Joseph A. Rothwell, Neil Murphy, Krasimira Aleksandrova, Matthias B. Schulze, Jelena Bešević, Nathalie Kliemann, Mazda Jenab, Pietro Ferrari, David Achaintre, Audrey Gicquiau, Béatrice Vozar, Augustin Scalbert, Inge Huybrechts, Heinz Freisling, Cornelia Prehn, Jerzy Adamski, Amanda J. Cross, Valeria Maria Pala, Marie-Christine Boutron-Ruault, Christina C. Dahm, Kim Overvad, Inger Torhild Gram, Torkjel M. Sandanger, Guri Skeie, Paula Jakszyn, Kostas K. Tsilidis, David J. Hughes, Bethany van Guelpen, Stina Bodén, Maria-José Sánchez, Julie A. Schmidt, Verena Katzke, Tilman Kühn, Sandra Colorado-Yohar, Rosario Tumino, Bas Bueno-de-Mesquita, Paolo Vineis, Giovanna Masala, Salvatore Panico, Anne Kirstine Eriksen, Anne Tjønneland, Dagfinn Aune, Elisabete Weiderpass, Gianluca Severi, Véronique Chajès, Marc J. Gunter

• BACKGROUND & AIMS: Colorectal cancer risk can be lowered by adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines. We derived metabolic signatures of adherence to these guidelines and tested their associations with colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort. METHODS: Scores reflecting adherence to the WCRF/AICR recommendations (scale, 1-5) were calculated from participant data on weight maintenance, physical activity, diet, and alcohol among a discovery set of 5738 cancer-free European Prospective Investigation into Cancer and Nutrition participants with metabolomics data. Partial least-squares regression was used to derive fatty acid and endogenous metabolite signatures of the WCRF/AICR score in this group. In an independent set of 1608 colorectal cancer cases and matched controls, odds ratios (ORs) and 95% CIs were calculated for colorectal cancer risk per unit increase in WCRF/AICR score and per the corresponding change inBACKGROUND & AIMS: Colorectal cancer risk can be lowered by adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines. We derived metabolic signatures of adherence to these guidelines and tested their associations with colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort. METHODS: Scores reflecting adherence to the WCRF/AICR recommendations (scale, 1-5) were calculated from participant data on weight maintenance, physical activity, diet, and alcohol among a discovery set of 5738 cancer-free European Prospective Investigation into Cancer and Nutrition participants with metabolomics data. Partial least-squares regression was used to derive fatty acid and endogenous metabolite signatures of the WCRF/AICR score in this group. In an independent set of 1608 colorectal cancer cases and matched controls, odds ratios (ORs) and 95% CIs were calculated for colorectal cancer risk per unit increase in WCRF/AICR score and per the corresponding change in metabolic signatures using multivariable conditional logistic regression. RESULTS: Higher WCRF/AICR scores were characterized by metabolic signatures of increased odd-chain fatty acids, serine, glycine, and specific phosphatidylcholines. Signatures were inversely associated more strongly with colorectal cancer risk (fatty acids: OR, 0.51 per unit increase; 95% CI, 0.29-0.90; endogenous metabolites: OR, 0.62 per unit change; 95% CI, 0.50-0.78) than the WCRF/AICR score (OR, 0.93 per unit change; 95% CI, 0.86-1.00) overall. Signature associations were stronger in male compared with female participants. CONCLUSIONS: Metabolite profiles reflecting adherence to WCRF/AICR guidelines and additional lifestyle or biological risk factors were associated with colorectal cancer. Measuring a specific panel of metabolites representative of a healthy or unhealthy lifestyle may identify strata of the population at higher risk of colorectal cancer.…