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

BACKGROUND & AIMS: Chronic viral hepatitis remains a leading cause of liver cancer-related mortality worldwide. We aimed to identify genetic markers associated with hepatocellular carcinoma (HCC) risk in precancerous liver biopsies from patients with chronic HBV or HCV infection.

METHODS

We conducted a multicenter nested case-control study including biopsied patients with chronic viral hepatitis from eight hospitals across Europe and Canada. Cases developed HCC a median of 7.1 years (range 1.5-26.8) after baseline liver biopsy, irrespective of antiviral treatment initiation, and were matched to controls by age, sex, infecting virus, fibrosis stage, and follow-up duration. A semi-supervised machine-learning approach was applied to liver RNA sequencing data, with de novo HCC development as the outcome. Immunohistochemistry and serum analyses were performed on available samples.

RESULTS

A 557-gene signature was derived from 106 high-quality liver transcriptome profiles and stratified patients by HCC risk in both the training cohort (p = 3.918 × 10-6) and the validation cohort (p = 0.032). The signature was externally validated for de novo HCC (n = 216; p = 0.048) and for HCC recurrence in patients with cirrhosis irrespective of viral etiology (n = 82; p = 0.026; n = 228; p = 0.030). Single-cell modular score analyses indicated that the HCC risk signature reflects fibrovascular tissue expansion, hepatocyte loss, and increased transcriptional activity of IgA-producing plasma cells. The latter correlated with periportal IgA protein staining in paired transcriptomic-immunohistochemistry analyses. In a small subcohort, serum IgA levels also correlated with liver gene expression, suggesting potential utility as a surrogate marker of liver tissue architecture.

CONCLUSIONS

A 557-gene liver transcriptomic signature, including IgA plasma cell-related transcripts, identified in pretreatment liver biopsies from patients with chronic HBV or HCV infection, is associated with future HCC risk.

IMPACT AND IMPLICATIONS: Chronic viral hepatitis remains a major global cause of hepatocellular carcinoma (HCC)-related mortality, underscoring the need for improved risk stratification strategies. We identified a 557-gene liver transcriptomic signature, including IgA plasma cell-related transcripts, in pretreatment liver biopsies from patients with chronic hepatitis B and C that is associated with future HCC development. The expression of IgA plasma cell transcripts correlated with periportal IgA protein deposition in liver tissue, supporting their biological relevance. These findings highlight a previously underappreciated association between intrahepatic IgA plasma cells and hepatocarcinogenesis and warrant further investigation into their mechanistic role and potential utility as biomarkers or therapeutic targets for HCC.