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The Hepatobiliary Cancer Working Group

Hepatobiliary cancers are a group of primary malignancies encompassing the liver, intra- and extra-hepatic biliary tracts, and the gall bladder. Within the liver, the most common primary cancer is hepatocellular carcinoma (HCC) which arises from hepatocytes and comprises upwards of 90% of all primary liver cancers (PLC). PLC constitute the fourth leading cause of cancer death worldwide while ranking seventh of all cancers in overall age standardized incidence rates. For HCC, both the incidence and mortality rates are higher in men than women, while the reverse is apparent for cancers of the gall bladder. These malignancies are highly lethal, in part because they have vague symptomology and are often diagnosed in late, advanced stages.

Established risk factors for HCC are chronic hepatitis infection, alcohol abuse and aflatoxin exposures, but considerable data also support obesity as a major emerging risk factor. Data from prospective cohort studies on dietary and lifestyle risk factors for hepatobiliary cancers is sparse, as is data on metabolic perturbations and underlying mechanisms in the development of these cancers. Provision of reliable, robust findings on the etiology, dietary/ lifestyle determinants, and genetic and metabolic contributors to the development of these cancers is the main objective of the EPIC Hepatobiliary Working Group.

To date, the Working Group has explored HCC risk associations with the role of dietary patterns, individual food groups, specific foods and nutrients. Our findings show strong positive HCC risk associations for obesity, adult weight gain, physical inactivity, diabetes, smoking, heavy alcohol consumption, and chronic hepatitis infection.

Higher HCC risk has also been observed for higher consumption of simple sugars, sugary drinks, dairy products (particularly milk and cheese, but not yohgurt) and with lower intake of vegetables, dietary fibres, fish, flavanols, antioxidant nutrients and monounsaturated fatty acids. Our findings also support the strong inverse HCC risk associations observed in many world regions with higher consumption of coffee, but we also demonstrate that the association is partly accounted for by inflammation and hepatocellular injury.

Using a case-control design nested within the EPIC cohort, the Working Group has assessed biomarker levels in baseline blood samples and delved into some underlying mechanisms of HCC development. The publications from the Working Group demonstrate positive HCC risk associations for lower circulating pre-diagnostic concentrations of vitamin D, zinc, selenium, and selenoprotein P, along with higher inflammation, hyperinsulinemia and increasing degree of liver dysfunction. The Working Group has also conducted extensive untargeted (using Nuclear Magnetic Resonance and High Resolution Liquid Chromatography Mass Spectroscopy) and targeted (Biocrates AbsoluteIDQ p180 Kit) metabolomic analyses. These analyses demonstrate imbalance and perturbation of amino acid, biogenic amine, bile acid, fatty acid oxidation, lipid and carbohydrate metabolism in HCC development, apparent from several years prior to diagnosis. We have also demonstrated a role for gut barrier dysfunction in HCC development; possibly linked to an effect of unhealthy dietary patterns and possible gut microbiome dysbiosis.

The findings of the working group highlight the importance of healthy dietary and lifestyle patterns for HCC prevention, and they highlight potential underlying mechanisms. Future efforts of the working will concentrate further elaborating these observations for HCC, and focusing additional efforts on assessing risk factors for biliary tract cancers.

PMIDs of selected publications from 2010 to present:

30582978, 29924298, 29563134, 28372583, 28152549, 27357089, 27339170, 26773278, 26561631, 26399231, 26238458, 26081477, 26130468, 25742480, 25528243, 25219573, 24644045, 24443059, 24615266, 23801371, 23649669, 23720454, 23670094, 23123507, 22618881, 22021666, 20176692

Contact details/Working Group leader

Mazda Jenab, PhD
Nutritional Epidemiology Group
International Agency for Research on Cancer (IARC/WHO)
25 avenue Tony Garnier
CS 90627
69366 LYON CEDEX 07
France