PNPLA3 I148M and Hepatocellular Carcinoma

Area of Science:

• Hepatology
• Genetics
• Oncology

Background:

• Hepatocellular carcinoma (HCC) is a major cause of cancer death globally.
• Metabolic dysfunction-associated steatotic liver disease (MASLD)-related HCC incidence is increasing, often without cirrhosis.
• Genetic factors influence liver disease progression and HCC development in MASLD.

Purpose of the Study:

• To review the epidemiology of HCC.
• To discuss the role of the PNPLA3 gene polymorphism (rs738409 C>G, I148M) in MASLD-related HCC.
• To explore the utility of PNPLA3-based polygenic risk scores for HCC prediction.

Main Methods:

• Literature review of epidemiological data on HCC.
• Analysis of genetic studies focusing on PNPLA3 and MASLD.
• Evaluation of research on polygenic risk scores in liver disease.

Main Results:

• The PNPLA3 I148M polymorphism is a key genetic determinant for MASLD spectrum, including HCC.
• Polygenic risk scores incorporating PNPLA3 improve HCC risk stratification compared to single variants.
• HCC can develop in MASLD patients without advanced fibrosis or cirrhosis.

Conclusions:

• Genetic predisposition, particularly PNPLA3 variants and polygenic risk scores, is crucial in MASLD-related HCC.
• Understanding genetic factors enhances prediction and management strategies for HCC in at-risk populations.
• Further research into genetic contributions can refine HCC risk assessment in MASLD.