Alteration of amino acid and biogenic amine metabolism in hepatobiliary cancers: Findings from a prospective cohort study.
Stepien M., Duarte-Salles T., Fedirko V., Floegel A., Barupal DK., Rinaldi S., Achaintre D., Assi N., Tjønneland A., Overvad K., Bastide N., Boutron-Ruault MC., Severi G., Kühn T., Kaaks R., Aleksandrova K., Boeing H., Trichopoulou A., Bamia C., Lagiou P., Saieva C., Agnoli C., Panico S., Tumino R., Naccarati A., Bueno-de-Mesquita HB., Peeters PH., Weiderpass E., Quirós JR., Agudo A., Sánchez MJ., Dorronsoro M., Gavrila D., Barricarte A., Ohlsson B., Sjöberg K., Werner M., Sund M., Wareham N., Khaw KT., Travis RC., Schmidt JA., Gunter M., Cross A., Vineis P., Romieu I., Scalbert A., Jenab M.
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 seven metabolites and four 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.