Nikos Papadimitriou, Nabila Kazmi, Konstantinos K Tsilidis, Rebecca C Richmond, Brigid M Lynch, Benedetta Bendinelli, Fulvio Ricceri, Maria-Jose Sánchez, Camino Trobajo-Sanmartín, Paula Jakszyn, Vittorio Simeon, Gianluca Severi, Vittorio Perduca, Therese Truong, Pietro Ferrari, Pekka Keski-Rahkonen, Elisabete Weiderpass, Fabian Eichelmann, Matthias B Schulze, Verena Katzke, Renée Turzanski Fortner, Alicia K Heath, Dagfinn Aune, Rhea Harewood, Christina C Dahm, Adrian Llorente, Marc J Gunter, Neil Murphy, Sarah J Lewis
{"title":"确定身体活动与结直肠癌关系的代谢组学介质。","authors":"Nikos Papadimitriou, Nabila Kazmi, Konstantinos K Tsilidis, Rebecca C Richmond, Brigid M Lynch, Benedetta Bendinelli, Fulvio Ricceri, Maria-Jose Sánchez, Camino Trobajo-Sanmartín, Paula Jakszyn, Vittorio Simeon, Gianluca Severi, Vittorio Perduca, Therese Truong, Pietro Ferrari, Pekka Keski-Rahkonen, Elisabete Weiderpass, Fabian Eichelmann, Matthias B Schulze, Verena Katzke, Renée Turzanski Fortner, Alicia K Heath, Dagfinn Aune, Rhea Harewood, Christina C Dahm, Adrian Llorente, Marc J Gunter, Neil Murphy, Sarah J Lewis","doi":"10.1158/1055-9965.EPI-24-1390","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Impact: </strong>These findings provide insights into PA-related biological mechanisms influencing colorectal cancer risk and suggest potential targets for cancer prevention interventions.</p>","PeriodicalId":9458,"journal":{"name":"Cancer Epidemiology Biomarkers & Prevention","volume":" ","pages":"578-587"},"PeriodicalIF":3.7000,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966109/pdf/","citationCount":"0","resultStr":"{\"title\":\"Identifying Metabolomic Mediators of the Physical Activity and Colorectal Cancer Relationship.\",\"authors\":\"Nikos Papadimitriou, Nabila Kazmi, Konstantinos K Tsilidis, Rebecca C Richmond, Brigid M Lynch, Benedetta Bendinelli, Fulvio Ricceri, Maria-Jose Sánchez, Camino Trobajo-Sanmartín, Paula Jakszyn, Vittorio Simeon, Gianluca Severi, Vittorio Perduca, Therese Truong, Pietro Ferrari, Pekka Keski-Rahkonen, Elisabete Weiderpass, Fabian Eichelmann, Matthias B Schulze, Verena Katzke, Renée Turzanski Fortner, Alicia K Heath, Dagfinn Aune, Rhea Harewood, Christina C Dahm, Adrian Llorente, Marc J Gunter, Neil Murphy, Sarah J Lewis\",\"doi\":\"10.1158/1055-9965.EPI-24-1390\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Impact: </strong>These findings provide insights into PA-related biological mechanisms influencing colorectal cancer risk and suggest potential targets for cancer prevention interventions.</p>\",\"PeriodicalId\":9458,\"journal\":{\"name\":\"Cancer Epidemiology Biomarkers & Prevention\",\"volume\":\" \",\"pages\":\"578-587\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2025-04-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966109/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Epidemiology Biomarkers & Prevention\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1158/1055-9965.EPI-24-1390\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Epidemiology Biomarkers & Prevention","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1055-9965.EPI-24-1390","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
Identifying Metabolomic Mediators of the Physical Activity and Colorectal Cancer Relationship.
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.
期刊介绍:
Cancer Epidemiology, Biomarkers & Prevention publishes original peer-reviewed, population-based research on cancer etiology, prevention, surveillance, and survivorship. The following topics are of special interest: descriptive, analytical, and molecular epidemiology; biomarkers including assay development, validation, and application; chemoprevention and other types of prevention research in the context of descriptive and observational studies; the role of behavioral factors in cancer etiology and prevention; survivorship studies; risk factors; implementation science and cancer care delivery; and the science of cancer health disparities. Besides welcoming manuscripts that address individual subjects in any of the relevant disciplines, CEBP editors encourage the submission of manuscripts with a transdisciplinary approach.