Abstract
INTRODUCTION: Esophageal adenocarcinoma (EAC) develops through histopathological stages, including Barrett's esophagus (BE). We analyzed the associations between plasma levels of one-carbon metabolism factors and risks of long-segment BE or EAC. METHODS: Plasma levels were measured from an Irish population-based case-control study (Factors INfluencing the Barrett Adenocarcinoma Relationship study; 204 long-segment BE cases, 211 EAC cases, and 251 controls). A "methyl replete score" was derived by assigning a score of 0 (median) to the levels of 3 dietary methyl donors (methionine, choline, and betaine) and summing across the metabolites. Multinomial logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between EAC or BE and sex-specific quartiles or score using the lowest level as the reference category and adjusted for potential confounders. RESULTS: Highest methionine, betaine, vitamin B6, and choline levels were all associated with 62%-82% reduced risks of EAC ( Ptrends < 0.001). Conversely, S-adenosylmethionine, S-adenosylmethionine/S-adenosylhomocysteine ratio, total homocysteine, and cystathionine were associated with a greater than 2-fold increased EAC risk. A higher methyl replete score was associated with reduced EAC risk (OR 0.33; 95% CI 0.16-0.66). The highest vs lowest plasma methionine levels were borderline statistically significantly associated with long-segment BE (OR 0.55; 95% CI 0.28-1.07), but all other associations were null. DISCUSSION: Several biomarkers of one-carbon metabolism are associated with EAC risk, particularly markers of dietary methyl group donors. Future studies to replicate and prospectively evaluate these markers are warranted.