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bioRxiv · 10.64898/2026.03.10.710938

Cross-etiology transcriptomic conservation in hepatocellular carcinoma reveals opposing proliferation and hepatocyte-loss programs validated across cohorts

Romero, R.·Toledo, C.
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Abstract

BackgroundHepatocellular carcinoma (HCC) arises from diverse etiologies, but the extent to which viral etiologies converge on reproducible transcriptomic state axes remains incompletely resolved. MethodsWe analyzed HBV- and HCV-associated HCC discovery cohorts using Hallmark GSVA, limma-based differential modeling, and cross-cohort meta-analysis. Conserved tumor-upregulated and tumor-downregulated genes were distilled into ProlifHub and HepLoss modules, combined as HCCStateScore = ProlifHubScore - HepLossScore. Module performance was evaluated across multiple independent GEO cohorts, module-size robustness was tested across alternative top-N definitions, and TCGA-LIHC was used for continuous Cox survival modeling. An HBV-derived injury axis was constructed from an ordinal ALT/AST/HBV-DNA injury index in GSE83148 and tested in GSE121248 with adjustment for E2F/G2M activity and CIBERSORTx-inferred immune composition. ResultsHBV- and HCV-associated HCC showed conserved activation of proliferation/repair programs and suppression of hepatocyte functional programs. The HCCStateScore validated across independent HCC cohorts with consistently positive tumor-non-tumor deltas and high discrimination, and module-size sensitivity analysis showed that performance was not dependent on the top-20 cutoff. In TCGA-LIHC, higher ProlifHubScore and HCCStateScore were associated with poorer overall survival in continuous Cox models, including after age/sex/stage adjustment. A compact HBV injury program remained tumor-associated after simultaneous adjustment for E2F/G2M activity and CIBERSORTx-derived immune-composition covariates, with concordant results using an extended FDR-defined injury set. ConclusionsHCC exhibits a robust cross-etiology transcriptomic state characterized by opposing proliferation and hepatocyte-loss programs. The module framework provides a portable bulk transcriptomic state score and supports a residual tumor-associated HBV injury component that is not fully explained by proliferation or inferred immune composition.

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Romero, R., Toledo, C.. 2026-03-13. Cross-etiology transcriptomic conservation in hepatocellular carcinoma reveals opposing proliferation and hepatocyte-loss programs validated across cohorts. https://doi.org/10.64898/2026.03.10.710938

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