A liver gene signature links liver cancer risk in chronic viral hepatitis to intrahepatic IgA plasma cells
Bibliographic record
Abstract
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: ) 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".