2026-04-14T08:50:42Zhttps://recercat.cat/oai/request

oai:recercat.cat:20.500.14342/52492025-04-30T19:06:06Zcom_2072_482405com_2072_183628col_2072_482409

Identifying metabolomic mediators of the physical activity and colorectal cancer relationship Papadimitriou, Nikos Kazmi, Nabila Tsilidis, Konstantinos K. Richmond, Rebecca C. Lynch, Brigid M. Bendinelli, Benedetta Ricceri, Fulvio Sánchez, Maria Jose Trobajo-Sanmartín, Camino Jakszyn, Paula Simeon, Vittorio Severi, Gianluca Perduca, Vittorio Truong, Therese Ferrari, Pietro Keski-Rahkonen, Pekka Weiderpass, Elisabete Eichelmann, Fabian Schulze, Matthias B. Katzke, Verena Andrea Turzanski‑Fortner, Renée Heath, Alicia K. Aune, Dagfnn Harewood, Rhea Dahm, Christina C. Llorente, Adrian Gunter, Marc J. Murphy, Neil Lewis, Sarah Jayne Universitat Ramon Llull. Facultat de Ciències de la Salut Blanquerna Metabolòmica Exercici Còlon -- Càncer Background: Current evidence suggests higher physical activity (PA) levels are associated with a reduced risk of colorectal cancer. However, the mediating role of the circulating metabolome in this relationship remains unclear. Methods: Targeted metabolomics data from 6,055 participants in the European Prospective Investigation into Cancer and Nutrition cohort were used to identify metabolites associated with PA and derive a metabolomic signature of PA levels. PA levels were estimated using the validated Cambridge PA index based on baseline questionnaires. Mediation analyses were conducted in a nested case–control study (1,585 cases, 1,585 controls) to examine whether individual metabolites and the metabolomic signature mediated the PA–colorectal cancer association. Results: PA was inversely associated with colorectal cancer risk (OR per category change: 0.90, 95% confidence interval, 0.83–0.97; P value = 0.009). PA levels were associated with 24 circulating metabolites after FDR correction, with the strongest associations observed for phosphatidylcholine acyl-alkyl (PC ae) C34:3 (FDR-adjusted P value = 1.18 × 10−10) and lysophosphatidylcholine acyl C18:2 (FDR-adjusted P value = 1.35 × 10−6). PC ae C34:3 partially mediated the PA–colorectal cancer association (natural indirect effect: 0.991, 95% confidence interval, 0.982–0.999; P value = 0.04), explaining 7.4% of the association. No mediation effects were observed for the remaining metabolites or the overall PA metabolite signature. Conclusions: PC ae C34:3 mediates part of the PA–colorectal cancer inverse association, but further studies with improved PA measures and extended metabolomic panels are needed. Impact: These findings provide insights into PA-related biological mechanisms influencing colorectal cancer risk and suggest potential targets for cancer prevention interventions. info:eu-repo/semantics/publishedVersion 2025-04 info:eu-repo/semantics/article http://hdl.handle.net/20.500.14342/5249 https://doi.org/10.1158/1055-9965.EPI-24-1390 eng Cancer epidemiology, biomarkers and prevention, 2025, 34(4): 578-587 © L'autor/a Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess 10 p. American Association for Cancer Research