Cancer development is an evolutionary process. The transition from premalignant lesions to overt malignancy is a critical window which has clinical implications: Premalignant nodules are typically monitored, while malignant lesions require immediate intervention. However, dissecting this transition has been challenging, largely because most studies rely on evolutionarily unrelated samples and cannot resolve true temporal changes.

In a study published in Cancer Cell on March 26, Prof. HUI Lijian's team from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences (CAS), along with Prof. LI Hong from Shanghai Institute of Nutrition and Health of CAS and Prof. JI Yuan from Zhongshan Hospital, revealed how genomic instability and immune remodeling jointly shape malignant transformation, providing a rare glimpse into the earliest stages of hepatocellular carcinoma (HCC) evolution.

The "nodule-in-nodule" lesions where very early HCC (veHCC) arising within premalignant dysplastic nodule (DN) are exceptionally rare. The researchers had screened more than 44,000 surgical specimens over nine years and collected 17 such cases, which enabled a direct comparison between paired premalignant and malignant components. Multi-layered profiling including whole-genome, transcriptomic and spatial analyses provided an integrated view of early hepatocarcinogenesis.

The researchers identified 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, they found that the accumulation of copy number alterations (CNAs) rather than single nucleotide variants was strongly associated with malignant transition.

Moreover, the researchers found that cancer-prone DNs displayed immune inactivity, which was different from the paradigm that HCC arises in chronic inflammation. Strikingly, they showed that 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 molecular paradigms in HCC initiation, highlighting the therapeutic potential of immunotherapy for early intervention in HCC development.