Abstract 747: Novel biomarkers of habitual alcohol intake and associations with risk of pancreatic and liver cancers and liver disease mortality
Authors: Loftfield Erikka , Stepien Magdalena , Viallon Vivian , Trijsburg Laura , Rothwell Joseph , Robinot Nivonirina , Biessy Carine , Bergdahl Ingvar A. , Bodén Stina , Schulze Matthias B. , Bergmann Manuela , Weiderpass Elisabete , Schmidt Julie A. , Zamora-Ros Rual , Nøst Therese H. , Sandanger Torkjel M. , Sonestedt Emily , Ohlsson Bodil , Katzke Verena , Kaaks Rudolf , Ricceri Fulvio , Tjønneland Anne , Dahm Christina C. , Sánchez Maria-Jose , Trichopoulou Antonia , Tumino Rosario , Chirlaque María-Dolores , Masala Giovanna , Ardanaz Eva , Vermeulen Roel , Brennan Paul , Albanes Demetrius , Weinstein Stephanie J. , Scalbert Augustin , Scalbert Augustin , Freedman Neal D. , Gunter Marc J. , Jenab Mazda , Sinha Rashmi , Keski-Rahkonen Pekka , Ferrari Pietro 
Published: July 2021

Abstract
Background: Alcohol is an established risk factor for several cancers, but modest alcohol-cancer associations may be missed due to measurement error in self-reported assessments. The identification of biomarkers of habitual alcohol intake may enhance evidence on the role of alcohol in cancer onset.
Methods: Untargeted metabolomics was used to identify metabolites correlated with habitual alcohol intake in a discovery dataset from the European Prospective Investigation into Cancer and Nutrition (EPIC; n=454). Significant correlations were replicated in independent datasets of controls from case-control studies nested within EPIC (n=281) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC; n=438) study. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) 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 alcohol intake: 2-hydroxy-3-methylbutyric acid and an unidentified compound (m/z(+):231.0839). A 1-SD increase in log2-transformed levels of 2-hydroxy-3-methylbutyric acid was associated with risk of HCC (OR=2.14; 95% CI=1.39-3.31) and pancreatic cancer (OR=1.65; 95% CI=1.17-2.32) in EPIC and liver cancer (OR=2.00; 95% CI=1.44-2.77) and liver disease mortality (OR=2.16; 95% CI=1.63-2.86) in ATBC. Conversely, a 1-SD increase in log2-transformed questionnaire-derived alcohol intake was not associated with risk of HCC or pancreatic cancer in EPIC or liver cancer in ATBC but was associated with risk of liver disease mortality (OR=2.19; 95% CI=1.60-2.98) 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.
Citation Format: Erikka Loftfield, Magdalena Stepien, Vivian Viallon, Laura Trijsburg, Joseph Rothwell, Nivonirina Robinot, Carine Biessy, Ingvar A. Bergdahl, Stina Bodén, Matthias B. Schulze, Manuela Bergmann, Elisabete Weiderpass, Julie A. Schmidt, Rual Zamora-Ros, Therese H. Nøst, Torkjel M. Sandanger, Emily Sonestedt, Bodil Ohlsson, Verena Katzke, Rudolf Kaaks, Fulvio Ricceri, Anne Tjønneland, Christina C. Dahm, Maria-Jose Sánchez, Antonia Trichopoulou, Rosario Tumino, María-Dolores Chirlaque, Giovanna Masala, Eva Ardanaz, Roel Vermeulen, Paul Brennan, Demetrius Albanes, Stephanie J. Weinstein, Augustin Scalbert, Augustin Scalbert, Neal D. Freedman, Marc J. Gunter, Mazda Jenab, Rashmi Sinha, Pekka Keski-Rahkonen, Pietro Ferrari. Novel biomarkers of habitual alcohol intake and associations with risk of pancreatic and liver cancers and liver disease mortality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 747.