Identification of portal vein tumor thrombus with an independent clonal origin in hepatocellular carcinoma via multi-omics data analysis

Objective: Multiple mechanisms underlying the development of portal vein tumor thrombus (PVTT) in hepatocellular carcinoma(HCC) have been reported recently. However, the origins of PVTT remain unknown. Increasing multi-omics data on PVTTs inHCCs have made it possible to investigate whether PVTTs originate from the corresponding primary tumors (Ts). Methods: The clonal relationship between PVTTs and their corresponding primary Ts was investigated using datasets deposited inpublic databases. One DNA copy number variations dataset and three gene expression datasets were downloaded for the analyses.Clonality analysis was performed to investigate the clonal relationship between PVTTs and Ts from an individual patient.Differential gene expression analysis was applied to investigate the gene expression profiles of PVTTs and Ts. Results: One out of 19 PVTTs had no clonal relationship with its corresponding T, whereas the others did. The PVTTs withindependent clonal origin showed different gene expression and enrichment in biological processes from the primary Ts. Based onthe unique gene expression profiles, a gene signature including 24 genes was used to identify pairs of PVTTs and primary Tswithout any clonal relationship. Validation in three datasets showed that these types of pairs of PVTTs and Ts can be identified bythe 24-gene signature. Conclusions: Our findings show a direct evidence for PVTT origin and consolidate the heterogeneity of PVTTs observed in clinic.The results suggest that PVTT investigation at a molecular level is clinically necessary for diagnosis and treatment.