Nada Assi1, Marc J Gunter1, Duncan C Thomas2, Michael Leitzmann3, Magdalena Stepien1, Véronique Chajès1, Thierry Philip4, Paolo Vineis5, Christina Bamia6,7, Marie-Christine Boutron-Ruault8,9, Torkjel M Sandanger10, Amaia Molinuevo11,12, Hendriek Boshuizen13, Anneli Sundkvist14, Tilman Kühn15, Ruth Travis16, Kim Overvad17, Elio Riboli5, Augustin Scalbert1, Mazda Jenab1, Vivian Viallon1,18, Pietro Ferrari1. 1. Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC), Lyon, France. 2. University of Southern California, Los Angeles, CA. 3. Department of Epidemiology and Preventive Medicine, Regensburg University, Regensburg, Germany. 4. Unité Cancer et Environnement, Centre Léon Bérard, Lyon, France. 5. Department of Epidemiology and Biostatistics, MRC-HPA Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom. 6. Hellenic Health Foundation, Athens, Greece. 7. WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece. 8. Université Paris-Saclay, Université Paris-Sud, Villejuif, France. 9. Gustave Roussy, Villejuif, France. 10. Department of Community Medicine, UiT the Arctic University of Norway, Tromsø, Norway. 11. Public Health Division of Gipuzkoa, Regional Government of the Basque Country, Donostia-San Sebastián, Spain. 12. CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain. 13. National Institute for Public Health and the Environment (RIVM), Antonie van Leeuwenhoeklaan 9, 3721 MA Bilthoven, Netherlands. 14. Department of Radiation Sciences Oncology, Umeå University 901 87 Umeå, Sweden. 15. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 16. Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom. 17. The Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark. 18. Université de Lyon, Université Claude Bernard Lyon1, Lyon, France.
Abstract
Background: Studies using metabolomic data have identified metabolites from several compound classes that are associated with disease-related lifestyle factors. Objective: In this study, we identified metabolic signatures reflecting lifestyle patterns and related them to the risk of hepatocellular carcinoma (HCC) in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Design: Within a nested case-control study of 147 incident HCC cases and 147 matched controls, partial least squares (PLS) analysis related 7 modified healthy lifestyle index (HLI) variables (diet, BMI, physical activity, lifetime alcohol, smoking, diabetes, and hepatitis) to 132 targeted serum-measured metabolites and a liver function score. The association between the resulting PLS scores and HCC risk was examined in multivariable conditional logistic regression models, where ORs and 95% CIs were computed. Results: The lifestyle component's PLS score was negatively associated with lifetime alcohol, BMI, smoking, and diabetes, and positively associated with physical activity. Its metabolic counterpart was positively related to the metabolites sphingomyelin (SM) (OH) C14:1, C16:1, and C22:2, and negatively related to glutamate, hexoses, and the diacyl-phosphatidylcholine PC aaC32:1. The lifestyle and metabolomics components were inversely associated with HCC risk, with the ORs for a 1-SD increase in scores equal to 0.53 (95% CI: 0.38, 0.74) and 0.28 (0.18, 0.43), and the associated AUCs equal to 0.64 (0.57, 0.70) and 0.74 (0.69, 0.80), respectively. Conclusions: This study identified a metabolic signature reflecting a healthy lifestyle pattern which was inversely associated with HCC risk. The metabolic profile displayed a stronger association with HCC than did the modified HLI derived from questionnaire data. Measuring a specific panel of metabolites may identify strata of the population at higher risk for HCC and can add substantial discrimination compared with questionnaire data. This trial was registered at clinicaltrials.gov as NCT03356535.
Background: Studies using metabolomic data have identified metabolites from several compound classes that are associated with disease-related lifestyle factors. Objective: In this study, we identified metabolic signatures reflecting lifestyle patterns and related them to the risk of hepatocellular carcinoma (HCC) in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Design: Within a nested case-control study of 147 incident HCC cases and 147 matched controls, partial least squares (PLS) analysis related 7 modified healthy lifestyle index (HLI) variables (diet, BMI, physical activity, lifetime alcohol, smoking, diabetes, and hepatitis) to 132 targeted serum-measured metabolites and a liver function score. The association between the resulting PLS scores and HCC risk was examined in multivariable conditional logistic regression models, where ORs and 95% CIs were computed. Results: The lifestyle component's PLS score was negatively associated with lifetime alcohol, BMI, smoking, and diabetes, and positively associated with physical activity. Its metabolic counterpart was positively related to the metabolites sphingomyelin (SM) (OH) C14:1, C16:1, and C22:2, and negatively related to glutamate, hexoses, and the diacyl-phosphatidylcholine PC aaC32:1. The lifestyle and metabolomics components were inversely associated with HCC risk, with the ORs for a 1-SD increase in scores equal to 0.53 (95% CI: 0.38, 0.74) and 0.28 (0.18, 0.43), and the associated AUCs equal to 0.64 (0.57, 0.70) and 0.74 (0.69, 0.80), respectively. Conclusions: This study identified a metabolic signature reflecting a healthy lifestyle pattern which was inversely associated with HCC risk. The metabolic profile displayed a stronger association with HCC than did the modified HLI derived from questionnaire data. Measuring a specific panel of metabolites may identify strata of the population at higher risk for HCC and can add substantial discrimination compared with questionnaire data. This trial was registered at clinicaltrials.gov as NCT03356535.
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