Germline mutations and somatic mosaicism in steatotic liver diseases and related liver carcinogenesis

Steatotic liver diseases, encompassing metabolic dysfunction-associated steatotic liver disease and alcohol-related liver disease, affect nearly one-third of the global population and are a leading cause of cirrhosis and hepatocellular carcinoma. The substantial interindividual variation in disease progression indicates important genetic contributions beyond environmental factors. Genome-wide association studies have identified multiple common variants predominantly affecting lipid metabolism, with PNPLA3 I148M representing the strongest genetic determinant across the disease spectrum. The shared genetic architecture across metabolic dysfunction-associated steatotic liver disease and alcohol-related liver disease supports convergent pathogenic mechanisms. Discoveries of somatic mosaicism in adult liver tissues have revealed convergent mutations in metabolic genes such as FOXO1, GPAM and CIDEB, conferring adaptive advantages against lipotoxicity. Also, clonal haematopoiesis of indeterminate potential is associated with the risk of chronic liver diseases, metabolic dysfunction-associated steatohepatitis and its related liver cancer risk. Inherited and somatic variants can influence hepatocellular carcinoma risk through direct effects on chronic liver disease progression and/or through specific cancer-promoting pathways involving telomere maintenance and WNT signalling. Although polygenic risk scores represent a promising approach for risk stratification, current implementations face important limitations that must be addressed before achieving their full clinical potential.