Abstract 3427: Serum metabolites and pancreatic ductal adenocarcinoma in two prospective cohorts
Authors: Zhang Ting , Moore Steven C. , Fu Sheng , Wang Kevin , Albanes Demetrius , Weinstein Stephanie J. , Yu Kai , Stolzenberg-Solomon Rachael Z. 
Published: March 2024

Abstract
Objective: Metabolomics may provide insight to understand the etiology and potential mechanisms for pancreatic ductal adenocarcinoma (PDAC) development beyond established risk factors of smoking, diabetes, and adiposity. We extended our previous metabolomic study by including additional participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) with the aim to examine prospective associations between serum metabolites and incident PDAC.
Method: We measured 1483 known metabolites in pre-diagnostic serum (up to 24 years) in two PDAC nested case-control studies within the PLCO (360 cases-control pairs) of mostly non-smoker men and women and Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC, 372 cases-control pairs) male smokers using liquid chromatography, high resolution/accurate mass spectrometry. Controls were incidence-density sampled and matched to cases by age, blood draw date, sex, race/ethnicity, and cohort. We used conditional logistic regression to calculate odds ratios and 95% confidence intervals for PDAC per standard deviation increase in log10-metabolite levels in each cohort and combined using fixed-effect meta-analyses and stratified by follow-up time. We also performed ElasticNet regression in each cohort to identify metabolites. We assessed associations of 72 predefined metabolic pathways with PDAC by comparing Fisher’s statistic of metabolite p-values per pathway with a null distribution based on 500,000 permutations.
Results: Sixty-six metabolites were associated with PDAC at a false discovery rate (FDR)&lt;0.05 with 26 below the Bonferroni threshold (P&lt;3.4 × 10−5). Among the 66 metabolites, 14 and 15 were selected in ElasticNet regressions in ATBC and PLCO, respectively, with two in both cohorts. Notable findings include: fibrinopeptide B(1-9); seven modified, di- or poly-peptides; eight xenobiotics related to tobacco smoke; amino acids, carbohydrates, and TCA cycle metabolites known to be regulated by mutant KRAS (aspartate, glutamate, lactate, pyruvate, and α-ketoglutarate); four secondary bile acids and three aromatic amino acids (tryptophan, phenylalanine, and tyrosine) that were positively, while four fibrinogen cleavage peptides were inversely associated with PDAC. Among the top identified metabolites, aspartate, α-glutamyltyrosine, pyroglutamylglutamine, and Glu-Gly-Asn-Val showed time-varying associations overall (P≤0.05) with greater magnitudes within the first 5 years after blood draw. Thirteen metabolic pathways were associated with PDAC (Bonferroni P≤0.05).
Conclusion: Our study suggests pre-diagnostic circulating metabolites, particularly those potentially related to subclinical disease, microbiome, and tobacco metabolism are associated with PDAC. The identified metabolites along with other known risk factors might be useful in algorithms to model disease risk and progression.
Citation Format: Ting Zhang, Steven C. Moore, Sheng Fu, Kevin Wang, Demetrius Albanes, Stephanie J. Weinstein, Kai Yu, Rachael Z. Stolzenberg-Solomon. Serum metabolites and pancreatic ductal adenocarcinoma in two prospective cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3427.