Polymorphisms in cyclooxygenase, lipoxygenase, and TP53 genes predict colorectal polyp risk reduction by aspirin in the seAFOod polyp prevention trial

Davies, John R., Mell, Tracey, Fuller, Harriett, Harland, Mark, Saleh, Rasha N. M., Race, Amanda D., Rees, Colin J., Brown, Louise C., Loadman, Paul M., Downing, Amy, Minihane, Anne Marie ORCID: https://orcid.org/0000-0001-9042-4226, Williams, Elizabeth A. and Hull, Mark A. (2023) Polymorphisms in cyclooxygenase, lipoxygenase, and TP53 genes predict colorectal polyp risk reduction by aspirin in the seAFOod polyp prevention trial. Cancer Prevention Research, 16 (11). 621–630. ISSN 1940-6207

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Abstract

Aspirin and eicosapentaenoic acid (EPA) reduce colorectal adenomatous polyp risk and affect synthesis of oxylipins including prostaglandin E2. We investigated whether 35 SNPs in oxylipin metabolism genes such as cyclooxygenase (PTGS) and lipoxygenase (ALOX), as well as 7 SNPs already associated with colorectal cancer risk reduction by aspirin (e.g., TP53; rs104522), modified the effects of aspirin and EPA on colorectal polyp recurrence in the randomized 2 X 2 factorial seAFOod trial. Treatment effects were reported as the incidence rate ratio (IRR) and 95% confidence interval (CI) by stratifying negative binomial and Poisson regression analyses of colorectal polyp risk on SNP genotype. Statistical significance was reported with adjustment for the false discovery rate as the P and q value. 542 (of 707) trial participants had both genotype and colonoscopy outcome data. Reduction in colorectal polyp risk in aspirin users compared with nonaspirin users was restricted to rs4837960 (PTGS1) common homozygotes [IRR, 0.69; 95% confidence interval (CI), 0.53–0.90); q ¼ 0.06], rs2745557 (PTGS2) compound heterozygote-rare homozygotes [IRR, 0.60 (0.41–0.88); q ¼ 0.06], rs7090328 (ALOX5) rare homozygotes [IRR 0.27 (0.11–0.64); q ¼ 0.05], rs2073438 (ALOX12) common homozygotes [IRR, 0.57 (0.41–0.80); q ¼ 0.05], and rs104522 (TP53) rare homozygotes [IRR, 0.37 (0.17–0.79); q ¼ 0.06]. No modification of colorectal polyp risk in EPA users was observed. In conclusion, genetic variants relevant to the proposed mechanism of action on oxylipins are associated with differential colorectal polyp risk reduction by aspirin in individuals who develop multiple colorectal polyps. SNP genotypes should be considered during development of personalized, predictive models of colorectal cancer chemoprevention by aspirin. Prevention Relevance: Single-nucleotide polymorphisms in genes controlling lipid mediator signaling may modify the colorectal polyp prevention activity of aspirin. Further investigation is required to determine whether testing for genetic variants can be used to target cancer chemoprevention by aspirin to those who will benefit most.

Item Type: Article
Additional Information: Funding Information: This project (NIHR128210) was funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership (to C.J. Rees, L.C. Brown, P.M. Loadman, E.A. Williams, M.A. Hull). Microfluidic array design was supported by the European Union-Biotechnology and Biological Sciences Research Council (UK)-funded Fatty Acid Metabolism (FAME) Consortium - Interlinking Diet with Cardio-metabolic Health (BB/P028233/1; R.N.M. Saleh and A.M. Minihane). M.A. Hull and C.J. Rees are NIHR Senior Investigators. A. Downing and M.A. Hull are supported by Cancer Research UK grant C23434/A24939. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Data were accessed from the GTEx Portal on 08/17/2023. The Authors wish to thank all the participants and research staff who contributed to the seAFOod polyp prevention trial. The Authors express their gratitude to Professors Tim Bishop and David Westhead for helpful review and advice. Professor Matthias Schulze provided useful advice about candidate SNPs. The Authors also acknowledge the significant contribution of Mr. John Whelpton acting as the Patient & Public representative in the STOP-ADENOMA Study Group. Publisher Copyright: ©2023 The Authors; Published by the American Association for Cancer Research.
Uncontrolled Keywords: medicine(all),sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/2700
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Nutrition and Preventive Medicine
Faculty of Medicine and Health Sciences > Research Centres > Lifespan Health
Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging
Faculty of Medicine and Health Sciences > Research Groups > Cardiovascular and Metabolic Health
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Depositing User: LivePure Connector
Date Deposited: 20 May 2024 13:30
Last Modified: 11 Jun 2024 11:30
URI: https://ueaeprints.uea.ac.uk/id/eprint/95242
DOI: 10.1158/1940-6207.CAPR-23-0111

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