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Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores
Open accessAbstract
Background & Aims Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification. Methods We examined at-risk individuals (NAFLD cohort, n = 2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank [UKBB] cohort, n = 364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5). Results In the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver ( p = 0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants ( p < 10 -13 ). The association between PRS and HCC was mainly mediated through severe fibrosis, but was independent of fibrosis in clinically relevant subgroups, and was also observed in those without severe fibrosis ( p < 0.05). In the UKBB cohort, PRS predicted HCC independently of classical risk factors and cirrhosis ( p < 10 -7 ). In the NAFLD cohort, we identified high PRS cut-offs (≥0.532/0.495 for PRS-HFC/PRS-5) that in the UKBB cohort detected HCC with ~90% specificity but limited sensitivity; PRS predicted HCC both in individuals with ( p < 10 -5 ) and without cirrhosis ( p < 0.05). Conclusions Our results are consistent with a causal relationship between hepatic fat and HCC. PRS improved the accuracy of HCC detection and may help stratify HCC risk in individuals with dysmetabolism, including those without severe liver fibrosis. Further studies are needed to validate our findings. Lay summary By analyzing variations in genes that contribute to fatty liver disease, we developed two risk scores to help predict liver cancer in individuals with obesity-related metabolic complications. These risk scores can be easily tested in the clinic. We showed that the risk scores helped to identify the risk of liver cancer both in high-risk individuals and in the general population.
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“Comprehensive polygenic risk scores are superior to PNPLA3 and TM6SF2 alone for risk prediction of progressive MASLD, especially in individuals with metabolic triggers, and the bene fi ts of their use over clinical risk factors alone becomes more evident for long-term prediction. 196,206,207”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [206]
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“Another model incorporated genetic variants in a risk score that predicted HCC independently of classical risk factors, but the AUROC when used alone was only 0.65. 206”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [206]
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Xue, H., Wang, L., Sun, D., Wu, Y., Yu, C., Huang, Y., Chan, S. O., Ling, W., Li, L., Li, L., et al. (2025) · Gastroenterology · doi:10.1053/j.gastro.2025.04.021 · Cited by 11
Kim, G., Park, Y., Oh, S. J., Jung, J., Han, S., Chang, H., Park, S. W., Kim, T. H., Park, H. W., Choe, J., et al. (2023) · Liver International · doi:10.1111/liv.15819 · Cited by 10
Germline Genetic Associations for Hepatobiliary Cancers
Chotiprasidhi, P., Sato-Espinoza, A. K., & Wangensteen, K. J. (2023) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2023.12.010 · Cited by 10
Wu, H., Li, S., Chen, L., Yang, X., & Tan, X. W. (2024) · Food & Function · doi:10.1039/d3fo04602h · Cited by 11
Giardoglou, P., Gavra, I. E., Amanatidou, A. I., Kalafati, I. P., Symianakis, P., Kafyra, M., Moulos, P., & Dedoussis, G. V. (2024) · Genes · doi:10.3390/genes16010033 · Cited by 10
Obesity and Liver Cancer in Japan: A Comprehensive Review
Nishikawa, H., Fukunishi, S., Asai, A., Nishiguchi, S., & Higuchi, K. (2021) · Anticancer Research · doi:10.21873/anticanres.14999 · Cited by 12
Balcar, L., Semmler, G., Oberkofler, H., Zandanell, S., Straßer, M., Datz, L., Niederseer, D., Feldman, A., Stickel, F., Datz, C., et al. (2021) · Digestive and Liver Disease · doi:10.1016/j.dld.2021.06.015 · Cited by 10
Clinical utility of polygenic risk scores for predicting NAFLD disorders
Dessein, A. J. J. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.02.005 · Cited by 10
Lauschke, V. M. (2023) · HepatoBiliary Surgery and Nutrition · doi:10.21037/hbsn-23-376 · Cited by 10
Liu, Z., Yuan, H., Suo, C., Li, J., Zhang, T., & Chen, X. (2025) · Digestive and Liver Disease · doi:10.1016/j.dld.2025.06.016 · Cited by 9
Liu, Y. (2025) · Liver Cancer · doi:10.1159/000550163 · Cited by 12
The future of hepatology – “The best way to predict the future is to create it”
Berg, T., & Krag, A. A. (2023) · Journal of Hepatology · doi:10.1016/j.jhep.2023.04.022 · Cited by 9
Implications of the evolving knowledge of the genetic architecture of MASLD
Valenti, L. V. C., & Moretti, V. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00866-0 · Cited by 9
Fassio, E., Barreyro, F., Perez, M. S., Dávila, D., Landeira, G., Gualano, G., & Ruffillo, G. (2022) · World Journal of Hepatology · doi:10.4254/wjh.v14.i2.354 · Cited by 13
Longo, M., Meroni, M., Erconi, V., Carli, F., Macchi, C., Fortunato, F., Ronchi, D., Sabatini, S., Paolini, E., Caro, E. R. D., et al. (2021) · Digestive and Liver Disease · doi:10.1016/j.dld.2020.12.070 · Cited by 9
