differences in selenium status and cancer subtypes across populations.

Limitations

Small number of endpoints with limited statistical power; cohort largely selenium-replete with few participants below proposed protective thresholds; single baseline selenium measurement may not reflect long-term exposure or tissue selenium; generalizability limited to BE patients; some SNP analyses limited by sample size and multiple comparisons; measurement variability in biomarker assays.

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. show less