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Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, yet effective risk stratification remains limited and there is currently no recommendation for surveillance outside of the setting of cirrhosis or chronic viral hepatitis 1, 2. Unfortunately, a significant proportion of HCC occurs in individuals without these risk factors, and how to screen these patients before HCC has developed is not known. While genetic variants such as PNPLA3 rs738409-G (corresponding to I148M) have been consistently linked to liver disease progression and hepatocellular carcinoma risk, integrating genetic information into clinically practical risk models has remained challenging 3. In this large, Chinese population-based prospective cohort study, Huang et al. demonstrate that hepatocellular carcinoma risk increases in a dose-dependent manner with the number of PNPLA3 rs738409-G alleles carried 4, 5, independent of established clinical risk factors. The authors focused on readily available clinical variables, including sex, body mass index, diabetes, and age, and showed that when these factors were considered alongside genetic risk, hepatocellular carcinoma risk was substantially amplified. In particular, male homozygous carriers of the PNPLA3 I148M variant and individuals aged ≥ 50 years exhibited the highest risk, with adjusted hazard ratios of 9.23 and 6.20, respectively, compared with female non-carriers and younger non-carriers consistent with other studies 6-8. Men ≥ 50 years old with overweight and homozygosity for I148M had an incidence of HCC that nearly reached the 0.2%/year threshold that is often used to determine eligibility for HCC surveillance 2. The study also suggests that the PNPLA3 I148M variant plays a more prominent role in hepatocellular carcinoma development among individuals without chronic hepatitis B infection, supporting the growing relevance of genetic risk in non-viral liver disease–related hepatocarcinogenesis 9. Overall, these findings highlight the potential value of combining simple clinical characteristics with genetic information to improve risk stratification. The novelty of this study lies in its pragmatic approach. Rather than relying on genome-wide polygenic risk scores, the authors demonstrate that a single genetic variant, when paired with common clinical features, may meaningfully refine hepatocellular carcinoma risk assessment in a population-based setting. It also includes a large sample size, prospective design, and a median follow-up of nearly 20 years. The primary limitation is the absence of baseline and longitudinal fibrosis assessments which limits evaluation of how genetic risk interacts with fibrosis progression over time. One wonders whether combinations of non-invasive tests such as Fibrosis-4, PNPLA3 genotype, and cardiometabolic risk factors may identify non-cirrhotic populations at sufficiently high risk for HCC to warrant surveillance. Despite this limitation, this study is an important step toward practical, genetic-informed risk stratification for hepatocellular carcinoma and provides a foundation for future efforts to integrate genetic and clinical data into population-level risk assessment. Vitchapong Prasitsumrit: writing – original draft. Vincent L. Chen: writing – review and editing. The authors have nothing to report. V.L.C. received grant support from KOWA, Ipsen, and AstraZeneca (paid to University of Michigan). This article is linked to Huang et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70532 and https://doi.org/10.1111/apt.70586. The authors have nothing to report.
Prasitsumrit et al. (Fri,) studied this question.