Erikka Loftfield1, Magdalena Stepien2, Vivian Viallon3, Laura Trijsburg3, Joseph A Rothwell2,4,5, Nivonirina Robinot6, Carine Biessy3, Ingvar A Bergdahl7, Stina Bodén8, Matthias B Schulze9,10, Manuela Bergman9,10, Elisabete Weiderpass11, Julie A Schmidt12, Raul Zamora-Ros13, Therese H Nøst14, Torkjel M Sandanger14, Emily Sonestedt15, Bodil Ohlsson15, Verena Katzke16, Rudolf Kaaks16, Fulvio Ricceri17, Anne Tjønneland18, Christina C Dahm19, Maria-Jose Sánchez20,21,22, Antonia Trichopoulou23, Rosario Tumino24, María-Dolores Chirlaque25,26, Giovanna Masala27, Eva Ardanaz28,29,30, Roel Vermeulen31, Paul Brennan32, Demetrius Albanes1, Stephanie J Weinstein1, Augustin Scalbert6, Neal D Freedman1, Marc J Gunter2, Mazda Jenab2, Rashmi Sinha1, Pekka Keski-Rahkonen6, Pietro Ferrari3. 1. Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute,National Institutes of Health, Bethesda, MD, USA. 2. Nutritional Epidemiology Group, International Agency for Research on Cancer (IARC-WHO), Lyon, France. 3. Nutritional Methodology and Biostatistics Group, International Agency for Research on Cancer (IARC-WHO), Lyon, France. 4. Gustave Roussy, F-94805, Villejuif, France. 5. Biomarkers Group, International Agency for Research on Cancer (IARC-WHO), Lyon, France. 6. Centre for Epidemiology and Population Health (U1018), Generations and Health team, Faculté de Médecine, Université Paris-Saclay, UVSQ, INSERM, Villejuif, France. 7. Biobank Research Unit, Umeå University, Sweden. 8. Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden. 9. Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 10. Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany. 11. International Agency for Research on Cancer, World Health Organization. 12. Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. 13. Unit of Nutrition and Cancer, Epidemiology Research Program, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain. 14. Department of Community Medicine, UiT- The Arctic University of Norway, Tromsø, Norway. 15. Department of Clinical Sciences in Malmö, Lund University, Malmö, Sweden. 16. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 17. Department of Clinical and Biological Sciences, University of Turin, Italy; Unit of Epidemiology, Regional Health Service ASL TO3, Grugliasco, TO, Italy. 18. Danish Cancer Society Research Center; University of Copenhagen, Department of Public Health. 19. Department of Public Health, Aarhus University, Denmark. 20. Escuela Andaluza de Salud Pública (EASP), Granada, Spain; Instituto de Investigación Biosanitaria ibs. GRANADA, Granada, Spain. 21. Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. 22. Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain. 23. Hellenic Health Foundation, Athens, Greece. 24. Cancer Registry and Histopathology Department, Provincial Health Authority (ASP 7), Ragusa, Italy. 25. Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia University, Murcia, Spain. 26. CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain. 27. Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network-ISPRO, Florence, Italy. 28. Navarra Public Health Institute, Pamplona, Spain. 29. IdiSNA, Navarra Institute for Health Research, Pamplona, Spain. 30. CIBER Epidemiology and Public Health CIBERESP, Madrid, Spain. 31. Institute for Risk Assessment Sciences, Division of Environmental Epidemiology, Utrecht University, Utrecht, the Netherlands. 32. Genetic Epidemiology Group, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
Abstract
BACKGROUND: Alcohol is an established risk factor for several cancers, but modest alcohol-cancer associations may be missed because of measurement error in self-reported assessments. Biomarkers of habitual alcohol intake may provide novel insight into the relationship between alcohol and cancer risk. METHODS: Untargeted metabolomics was used to identify metabolites correlated with self-reported habitual alcohol intake in a discovery dataset from the European Prospective Investigation into Cancer and Nutrition (EPIC; n = 454). Statistically significant correlations were tested in independent datasets of controls from case-control studies nested within EPIC (n = 280) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC; n = 438) study. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations of alcohol-associated metabolites and self-reported alcohol intake with risk of pancreatic cancer, hepatocellular carcinoma (HCC), liver cancer, and liver disease mortality in the contributing studies. RESULTS: Two metabolites displayed a dose-response association with self-reported alcohol intake: 2-hydroxy-3-methylbutyric acid and an unidentified compound. A 1-SD (log2) increase in levels of 2-hydroxy-3-methylbutyric acid was associated with risk of HCC (OR = 2.54, 95% CI = 1.51 to 4.27) and pancreatic cancer (OR = 1.43, 95% CI = 1.03 to 1.99) in EPIC and liver cancer (OR = 2.00, 95% CI = 1.44 to 2.77) and liver disease mortality (OR = 2.16, 95% CI = 1.63 to 2.86) in ATBC. Conversely, a 1-SD (log2) increase in questionnaire-derived alcohol intake was not associated with HCC or pancreatic cancer in EPIC or liver cancer in ATBC but was associated with liver disease mortality (OR = 2.19, 95% CI = 1.60 to 2.98) in ATBC. CONCLUSIONS: 2-hydroxy-3-methylbutyric acid is a candidate biomarker of habitual alcohol intake that may advance the study of alcohol and cancer risk in population-based studies.
BACKGROUND: Alcohol is an established risk factor for several cancers, but modest alcohol-cancer associations may be missed because of measurement error in self-reported assessments. Biomarkers of habitual alcohol intake may provide novel insight into the relationship between alcohol and cancer risk. METHODS: Untargeted metabolomics was used to identify metabolites correlated with self-reported habitual alcohol intake in a discovery dataset from the European Prospective Investigation into Cancer and Nutrition (EPIC; n = 454). Statistically significant correlations were tested in independent datasets of controls from case-control studies nested within EPIC (n = 280) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC; n = 438) study. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations of alcohol-associated metabolites and self-reported alcohol intake with risk of pancreatic cancer, hepatocellular carcinoma (HCC), liver cancer, and liver disease mortality in the contributing studies. RESULTS: Two metabolites displayed a dose-response association with self-reported alcohol intake: 2-hydroxy-3-methylbutyric acid and an unidentified compound. A 1-SD (log2) increase in levels of 2-hydroxy-3-methylbutyric acid was associated with risk of HCC (OR = 2.54, 95% CI = 1.51 to 4.27) and pancreatic cancer (OR = 1.43, 95% CI = 1.03 to 1.99) in EPIC and liver cancer (OR = 2.00, 95% CI = 1.44 to 2.77) and liver disease mortality (OR = 2.16, 95% CI = 1.63 to 2.86) in ATBC. Conversely, a 1-SD (log2) increase in questionnaire-derived alcohol intake was not associated with HCC or pancreatic cancer in EPIC or liver cancer in ATBC but was associated with liver disease mortality (OR = 2.19, 95% CI = 1.60 to 2.98) in ATBC. CONCLUSIONS: 2-hydroxy-3-methylbutyric acid is a candidate biomarker of habitual alcohol intake that may advance the study of alcohol and cancer risk in population-based studies.
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