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Cited by 125Liver Disease Diagnosis and TreatmentGenetic Associations and EpidemiologyHepatocellular Carcinoma Treatment and Prognosis

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Rare Pathogenic Variants Predispose to Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease

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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, De Francesco, Raffaele, Reeves, Helen Louise, Valenti, Luca Vittorio Carlo·2019·Scientific Reports
DOI 10.1038/s41598-019-39998-2PMC PMC6403344
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Abstract

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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Figure 1 Study design. (a) Study cohorts composition and enrolment criteria. (b) Study flow-chart. NAFLD: non-alcoholic fatty liver disease. HCC: hepatocellular carcinoma.
Figure 1 Study design. (a) Study cohorts composition and enrolment criteria. (b) Study flow-chart. NAFLD: non-alcoholic fatty liver disease. HCC: hepatocellular carcinoma.CC BY · PubMed Central
Figure 2 Enrichment in pathogenic variants in patients with NAFLD-HCC. (a) Frequency of pathogenic variants (mutational rate %: sum of mutated/total alleles) in NAFLD-HCC cases vs. controls. (b) Frequency of likely pathogenic variants (rare variants with high likelihood of altering protein activity) in NAFLD-HCC cases vs. controls. *p < 0.05; **p < 0.01; ***p < 0.005 by Fisher’s exact test.
Figure 2 Enrichment in pathogenic variants in patients with NAFLD-HCC. (a) Frequency of pathogenic variants (mutational rate %: sum of mutated/total alleles) in NAFLD-HCC cases vs. controls. (b) Frequency of likely pathogenic variants (rare variants with high likelihood of altering protein activity) in NAFLD-HCC cases vs. controls. *p < 0.05; **p < 0.01; ***p < 0.005 by Fisher’s exact test.CC BY · PubMed Central
Figure 3 Genes enriched in pathogenic variants. Comutation plot showing the distribution of rare pathogenic variants (upper panel), as well as of common genetic variants (bottom panel) predisposing to hepatic fat accumulation and NAFLD-HCC in the 251 individuals of the EPIDEMIC project. Genes significantly enriched in variants in cases vs. controls are marked by and asterisk (*by Fisher’s exact test). Gene abbreviations are shown in Supplementary Material.
Figure 3 Genes enriched in pathogenic variants. Comutation plot showing the distribution of rare pathogenic variants (upper panel), as well as of common genetic variants (bottom panel) predisposing to hepatic fat accumulation and NAFLD-HCC in the 251 individuals of the EPIDEMIC project. Genes significantly enriched in variants in cases vs. controls are marked by and asterisk (*by Fisher’s exact test). Gene abbreviations are shown in Supplementary Material.CC BY · PubMed Central
Figure 4 Genetic risk score. Diagnostic accuracy of the Genetic risk score (GRS) for NAFLD-HCC in the 655 individuals included in the study. (a) comparison of the diagnostic accuracy in the study cohorts; p < 0.05 for diagnostic accuracy in the overall vs. single cohorts. (b) Diagnostic accuracy of GRS vs. PNPLA3 I148M variant alone and a combination of PNPLA3 I148M and TM6SF2 E167K variants in determining NAFLD HCC risk; p < 2*10−8 for alternative genetic scores vs. the overall GRS. (c) Additive value of adding GRS to a diagnostic model based on clinical risk factors, in determining NAFLD-HCC risk in the 251 individuals of the EPIDEMIC study; p = 0.17. Comparison of diagnostic accuracy was performed by two-sided Venkatraman test.
Figure 4 Genetic risk score. Diagnostic accuracy of the Genetic risk score (GRS) for NAFLD-HCC in the 655 individuals included in the study. (a) comparison of the diagnostic accuracy in the study cohorts; p < 0.05 for diagnostic accuracy in the overall vs. single cohorts. (b) Diagnostic accuracy of GRS vs. PNPLA3 I148M variant alone and a combination of PNPLA3 I148M and TM6SF2 E167K variants in determining NAFLD HCC risk; p < 2*10−8 for alternative genetic scores vs. the overall GRS. (c) Additive value of adding GRS to a diagnostic model based on clinical risk factors, in determining NAFLD-HCC risk in the 251 individuals of the EPIDEMIC study; p = 0.17. Comparison of diagnostic accuracy was performed by two-sided Venkatraman test.CC BY · PubMed Central

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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
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2019-03-06
Volume
9
Issue
1
Pages
3682-3682
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-019-39998-2
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
Licence
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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