Loftfield, ErikkaStepien, MagdalenaViallon, VivianTrijsburg, LauraRothwell, Joseph ARobinot, NivonirinaBiessy, CarineBergdahl, Ingvar ABodén, StinaSchulze, Matthias BBergman, ManuelaWeiderpass, ElisabeteSchmidt, Julie AZamora-Ros, RaulNøst, Therese HSandanger, Torkjel MSonestedt, EmilyOhlsson, BodilKatzke, VerenaKaaks, RudolfRicceri, FulvioTjønneland, AnneDahm, Christina CSánchez, Maria-JoseTrichopoulou, AntoniaTumino, RosarioChirlaque, María-DoloresMasala, GiovannaArdanaz, EvaVermeulen, RoelBrennan, PaulAlbanes, DemetriusWeinstein, Stephanie JScalbert, AugustinFreedman, Neal DGunter, Marc JJenab, MazdaSinha, RashmiKeski-Rahkonen, PekkaFerrari, Pietro2025-01-072025-01-072021https://hdl.handle.net/10668/24660Alcohol 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. 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. 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. 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.enAlcohol DrinkingBiomarkersCarcinoma, HepatocellularCase-Control StudiesHumansLiver NeoplasmsProspective StudiesRisk Factorsresearch article34010397open access10.1093/jnci/djab0781460-2105PMC8562969https://europepmc.org/articles/pmc8562969?pdf=renderhttps://pmc.ncbi.nlm.nih.gov/articles/PMC8562969/pdf