Grant title: Investigating the role of thyroid hormone metabolism in liver cancer development: integrating lifestyle and omics data from large cohort studies (HepaThyroid-omics)
Institution: International Agency for Research on Cancer
Grant awarded: September 2025
Our team of international collaborators is deeply grateful to Wereld Kanker Onderzoek Fonds and World Cancer Research Fund International, for this important funding. We’re excited to launch our HepaThyroid-omics project, which will explore the role of thyroid hormone metabolism in the development of hepatocellular carcinomas. Our project integrates data from multiple prospective cohorts and genetic databases, and represents one of the largest and most comprehensive investigations into the influence of thyroid hormones on the development of these increasingly common, highly aggressive and often fatal tumours – Dr Mazda Jenab
Background
The incidence of hepatocellular carcinoma, the main cancer of the liver, is increasing dramatically in many world regions (eg Europe/Japan), in tandem with increasing obesity rates and rapid adoption of unhealthy dietary and lifestyle behaviours. Hepatocellular carcinoma is highly fatal, owing largely to the fact that it is often diagnosed in advanced stages and has few treatment options. Thus, prevention is the main strategy for hepatocellular carcinoma control.
To be effective, hepatocellular carcinoma prevention requires understanding of the physiological and metabolic mechanisms whereby it develops. The liver is a central metabolic organ involved in regulation of thyroid-related hormones (TH) that are essential for metabolism and energy regulation.
Upon diagnosis, many hepatocellular carcinoma patients demonstrate low TH levels. TH are also likely affected by dietary and lifestyle factors. But to date, the role of TH in hepatocellular carcinoma development or their possible alteration by dietary and lifestyle exposures has not been well investigated.
Aims and objectives
We aim to assess relationships between blood TH levels and risk of hepatocellular carcinoma.
For robustness, we will also analyse how genetic markers linked to TH levels are associated with hepatocellular carcinoma risk, using existing data from 5 large-scale genetic datasets.
Next, we will use existing metabolomics data (data on small molecules in the body) from the UK Biobank cohort to explore mechanistic pathways underlying hepatocellular carcinoma. Lastly, we will assess whether diet and lifestyle factors affect TH levels.
How it will be done
For our first aim, we will analyse levels TSH, free-T4, free-T3, rT3, using commercially available kits, in blood samples from the EPIC and Biobank-Japan prospective cohorts. Levels of each hormone will be compared between cases and controls.
For our second aim, we will use available genetic data from a total of 6,210 hepatocellular carcinoma cases and >1,171,000 control subjects from 5 international databases.
Thirdly, we will use available blood metabolomics data from the UK Biobank prospective cohort to identify metabolites and pathways that overlap the development of hepatocellular carcinoma and diseases of fat accumulation in the liver and cirrhosis, which predispose to hepatocellular carcinoma.
Lastly, we will assess the dietary and lifestyle factors that are linked to TH levels using measurements developed in our first aim in the EPIC cohort as well as a Japanese cohort with >53,000 participants. Both cohorts also have detailed dietary and lifestyle data.
Potential impact
This project will elucidate the role of TH in hepatocellular carcinoma development and identify underlying mechanistic pathways. It will also produce evidence on the role of dietary and lifestyle cancer risk factors on TH metabolism, strengthening the mechanistic evidence towards adopting healthy habits for cancer prevention. These new insights will guide public awareness and future cancer prevention policies for these hard-to-detect, highly aggressive and often fatal tumours.