Hepatocellular carcinoma patients frequently suffer fatal tumor recurrence after surgical removal; multi-region genomic sequencing reveals that whether cancer recurs locally or metastasizes is dictated by pre-existing intra-tumoral clonal diversity.
Hepatocellular carcinoma (HCC) is one of the deadliest malignancies globally. Even when surgeons successfully remove the primary liver tumor with clean surgical margins, more than half of patients experience lethal tumor recurrence within five years.
Oncologists could not reliably predict which patients would experience true intrahepatic metastasis (spread of the original tumor) versus de novo multicentric recurrence (a brand-new tumor arising in cirrhotic liver tissue).
Publishing in Gut, clinical researchers performed multi-region exome sequencing across resected primary tumors and paired recurrent lesions. The genomic mapping proves that high clonal diversity within the primary tumor directly drives rapid, therapy-resistant intrahepatic metastasis, whereas low-diversity tumors predominantly recur as independent primary lesions.
Profiling intra-tumoral clonal architecture at the time of surgery enables oncologists to tailor adjuvant therapies, reserving aggressive targeted immunotherapies for patients harboring high-diversity metastatic clones.
Clonal diversity underpins distinct modes of recurrence in hepatocellular carcinoma: the PLANet cohort study
Background Hepatocellular carcinoma (HCC) has a high postsurgery recurrence rate yet the underlying molecular mechanisms remain poorly understood. Objective Using multi-region sampling of paired primary and recurrent tumours, we examine the molecular and evolutionary events underlying HCC recurrence to inform neoadjuvant and adjuvant treatment strategies. Design Within the Precision Medicine in Liver Cancer across an Asia-Pacific Network (PLANet) prospective surgical cohort, multiregion whole genome sequencing (WGS) (408 samples) and RNA sequencing (406 samples) were carried out on primary tumours from 106 patients with HCC. A recurrence cohort of 24 patients with paired primary and recurrent tumours was assembled, generating 166 WGS and 113 RNA-seq samples. Tumour phylogenies were constructed to define seeding patterns. Integrated transcriptomic analyses were done to characterise the RNA subtype and immune microenvironment. Results We identified two main recurrence patterns, polyclonal and monoclonal seeding. More than half of intrahepatic recurrences were polyclonal, associated with early recurrence, high phenotypic plasticity and a regulatory T cell enriched immunosuppressive microenvironment. In comparison, most distant metastases showed monoclonal origins and appeared to come from a dominant, aggressive C5/C6 subclone within the primary tumour. Molecular features in the primary tumours determine different modes of recurrence. Polyclonal intrahepatic recurrence tumours also showed increased genomic instability and higher sensitivity associated with immune-checkpoint blockade. Furthermore, we built a multi-omics model that can predict HCC recurrence with high accuracy (area under the curve=0.86), identifying high-risk patients despite curative intent resection. Conclusion These findings show the impact of clonal structure and the tumour microenvironment on recurrence, offering insights that may help improve patient risk assessment and treatment planning.
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