Revamped transposon-induced hepatocellular carcinoma model reveals deep similarities of cancer-driver landscapes across mice and humans

In mouse liver, 3xfOnc3 Sleeping Beauty mutagenesis produced heterogeneous hepatocellular tumors in 60% of mice within 12 months, enabling background-corrected driver discovery.

• Why it matters: Driver calling is constrained by statistical uncertainty and by which mutations are available for selection, limiting how reliably screens capture functional cancer perturbations.
• What they did: The three-frame SB system (3xfOnc3) was run in vivo in mouse liver, then tumor-selected integrations were filtered using an empirical targetability reference and background-aware prioritization to yield 315 driver candidates, including 243 protein-coding genes.
• The result: Tumors were multiclonal with context-dependent expansion of identical integration-marked lineages, and enriched young L1 subfamily hits plus human orthologue enrichment for Cancer Gene Census genes and protein-altering pan-cancer mutations supported cross-species relevance.

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