Plasma metabolites of one-carbon metabolism are associated with esophageal adenocarcinoma in a population-based study.

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's Adenocarcinoma Relationship (FINBAR) 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) or 1 (> median) to the levels of three 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 (PLP), and choline levels were all associated with 62-82% reduced risks of EAC (ptrends <0.001). Conversely, S-adenosylmethionine (SAM), the SAM/S-adenosylhomocysteine (SAH) ratio, total homocysteine (tHcy), and cystathionine were associated with a greater than two-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 versus lowest plasma methionine levels were borderline statistically significantly associated long-segment BE (OR 0·55; 95%CI: 0·28-1·07), but all other associations were null.

Conclusions: 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.