Association between prediagnostic serum metabolites and pancreatic ductal adenocarcinoma risk in two prospective cohorts

Pancreatic ductal adenocarcinoma (PDAC) is highly fatal, with incidence rising worldwide. Metabolomics may provide insight into etiology and mechanisms contributing to pancreatic carcinogenesis. We examined associations between 1483 prediagnostic (up to 24 years) serum metabolites and PDAC in nested case-control studies within a cohort of male Finnish smokers and another of American men and women (n = 732 matched pairs). We used conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals per standard deviation increase in log-metabolite level within each cohort and combined using fixed-effect meta-analyses. We performed elastic net regression (EN) to select metabolites and calculated area under the curve (AUC) for established PDAC risk factors (smoking, diabetes, and overweight/obesity), selected metabolites, and their combination. Sixty-six metabolites were associated with PDAC at false discovery rate <0.05, with 26 below Bonferroni threshold (p < 3.4 × 10^-5) and 38 not reported previously. Notable findings include fibrinopeptide B (1-9); 13 modified, di- or poly-peptides; 11 tobacco-chemical related xenobiotics; glycolysis-gluconeogenesis-tricarboxylic acid (TCA) cycle metabolites (aspartate, glutamate, lactate, α-ketoglutarate, and pyruvate); and four secondary and two primary bile acids that were positively (OR = 1.18-1.58) and five fibrinogen cleavage peptides that were inversely (OR = 0.70-0.84) associated with PDAC. AUCs for combined metabolites-risk factors outperformed known risk factors (p ≤ .01) but not metabolites (p ≥ .31) alone. Systemic metabolism is prospectively associated with PDAC. New metabolite associations include those related to immune response, tobacco, microbiome, glycolysis-gluconeogenesis and TCA cycle, and adiposity or diabetes. The EN selected metabolites were more sensitive indicators of prediagnostic metabolic processes and exposures associated with PDAC than established risk factors.