Prediagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma

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  • 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
  • Gianluca Severi
  • Francesca Romana Mancini
  • Catherine Dong
  • Rudolf Kaaks
  • Renee Turzanski Fortner
  • Manuela M. Bergmann
  • Heiner Boeing
  • Antonia Trichopoulou
  • Anna 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

Bile acids (BAs) 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/unconjugated) in prediagnostic 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% confidence intervals [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. Increase in BA concentration is accompanied by a shift in BA profile toward 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.

OriginalsprogEngelsk
TidsskriftInternational Journal of Cancer
Vol/bind150
Udgave nummer8
Sider (fra-til)599-608
Antal sider10
ISSN0020-7136
DOI
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
This work was supported in part by the French National Cancer Institute (L'Institut National du Cancer; INCa; grant numbers 2009‐139 and 2014‐1‐RT‐02‐CIRC‐1; PI: M. Jenab) and by internal funds of the IARC. The coordination of EPIC is financially supported by the International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam‐Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro‐AIRC‐Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra and the Catalan Institute of Oncology—ICO (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC‐Norfolk; C8221/A29017 to EPIC‐Oxford), Medical Research Council (1000143 to EPIC‐Norfolk; MR/M012190/1 to EPIC‐Oxford) (United Kingdom). The funding sources had no influence on the design of the study; the collection, analysis and interpretation of data; the writing of the report; or the decision to submit the article for publication. Funding information

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© 2021 UICC.

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