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While chronic hepatitis B and C infections remain primary risk factors, emerging evidence highlights the increasing contributions of metabolic dysfunction\u2010associated steatotic liver disease (MASLD) and alcohol\u2010associated liver disease (ALD) to HCC development. Genetic predispositions play a crucial role in modulating individual susceptibility to HCC, particularly through variants affecting viral persistence, lipid metabolism, and fibrogenesis. This review aims to summarize key genetic variants associated with precancerous conditions leading to HCC. The genetic risk factors, such as TP53 R249S mutant, TERT promoter mutations, and Wnt\/B\u2010catenin pathway alterations, influence disease progression and treatment response in HCC subjects with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. In MASLD\u2010related HCC, variants in PNPLA3, TM6SF2, and MBOAT7 modulate hepatic lipid metabolism and fibrosis. ALD\u2010associated HCC is influenced by polymorphisms in ADH1B, ADH1C, and ALDH2, which affect alcohol metabolism and oxidative stress. Additionally, inherited metabolic disorders, including Wilson's disease and hemochromatosis, further contribute to HCC susceptibility. Despite previous insights into HCC\u2010related genetic cues, challenges such as limited population\u2010specific data, lack of genetic screening programs, and ethical concerns regarding genetic tests hinder the translation of genetic discoveries into personalized HCC prevention strategies. Expanding population\u2010specific studies, improving genetic screening accessibility, and developing standardized risk prediction models will be crucial in shifting traditional medications toward a precision medicine setting for HCC management.<\/jats:p>","DOI":"10.1002\/ijc.70092","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T14:35:37Z","timestamp":1755700537000},"page":"488-502","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Genetic variants underlying precancerous conditions of hepatocellular carcinoma"],"prefix":"10.1002","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9518-8170","authenticated-orcid":false,"given":"Jonathan Jaime G.","family":"Guerrero","sequence":"first","affiliation":[{"name":"College of Medicine University of the Philippines  Manila Philippines"},{"name":"College of Public Health University of the Philippines  Manila 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