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Rothwell, J.A.* ; Murphy, N.* ; Bešević, J.* ; Kliemann, N.* ; Jenab, M.* ; Ferrari, P.* ; Achaintre, D.* ; Gicquiau, A.* ; Vozar, B.* ; Scalbert, A.* ; Huybrechts, I.* ; Freisling, H.* ; Prehn, C.* ; Adamski, J. ; Cross, A.J.* ; Pala, V.M.* ; Boutron-Ruault, M.C.* ; Dahm, C.C.* ; Overvad, K.* ; Gram, I.T.* ; Sandanger, T.M.* ; Skeie, G.* ; Jakszyn, P.* ; Tsilidis, K.K.* ; Aleksandrova, K.* ; Schulze, M.B.* ; Hughes, D.J.* ; van Guelpen, B.* ; Bodén, S.* ; Sánchez, M.J.* ; Schmidt, J.A.* ; Katzke, V.* ; Kühn, T.* ; Colorado-Yohar, S.* ; Tumino, R.* ; Bueno-de-Mesquita, B.* ; Vineis, P.* ; Masala, G.* ; Panico, S.* ; Eriksen, A.K.* ; Tjønneland, A.* ; Aune, D.* ; Weiderpass, E.* ; Severi, G.* ; Chajès, V.* ; Gunter, M.J.*

Metabolic signatures of healthy lifestyle patterns and colorectal cancer risk in a European cohort.

Clin. Gastroenterol. Hepatol. 20, E1061-E1082 (2022)

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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 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 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.

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