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Rare Pathogenic Variants Predispose to Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease
Open accessAbstract
Abstract Nonalcoholic fatty liver disease (NAFLD) is a rising cause of hepatocellular carcinoma (HCC). We examined whether inherited pathogenic variants in candidate genes (n = 181) were enriched in patients with NAFLD-HCC. To this end, we resequenced peripheral blood DNA of 142 NAFLD-HCC, 59 NAFLD with advanced fibrosis, and 50 controls, and considered 404 healthy individuals from 1000 G. Pathogenic variants were defined according to ClinVar, likely pathogenic as rare variants predicted to alter protein activity. In NAFLD-HCC patients, we detected an enrichment in pathogenic (p = 0.024), and likely pathogenic variants (p = 1.9*10 −6 ), particularly in APOB (p = 0.047). APOB variants were associated with lower circulating triglycerides and higher HDL cholesterol (p < 0.01). A genetic risk score predicted NAFLD-HCC (OR 4.96, 3.29–7.55; p = 5.1*10 −16 ), outperforming the diagnostic accuracy of common genetic risk variants, and of clinical risk factors (p < 0.05). In conclusion, rare pathogenic variants in genes involved in liver disease and cancer predisposition are associated with NAFLD-HCC development.
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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 [196]
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“Overall evidence suggests that the PNPLA3 p.I148M and TM6SF2 p.E167K variants are major risk factors for progressive MASLD, and genotyping helps to noninvasively predict progressive MASH, cirrhosis and HCC when considered alongside clinical factors, 194 -196 but accuracy is suboptimal for prediction of liver disease severity and progression at the individual level.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [196]
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Metadata
- Authors
- Pelusi, S., Baselli, G., Pietrelli, A., Dongiovanni, P., Donati, B., McCain, M. V., Meroni, M., Fracanzani, A. L., Romagnoli, R., Petta, S., Grieco, A., Miele, L., Soardo, G., Bugianesi, E., Fargion, S., Aghemo, A., D’Ambrosio, R., Xing, C., Romeo, S., De Francesco, R., Reeves, H. L., & Valenti, L. V. C.
- Affiliations
- University of Milan (IT)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Newcastle University (GB)
- University of Turin (IT)
- University of Palermo (IT)
- Agostino Gemelli University Polyclinic (IT)
- University of Udine (IT)
- Humanitas University (IT)
- The University of Texas Southwestern Medical Center (US)
- Magna Graecia University (IT)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- Corresponding author
- Valenti, Luca Vittorio Carlo
- ORCID
- Pelusi, Serena
- Baselli, Guido
- Pietrelli, Alessandro
- Dongiovanni, Paola
- Donati, Benedetta
- McCain, Misti Vanette
- Meroni, Marica
- Fracanzani, Anna Ludovica
- Romagnoli, Renato
- Petta, Salvatore
- Grieco, Antonio
- Miele, Luca
- Soardo, Giorgio
- Bugianesi, Elisabetta
- Fargion, Silvia
- Aghemo, Alessio
- D’Ambrosio, Roberta
- Xing, Chao
- Romeo, Stefano
- Reeves, Helen Louise
- Valenti, Luca Vittorio Carlo
- Venue
- Scientific Reports
- Published
- 2019-03-06
- Volume
- 9
- Issue
- 1
- Pages
- 3682-3682
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC6403344
- OpenAlex
- W2919587539
- Cited by
- 125
- References
- 55
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 16 · 2023: 15 · 2022: 23 · 2021: 28 · 2020: 17 · 2019: 4
- FWCI
- 13.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Institutional Research Information System (University of Udine) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion, other-oa)
- PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- European Commission (HEALTH-F2-2009-241762)
- Associazione Italiana per la Ricerca sul Cancro (MFAG-16888)
- Ministry of Health, Italy | Agenzia Italiana del Farmaco, Ministero della Salute (RF-2016-02364358)
- 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, rare pathogenic variants, apolipoprotein B, genetic susceptibility, polygenic risk score, HDL cholesterol, liver fibrosis, cancer susceptibility genes
- MeSH terms
- Sequestosome-1 Protein, Aged, Female, Carcinoma, Hepatocellular, Humans, Cholesterol, HDL, Liver Neoplasms, Male, Middle Aged, Risk Factors, Reproducibility of Results, Case-Control Studies, Genetic Predisposition to Disease, Glial Cell Line-Derived Neurotrophic Factor Receptors, Apolipoprotein B-100, Non-alcoholic Fatty Liver Disease
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