Alteration of amino acid and biogenic amine metabolism in hepatobiliary cancers: Findings from a prospective cohort study

Magdalena Stepien, Talita Duarte-Salles, Veronika Fedirko, Anne Floegel, Dinesh Kumar Barupal, Sabina Rinaldi, David Achaintre, Nada Assi, Anne Tjønneland, Kim Overvad, Nadia Bastide, Marie-Christine Boutron-Ruault, Gianluca Severi, Tilman Kühn, Rudolf Kaaks, Krasimira Aleksandrova, Heiner Boeing, Antonia Trichopoulou, Christina Bamia, Pagona Lagiou, Calogero Saieva, Claudia Agnoli, Salvatore Panico, Rosario Tumino, Alessio Naccarati, H B As Bueno-de-Mesquita, Petra H Peeters, Elisabete Weiderpass, J Ramón Quirós, Antonio Agudo, María-José Sánchez, Miren Dorronsoro, Diana Gavrila, Aurelio Barricarte, Bodil Ohlsson, Klas Sjöberg, Mårten Werner, Malin Sund, Nick Wareham, Kay-Tee Khaw, Ruth C Travis, Julie A Schmidt, Marc Gunter, Amanda Cross, Paolo Vineis, Isabelle Romieu, Augustin Scalbert, Mazda Jenab

Perturbations in levels of amino acids (AA) and their derivatives are observed in hepatocellular carcinoma (HCC). Yet, it is unclear whether these alterations precede or are a consequence of the disease, nor whether they pertain to anatomically related cancers of the intrahepatic bile duct (IHBC), and gallbladder and extrahepatic biliary tract (GBTC). Circulating standard AA, biogenic amines and hexoses were measured (Biocrates AbsoluteIDQ-p180Kit) in a case-control study nested within a large prospective cohort (147 HCC, 43 IHBC and 134 GBTC cases). Liver function and hepatitis status biomarkers were determined separately. Multivariable conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI) for log-transformed standardised (mean=0, SD=1) serum metabolite levels and relevant ratios in relation to HCC, IHBC or GBTC risk. Fourteen metabolites were significantly associated with HCC risk, of which 7 metabolites and 4 ratios were the strongest predictors in continuous models. Leucine, lysine, glutamine and the ratio of branched chain to aromatic AA (Fischer's ratio) were inversely, while phenylalanine, tyrosine and their ratio, glutamate, glutamate/glutamine ratio, kynurenine and its ratio to tryptophan were positively associated with HCC risk. Confounding by hepatitis status and liver enzyme levels was observed. For the other cancers no significant associations were observed. In conclusion, imbalances of specific AA and biogenic amines may be involved in HCC development. This article is protected by copyright. All rights reserved.