Molecular insights into early malignant transition of hepatocellular carcinoma

Abstract The molecular continuum of premalignant-to-malignant transition remains elusive in carcinogenesis, primarily due to the difficulty in sampling transitional lesions. Here, we present comprehensive genomic and immunological profiling of 21 very early hepatocellular carcinomas (veHCCs) arising within 17 cancer-prone DNs. Surprisingly, 82% of cancer-prone DNs harbored TERT alterations, suggesting a predisposing rather than causative role in malignancy transition. A substantial increase in CNA burden, rather than SNV, was noted, indicating a role of chromosome instability in malignancy transition. Additionally, veHCC-originating DNs showed immune inactivity, not falling into the prevailing paradigm that HCCs develop in a context of chronic inflammation. 43% of veHCCs showed an inflamed phenotype with relatively mild CNA burden but already exhibited immune evasion features. Two major evolutionary scenarios were thus proposed: 1) CNA-dominant progression and 2) early immune evasion of those with mild CNA burden. Collectively, our findings illustrate previously unexplored molecular paradigms in HCC initiation, highlighting the therapeutic potential of immunotherapy for early intervention.