Pre-diagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma

Magdalena Stepien, Marina Lopez-Nogueroles, Agustin Lahoz, Tilman Kühn, Gabriel Perlemuter, Cosmin Voican, Dragos Ciocan, Marie-Christine Boutron-Ruault, Eugene Jansen, Vivian Viallon, Michael Leitzmann, Anne Tjønneland, Gianluca Severi, Francesca Romana Mancini, Catherine Dong, Rudolf Kaaks, Renee Turzanski Fortner, Manuela M Bergmann, Heiner Boeing, Antonia TrichopoulouAnna Karakatsani, Eleni Peppa, Domenico Palli, Vittorio Krogh, Rosario Tumino, Carlotta Sacerdote, Salvatore Panico, H Bas Bueno-de-Mesquita, Guri Skeie, Susana Merino, Raul Zamora Ros, Maria Jose Sánchez, Pilar Amiano, Jose Mª Huerta, Aurelio Barricarte, Klas Sjöberg, Bodil Ohlsson, Hanna Nyström, Marten Werner, Aurora Perez-Cornago, Julie A Schmidt, Heinz Freisling, Augustin Scalbert, Elisabete Weiderpass, Sofia Christakoudi, Marc J Gunter, Mazda Jenab

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Abstract

Bile acids (BA) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory, and immune-related processes. The liver is the primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/un-conjugated) in pre-diagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (ORdoubling = 2.30, 95%CI = 1.76-3.00) and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increased in BA concentration is accompanied by a shift in BA profile towards higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.

Original languageEnglish
JournalInternational Journal of Cancer
Early online date29 Nov 2021
DOIs
Publication statusEarly online date - 29 Nov 2021
Externally publishedYes

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