Four gene intrahepatic metastasis–risk signature predicts hepatocellular carcinoma malignant potential and early recurrence from intrahepatic metastasis

Background Hepatocellular carcinoma has a high recurrence rate even after curative surgery, and hepatocellular carcinoma risk–predictive biomarkers will enable identification of patients who most need close monitoring and cancer-preventive intervention. Hepatocellular carcinoma has 2 different recurrence patterns—a multicentric recurrence and an intrahepatic metastasis. We have reported that the molecular gene signature from the gene expression of adjacent liver can be used to predict multicentric recurrence of hepatocellular carcinoma, but the signature to predict recurrence from intrahepatic metastasis has not been established. We aimed to identify the recurrence from intrahepatic metastasis gene signature from the gene expression of tumor to predict recurrence from intrahepatic metastasis. Methods The intrahepatic metastasis-risk signature was created based on the exhaustive analysis using a microarray transcriptome database of hepatocellular carcinoma. The intrahepatic metastasis-risk signature was measured in a cohort of 80 hepatocellular carcinoma patients, and the correlation with hepatocellular carcinoma recurrence and overall survival and each gene signature were analyzed and validated. Results The gene signature assay classified the patients into high- (n = 20), intermediate- (n = 40), and low-risk (n = 20) groups. The high-risk prediction was independently associated with higher early hepatocellular carcinoma recurrence (hazard ratio = 3.7, P = .03) in multivariable modeling adjusted by tumor size, tumor number, and microvascular invasion. Gene set enrichment analysis demonstrates that the gene sets associated with “cell cycle” or “histone modulation” are highly enriched in the high intrahepatic metastasis gene signature group Conclusion The intrahepatic metastasis gene signature predicts early recurrence and is associated with malignant potential related to the promoted cell cycle.