Associations between metabolites and pancreatic cancer risk in a large prospective epidemiological study. Issue 11 (14th February 2020)

• Record Type: Journal Article
• Authors: Stolzenberg-Solomon, Rachael; Derkach, Andriy; Moore, Steven; Weinstein, Stephanie J; Albanes, Demetrius; Sampson, Joshua
• Is Part Of: Gut. Volume 69:Issue 11(2020)
• Page Start: 2008
• Page End: 2015
• Publication Date: 2020-02-14
• Subjects: cancer epidemiology -- epidemiology -- pancreatic cancer; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2019-319811
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Objective: To assess whether prediagnostic metabolites were associated with incident pancreatic ductal adenocarcinoma (PDAC) in a prospective cohort study. Design: We conducted an untargeted analysis of 554 known metabolites measured in prediagnostic serum (up to 24 years) to determine their association with incident PDAC in a nested case-control study of male smokers (372 matched case-control sets) and an independent nested case-control study that included women and non-smokers (107 matched sets). Metabolites were measured using Orbitrap Elite or Q-Exactive high-resolution/accurate mass spectrometers. Controls were matched to cases by age, sex, race, date of blood draw, and follow-up time. We used conditional logistic regression adjusted for age to calculate ORs and 95% CIs for a 1 SD increase in log-metabolite level separately in each cohort and combined the two ORs using a fixed-effects meta-analysis. Results: Thirty-one metabolites were significantly associated with PDAC at a false discovery rate <0.05 with 12 metabolites below the Bonferroni-corrected threshold (p<9.04×10 –5 ). Similar associations were observed in both cohorts. The dipeptides glycylvaline, aspartylphenylalanine, pyroglutamylglycine, phenylalanylphenylalanine, phenylalanylleucine and tryptophylglutamate and amino acids aspartate and glutamate were positively while the dipeptides tyrosylglutamine and α-glutamyltyrosine, fibrinogen cleavage peptide DSGEGDFXAEGGGVR and glutathione-related amino acid cysteine-glutathione disulfide were inversely associated with PDAC after Bonferroni correction. Five top metabolites demonstrated significant time-varying associations (p<0.023) with the strongest associations observed 10–15 years after participants' blood collection and attenuated thereafter. Conclusion: Our results suggest that prediagnostic metabolites related to subclinical disease, γ-glutamyl cycle metabolism and adiposity/insulin resistance are associated with PDAC.