A liver gene signature links liver cancer risk in chronic viral hepatitis to intrahepatic IgA plasma cells

<h2>Abstract</h2><h3>Background & Aims</h3> Chronic viral hepatitis remains a leading cause of liver cancer deaths globally. We here aim to identify genetic markers associated with HCC risk in precancerous liver biopsies from HBV and HCV patients. <h3>Methods</h3> We performed a multicenter nested-case control study of biopsied chronic viral hepatitis patients from 8 hospitals across Europe and Canada. Cases developed HCC a median 7.1 (1.5-26.8) years after baseline liver biopsy, irrespective of antiviral treatment initiation and were matched with controls for age, gender, infecting virus, fibrosis stage and follow-up duration. A semi-supervised machine learning approach was applied on liver RNA sequencing data with <i>de novo</i> HCC development as an outcome. Immunohistochemistry (IHC) and serum analyses were performed on available samples. <h3>Results</h3> A 557-gene signature was derived from 106 high-quality liver transcriptome profiles able to stratify patients for HCC risk in both training (P=1.498*10<sup>-5</sup>) and validation cohorts (P=0.027), and was externally validated for de novo HCC (n=216; P=0.048) and HCC recurrence in cirrhotic patients irrespective of viral aetiology (n=82; P=0.026 and n=228; P=0.030). Single-cell modular score analyses elucidated that the HCC risk signature reflects the expansion of fibrovascular tissue, a decline in hepatocytes and a higher transcriptional activity of IgA plasma cells. The latter correlated with periportal IgA protein staining on paired transcriptome-IHC analysis. Finally, in a small subcohort serum IgA levels were found to correlate with liver gene expression levels as well and could hence inform about liver infrastructure. <h3>Conclusions</h3> A 557-liver gene signature including IgA plasma cell transcripts in pretreatment liver biopsies from chronic HBV and HCV patients associated with HCC risk.

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Publication Details

Journal
JHEP Reports
Published
2025-12-20
DOI
https://doi.org/10.1016/j.jhepr.2025.101714
Primary Topic
Hepatitis C virus research
Type
article
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0.00

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article

A liver gene signature links liver cancer risk in chronic viral hepatitis to intrahepatic IgA plasma cells

André Boonstra, Bart Cuypers, Pieter Meysman, Kris Laukens et al.
JHEP Reports
Hepatitis C virus research
article

A liver gene signature links liver cancer risk in chronic viral hepatitis to intrahepatic IgA plasma cells

André Boonstra, Bart Cuypers, Pieter Meysman, Kris Laukens, Paloma Sangro, Arno Furquim d’Almeida, Thomas Vanwolleghem, Harry L.A. Janssen, Jordan J. Feld, Stijn Van Hees, Ahmed Mohamed Elsharkawy, Dirk Sprengers, Geert Robaeys, P. Michielsen, Sven Francque, Ann L. C. Driessen, Bruno Sangro, Axelle Vanderlinden, Nicolaas Van Renne, Luisa Vonghia, Owen Cain, F. Ballet, Rob de Man, Stefan Bourgeois
article en

Abstract

<h2>Abstract</h2><h3>Background & Aims</h3> Chronic viral hepatitis remains a leading cause of liver cancer deaths globally. We here aim to identify genetic markers associated with HCC risk in precancerous liver biopsies from HBV and HCV patients. <h3>Methods</h3> We performed a multicenter nested-case control study of biopsied chronic viral hepatitis patients from 8 hospitals across Europe and Canada. Cases developed HCC a median 7.1 (1.5-26.8) years after baseline liver biopsy, irrespective of antiviral treatment initiation and were matched with controls for age, gender, infecting virus, fibrosis stage and follow-up duration. A semi-supervised machine learning approach was applied on liver RNA sequencing data with <i>de novo</i> HCC development as an outcome. Immunohistochemistry (IHC) and serum analyses were performed on available samples. <h3>Results</h3> A 557-gene signature was derived from 106 high-quality liver transcriptome profiles able to stratify patients for HCC risk in both training (P=1.498*10<sup>-5</sup>) and validation cohorts (P=0.027), and was externally validated for de novo HCC (n=216; P=0.048) and HCC recurrence in cirrhotic patients irrespective of viral aetiology (n=82; P=0.026 and n=228; P=0.030). Single-cell modular score analyses elucidated that the HCC risk signature reflects the expansion of fibrovascular tissue, a decline in hepatocytes and a higher transcriptional activity of IgA plasma cells. The latter correlated with periportal IgA protein staining on paired transcriptome-IHC analysis. Finally, in a small subcohort serum IgA levels were found to correlate with liver gene expression levels as well and could hence inform about liver infrastructure. <h3>Conclusions</h3> A 557-liver gene signature including IgA plasma cell transcripts in pretreatment liver biopsies from chronic HBV and HCV patients associated with HCC risk.

JHEP ReportsVol. 8(4)
University Health Network (CA), University of Antwerp (BE), Queen Elizabeth Hospital Birmingham (GB), Toronto General Hospital (CA), Erasmus MC (NL), GZA Ziekenhuizen Campus Sint-Augustinus (BE), Antwerp University Hospital (BE), Clinica Universidad de Navarra (ES), NIHR Surgical Reconstruction and Microbiology Research Centre (GB), ERN GUARD-Heart (NL), Ziekenhuisnetwerk Antwerpen Stuivenberg (BE), NIHR Birmingham Biomedical Research Centre (GB), Instituut voor Tropische Geneeskunde (BE), Hasselt University (BE)
Gilead Sciences, Vlaams Supercomputer Centrum, Fonds Wetenschappelijk Onderzoek, Universiteit Antwerpen, Vlaamse regering, Fondation contre le Cancer, Cilag
Openalex Percentile: Top 45%
Hepatitis C virus research
DOIOpen Access PDFOpenAlex
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