Role of p53 and β-catenin Mutations in Conjunction with CK19 Expression on Early Tumor Recurrence and Prognosis of Hepatocellular Carcinoma

Cytokeratin 19 (CK19), a molecular marker of hepatic progenitor cells and cholangiocytes, is expressed in hepatocellular carcinomas (HCC), but not in normal hepatocytes. However, role of CK19 in HCC progression, especially when interacted with p53 and beta-catenin mutations, remained largely unknown. From January 1983 to December 1997, 210 surgically resected, unifocal, primary HCCs were studied retrospectively. CK19 protein expression was detected by immunohistochemistry while mutations of p53 and beta-catenin genes were detected by direct DNA sequencing. CK19 protein expression was detected in 35.7% (75/210), p53 mutation in 47.2% (83/176) and beta-catenin mutation in 14.5% (27/186). The tumor size (p = 0.0023), grade (p = 0.00093), tumor stage (p = 4 x 10(-7)), high alpha-fetoprotein (p = 0.0004), p53 mutation (p = 0.024), absence of beta-catenin mutation (p = 0.0013), and CK19 expression (p = 3 x 10(-5)) were markers predictive of early tumor recurrence (ETR). CK19 expression, stage, and ETR were strong indicators of poor prognosis (all p < 0.0001). Importantly, combination analysis showed an additive unfavorable prognostic interaction of CK19 expression and p53 mutation. On the contrary, concurrent CK19 expression and beta-catenin mutation was rare and CK19 expression abolished the suppression effect of beta-catenin mutation on HCC progression. CK19 expression is associated with more aggressive HCC. CK19 cooperates with p53 mutation towards advanced disease. In contrast, CK19 expression and beta-catenin mutation play dramatic opposite roles in vascular invasion, ETR and the prognosis of HCC.