Cancer development is a gradual evolutionary process, yet the transition from premalignant lesions to overt malignancy remains poorly understood. This critical window has major clinical implications: premalignant nodules are typically monitored, whereas malignant lesions require immediate intervention. However, dissecting this transition has been challenging, largely because most studies rely on evolutionarily unrelated samples and therefore cannot resolve true temporal changes.
In a study published in Cancer Cell, a research team led by Prof. HUI Lijian from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences, collaborated with Prof. LI Hong from Shanghai Institute of Nutrition and Health and Prof. JI Yuan from Zhongshan Hospital, reports a rare glimpse into the earliest stages of hepatocellular carcinoma (HCC) evolution, revealing how genomic instability and immune remodeling jointly shape malignant transformation.
HUI Lijian et al. overcome this limitation by leveraging exceptionally rare “nodule-in-nodule” lesions, where very early HCC (veHCC) arising within premalignant dysplastic nodule (DN). After a nine-year effort screening more than 44,000 surgical specimens, the authors collected 17 such cases, enabling direct comparison between paired premalignant and malignant components. Multi-layered profiling, including whole-genome, transcriptomic and spatial analyses, provides an integrated view of early hepatocarcinogenesis.
The study identifies telomerase reverse transcriptase (TERT) alterations in 82% of cancer-prone DNs, suggesting a predisposing rather than causative role of TERT alteration in malignant transition. Notably, the accumulation of copy number alterations (CNAs), rather than single nucleotide variants, is strongly associated with malignant transition. Intriguingly, different from the paradigm that HCC arises in chronic inflammation, cancer-prone DNs display immune inactivity. Strikingly, 43% of veHCCs showed an inflamed yet immune evasive phenotype.
These findings propose two evolutionary scenarios of early hepatocarcinogenesis, CNA dominant progression and inflamed progression with early immune evasion. This study illustrates previously unexplored molecular paradigms in HCC initiation, highlighting the therapeutic potential of immunotherapy for early intervention in HCC development.
By capturing a fleeting evolutionary state, this study provides a rare and mechanistic view of how cancer begins and underscores the importance of studying malignancy at its point of origin.
Reference：https://www.cell.com/cancer-cell/fulltext/S1535-6108(26)00157-1
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