# Plasma Metabolites of One-Carbon Metabolism Are Associated With Esophageal Adenocarcinoma in a Population-Based Study

## TL;DR

High levels of certain plasma metabolites linked to reduced risk of esophageal adenocarcinoma in a population study.

## Contribution

Identified specific one-carbon metabolism metabolites associated with EAC risk in a population-based study.

## Key findings

- High methionine, betaine, vitamin B6, and choline levels reduced EAC risk by 62%–82%.
- Higher S-adenosylmethionine and homocysteine levels increased EAC risk over 2-fold.
- A 'methyl replete score' was associated with a 67% lower EAC risk.

## Abstract

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.

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) or 1 (>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.

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.

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.