Circulating Inflammation Biomarkers and the Risk of Esophageal Adenocarcinoma: A Nested Case-Control Study in the Department of Defense Serum Repository

Background: We previously identified associations of esophageal adenocarcinoma risk with four inflammation-related candidate biomarkers: TNF receptor 2 (TNFR2), IL17A, VEGFR3, and resistin. Methods: We aimed to replicate these candidates and discover novel associations with additional proteins. We conducted a nested case-control study of men with prediagnostic biospecimens stored at the US Department of Defense Serum Repository, including 203 incident esophageal adenocarcinoma cases. Controls were matched to cases in a ∼2:1 ratio by date of birth, race, service branch, and blood draw date. Multiplex immunoassays (Olink/Proseek panels) measured 254 proteins detected in ≥10% of all samples. Multivariable-adjusted conditional logistic regression models calculated associations between biomarker quantiles and esophageal adenocarcinoma. P values (<0.05) were used to indicate the statistical significance of candidates, and FDR was applied to the additional proteins. ORs from the current analysis and those from previous studies were combined for the candidate markers using fixed-effects meta-analysis. Results: Among the four candidates, the highest category of TNFR2 was associated with significantly increased esophageal adenocarcinoma risk (ORQ4 vs. Q1 = 1.87; 95% confidence interval: 1.02-3.42). In the meta-analysis, associations with esophageal adenocarcinoma were positive for TNFR2 (meta-analyzed ORhighest-vs.-lowest = 2.04; 1.12-2.95) and inverse for IL17A (metaanalyzed ORhighest-vs.-lowest = 0.53; 0.26-0.80). Of the additional 250 proteins, 45 were associated with esophageal adenocarcinoma risk and 6 (monocyte chemotactic protein 3, IL6, TNFR1, hepatocyte growth factor, TFF3, and FURIN) remained significant after FDR correction. Conclusions: We confirmed associations of TNFR2 and IL17A with esophageal adenocarcinoma risk. Additionally, our study expands the range of proteins associated with esophageal adenocarcinoma development. Impact: This is the largest assessment to discover novel associations of inflammation-related proteins with esophageal adenocarcinoma to date.