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 machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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 source (direct Gemma or distilled Codex), 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".