Busca, C., Arias, P., Sánchez‐Conde, M., Rico, M. C., Montejano, R., Martín‐Carbonero, L., Valencia, E., Moreno, V., Bernardino, J. I., Olveira, A., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.905126 · Cited by 9
New Glance at the Role of TM6SF2 in Lipid Metabolism and Liver Cancer
Jiang, X., Qian, H., & Ding, W. (2021) · Hepatology · doi:10.1002/hep.31851 · Cited by 9
African genetic ancestry and protection against fatty liver disease
Romeo, S., & Valenti, L. V. C. (2022) · Liver International · doi:10.1111/liv.15364 · Cited by 9
Machado, M. V. (2023) · Annals of Hepatology · doi:10.1016/j.aohep.2023.101101 · Cited by 9
Genomic Signatures of MASLD: How Genomics Is Redefining Our Understanding of Metabolic Liver Disease
Saliba‐Gustafsson, P., Härdfeldt, J., Pedrelli, M., & Parini, P. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262210881 · Cited by 9
Rich, N. E., Villanueva, A., Marrero, J. A., & Kanwal, F. (2026) · Gastroenterology · doi:10.1053/j.gastro.2026.03.006 · Cited by 9
HCV Activates Somatic L1 Retrotransposition—A Potential Hepatocarcinogenesis Pathway
Sudhindar, P. D., Wainwright, D., Saha, S. K., Howarth, R., McCain, M. V., Bury, Y. A., Saha, S. S., McPherson, S., Reeves, H. L., Patel, A. H., et al. (2021) · Cancers · doi:10.3390/cancers13205079 · Cited by 8
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Diabetes and the risk of cirrhosis and HCC: An analysis of the UK Biobank
Ye, F., Chen, L., & Zheng, X. (2023) · Hepatology Communications · doi:10.1097/hc9.0000000000000280 · Cited by 9
Mann, J. P., & Hoare, M. (2022) · Liver International · doi:10.1111/liv.15283 · Cited by 7
Metadata
- Authors
- Bianco, C., Jamialahmadi, O., Pelusi, S., Baselli, G., Dongiovanni, P., Zanoni, I., Santoro, L., Maier, S., Liguori, A., Meroni, M., Borroni, V., D’Ambrosio, R., Spagnuolo, R., Alisi, A., Federico, A., Bugianesi, E., Petta, S., Miele, L., Vespasiani-Gentilucci, U., Anstee, Q. M., Stickel, F., Hampe, J., Fischer, J., Berg, T., Fracanzani, A. L., Soardo, G., Reeves, H., Prati, D., Romeo, S., & Valenti, L.
- Affiliations
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Sahlgrenska University Hospital (SE)
- University of Milan (IT)
- University of Udine (IT)
- Agostino Gemelli University Polyclinic (IT)
- Bambino Gesù Children's Hospital (IT)
- University of Campania "Luigi Vanvitelli" (IT)
- Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT)
- University of Palermo (IT)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- University Hospital Zurich (CH)
- University Hospital Carl Gustav Carus (DE)
- University Hospital Leipzig (DE)
- Corresponding author
- Romeo, Stefano
- Valenti, Luca
- ORCID
- Bianco, Cristiana
- Jamialahmadi, Oveis
- Pelusi, Serena
- Baselli, Guido
- Dongiovanni, Paola
- Maier, Silvia
- Liguori, Antonio
- Meroni, Marica
- Borroni, Vittorio
- D’Ambrosio, Roberta
- Spagnuolo, Rocco
- Alisi, Anna
- Federico, Alessandro
- Bugianesi, Elisabetta
- Petta, Salvatore
- Miele, Luca
- Anstee, Quentin M.
- Stickel, Felix
- Hampe, Jochen
- Fischer, Janett
- Berg, Thomas
- Fracanzani, Anna Ludovica
- Soardo, Giorgio
- Reeves, Helen
- Prati, Daniele
- Romeo, Stefano
- Valenti, Luca
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2021-04
- Volume
- 74
- Issue
- 4
- Pages
- 775-782
- ISSN
- 0168-8278 (ISSN-L)
- PMC
- PMC7987554
- OpenAlex
- W3106622583
- Cited by
- 385
- References
- 37
- Citations by year
- 2026: 60 · 2025: 60 · 2024: 68 · 2023: 80 · 2022: 64 · 2021: 52
- FWCI
- 35.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Hepatology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Institutional Research Information System (University of Udine) (submittedVersion, cc-by-nc-nd)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity) (cc-by-nc-nd)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_169196)
- Marianne and Marcus Wallenberg Foundation (KAW 2017.0203)
- Knut och Alice Wallenbergs Stiftelse
- Swiss Foundation for Alcohol Research
- AbbVie
- Akebia Therapeutics
- Amgen
- Novo Nordisk
- Novo Nordisk Fonden (DIA 2017-205, 9321-430)
- Hjärt-Lungfonden (20120533)
- European Research Council
- Seventh Framework Programme
- Diabetesförbundet
- Sanofi
- Pfizer
- Celgene
- Vetenskapsrådet (2016-01527)
- European Commission
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (RC100017A)
- Associazione Italiana per la Ricerca sul Cancro (16888)
- Ministero della Salute (RF-2016-02364358)
- Cancer Research UK (C18342/A23390, C9380/A18084, C9380/A26813)
- Gilead Sciences
- AstraZeneca
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- hepatocellular carcinoma, non-alcoholic fatty liver disease, polygenic risk score, HCC risk stratification, hepatic steatosis, liver fibrosis, PNPLA3, TM6SF2, GCKR, MBOAT7, HSD17B13, genetic susceptibility, liver cirrhosis, HCC detection, UK Biobank
- MeSH terms
- Mediation Analysis, Cross-Sectional Studies, Europe, Female, Carcinoma, Hepatocellular, Humans, Liver, Liver Cirrhosis, Liver Neoplasms, Male, Middle Aged, Predictive Value of Tests, Prognosis, Risk Factors, Risk Assessment, Genetic Predisposition to Disease, Multifactorial Inheritance, Adiposity, Non-alcoholic Fatty Liver Disease
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