Plasma Metabolomics Analysis of Aspirin Treatment and Risk of Colorectal Adenomas

• Type of Material: Article
• Authors: Elizabeth L Barry, Geisel School of Medicine at Dartmouth; Veronika Fedirko, Emory University; Yutong Jin, Emory University; Ken Liu, Emory University; Leila A Mott, Geisel School of Medicine at Dartmouth; Janet L Peacock, Geisel School of Medicine at Dartmouth; Michael N Passarelli, Geisel School of Medicine at Dartmouth; John A Baron, Geisel School of Medicine at Dartmouth; Dean Jones, Emory University
• Language: English
• Date: 2022-08-01
• Publisher: AMER ASSOC CANCER RESEARCH
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022, American Association for Cancer Research
• Final Published Version (URL): http://dx.doi.org/10.1158/1940-6207.CAPR-21-0555
• Title of Journal or Parent Work: CANCER PREVENTION RESEARCH
• Volume: 15
• Issue: 8
• Start Page: 521
• End Page: 532
• Grant/Funding Information: Aspirin and placebo tablets were provided by the Bayer Corporation.; This research was funded by the National Cancer Institute at the National Institutes of Health (R01CA188038 to E. L. Barry and R01CA059005 to J. A. Baron).; The study biorepository was supported by the National Institute of General Medical Sciences at the National Institutes of Health (P20GM104416 to M. R. Karagas).
• Keywords: MENDELIAN RANDOMIZATION; CANCER; METAANALYSIS; ACID; Science & Technology; PERFORMANCE; STANDARDS; MASS-SPECTROMETRY; Life Sciences & Biomedicine; Oncology; PREVENTION

Abstract

Despite substantial observational and experimental evidence that aspirin use can provide protection against the development of colorectal neoplasia, our understanding of the molecular mechanisms involved is inadequate and limits our ability to use this drug effectively and safely for chemoprevention. We employed an untargeted plasma metabolomics approach using liquid chromatography with high-resolution mass spectroscopy to explore novel metabolites that may contribute to the chemopreventive effects of aspirin. Associations between levels of metabolic features in plasma and aspirin treatment were investigated among 523 participants in a randomized placebo-controlled clinical trial of two doses of aspirin (81 or 325 mg/day) and were linked to risk of colorectal adenoma occurrence over 3 years of follow-up. Metabolic pathways that were altered with aspirin treatment included linoleate and glycerophospholipid metabolism for the 81-mg dose and carnitine shuttle for both doses. Metabolites whose levels increased with 81 mg/day aspirin treatment and were also associated with decreased risk of adenomas during follow-up included certain forms of lysophosphatidylcholine and lysophosphatidylethanolamine as well as trihydroxyoctadecenoic acid, which is a derivative of linoleic acid and is upstream of cyclooxygenase inhibition by aspirin in the linoleate and arachidonic acid metabolism pathways. In conclusion, our findings regarding lysophospholipids and metabolites in the linoleate metabolism pathway may provide novel insights into the chemopreventive effects of aspirin in the colorectum, although they should be considered hypothesis-generating at this time.