Esophageal adenocarcinoma (EA) is the most common form of esophageal cancer in the US and western countries and incidence has increased by 675% over the past 30 years. Five-year survival is very poor at less than 20%. Thus, it is very critical to conduct studies to understand the etiology and to develop prevention strategies. Most EA arises in Barrett's Esophagus (BE), a condition of intestinal metaplasia in which the normal lining of the esophagus is replaced by intestinal-type tissue. The etiology of BE and EA are poorly understood and very few modifiable risk factors have been identified. EA is presumed to arise from BE through a metaplasia-dysplasia-carcinoma sequence of cumulative genetic and epigenetic modifications including aberrations in DNA methylation. Recent studies suggest hypo- methylation may be a key factor that appears early in carcinogenesis. Very recently, we found dietary intakes of vitamins involved in one-carbon metabolism (OCM; folate and vitamin B6) were inversely associated with both BE and EA risk in a population-based case-control study suggesting that OCM is an important risk factor in esophageal carcinogenesis and its effect may be early in the carcinogenesis process. An important component of OCM is the methionine cycle. In particular, methionine metabolism is essential in DNA and RNA methylation. S-adenosyl-methionine (SAM), the direct metabolite of methionine, is the methyl donor for nearly all methylation reactions in the body. Blood SAM is positively linked to DNA methylation, including global methylation, in tissues. We recently found higher plasma SAM levels were associated with decreased neoplasia risk in two studies; higher SAM levels were associated decreased colorectal adenoma, a cancer precursor, and with decreased risk of both low-grade and aggressive prostate cancers, a result consistent with the adenoma findings. Thus, there are preliminary data that SAM may have an effect at early and late stages of carcinogenesis. Combined with our preliminary data that dietary OCM factors have a role in BE and EA risk, we hypothesize that methionine cycle metabolism, and specifically SAM and SAH have a role in EA carcinogenesis. We propose to test this hypothesis in a pilot study using plasma samples from a population-based case-control study of BE and EA. Included in the analysis will be 218 BE cases, 208 EA cases, and 259 healthy controls. This will be the first study to evaluate this novel hypothesis.