How genes and alcohol interact to affect liver cancer risk

Understanding Gene ENvironment Interaction in ALcohol-related Hepatocellular Carcinoma

This project will test if certain gene variants together with alcohol use and metabolic problems raise the risk of liver cancer in people with fatty or cryptogenic liver disease, especially men with diabetes or obesity.

Quick facts

• Phase: NA
• Study type: Interventional
• Enrollment: 1000 (estimated)
• Ages: 45 Years to 75 Years
• Sex: All
• Sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico (other)
• Locations: 1 site (Milan, Milano)
• Trial ID: NCT07272200 on ClinicalTrials.gov

What this trial studies

The project will combine genetic testing and detailed clinical data from the existing EPIDEMIC and SERENA cohorts to measure how inherited variants and environmental exposures interact in alcohol-related hepatocellular carcinoma (HCC). Eligible participants include people with NAFLD or cryptogenic liver disease, with a focused subgroup of men who have type 2 diabetes or obesity and carry multiple risk variants in PNPLA3, TM6SF2, and MBOAT7. Investigators will quantify alcohol intake, metabolic risk factors, and genetic profiles and correlate these with HCC occurrence to model gene–environment risk. The work is performed at a single center in Milan using previously approved cohort frameworks and new genetic analyses.

Who should consider this trial

Good fit: Ideal candidates are participants already enrolled in the EPIDEMIC or SERENA cohorts with NAFLD or cryptogenic liver disease, especially men with type 2 diabetes or obesity who carry at least three risk variants in PNPLA3, TM6SF2, and MBOAT7 and who can give informed consent.

Not a fit: People with heavy alcohol use (>60 g/day for men, >40 g/day for women), chronic viral or autoimmune hepatitis, known genetic liver diseases (eg, hemochromatosis, Wilson's, A1AT deficiency), or use of drugs that induce steatosis are excluded and unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this work could help identify people at higher risk of alcohol-related liver cancer so they can get closer monitoring or targeted prevention.

How similar studies have performed: Prior genetic studies have linked PNPLA3, TM6SF2, and MBOAT7 to fatty liver and HCC risk, but comprehensive gene–environment interaction work specifically in alcohol-related HCC is limited, making this a relatively novel integrative effort.

Eligibility criteria

Inclusion Criteria:

Patients from the EPIDEMIC (approval no. 1822 of 27 August 2013) and SERENA (last amendment no. 1151\_2021 of 9 November 2021), already approved by the CE Milano Area 2 will be included.

* Diagnosis of NAFLD or cryptogenic liver disease, allowing a more liberal alcohol intake limit (\<60/40 g/day in M/F), so that subjects with a moderate alcoholic component of the hepatopathy are also included, Important factor given the high epidemiological weight of this group
* Any of the following:
* Male patient with type 2 diabetes or obesity carrying at least three genetic variants in PNPLA3, TM6SF2, MBOAT7.
* Willingness to sign informed consent.

Exclusion Criteria:

* Alcohol intake \>60/40 g/day in M/F
* Chronic viral or autoimmune hepatitis
* Any previously diagnosed liver genetic disease associated with increased risk of HCC (such as hereditary hemochromatosis, Wilson's disease, Alpha-1 antitrypsin deficiency)
* Use of drugs known to induce steatosis and liver disease
* HCC previously diagnosed the study start date.
* Other pathological conditions with prognosis less than two years.

Where this trial is running

Milan, Milano

• Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica — Milan, Milano, Italy (RECRUITING)

Study contacts

• Study coordinator: Serena Pelusi

Conditions: HCC, Genetic Predisposition