Abstract
Recurrence after liver resection for hepatocellular carcinoma (HCC) is a major clinical problem, and prognostic markers for recurrence are urgently required. For 390 HCC cases, segmented linear regression analysis with two segments was performed, and the interval for the early and late recurrence groups was partitioned at the crosspoint (676 days). We investigated whether gene expression in non-tumorous tissues of remnant liver from 39 hepatitis C virus-positive HCC cases may be associated with early recurrence of this disease. By microarray analysis, 21 genes were identified as candidate recurrence-associated genes. Further gene expression analysis was performed, and the localization and expression of the gene products of these candidate genes were immunohistochemically evaluated. Low expression of the GBP1 gene and high expression of the TSC22D3 gene were significantly (both P=0.04) associated with the risk of early recurrence. Through backward step-wise multivariate logistic regression analysis for the 21 candidate genes, high expression of GBP1 reduced [odds ratio (OR)=0.20; 95% confidence interval (CI) 0.06-0.73, P=0.02] and high expression of TSC22D3 increased the risk of early recurrence (OR=19.6; 95% CI 1.14-337.2; P=0.04). Immunohistochemical analysis revealed that hepatocytes showed strong membranous expression for GBP1 in the late recurrence group, but weak membranous expression for GBP1 in the early recurrence group. TSC22D3 was frequently expressed in lymphocytes and in a few hepatocytes in tissues of the early recurrence group. Our observations suggest that the combination of the high expression of the TSC22D3 gene and low expression of the GBP1 gene in the non-tumorous tissue of the remnant liver is significantly associated with early recurrence after surgical resection of HCC.