Analysis of microsatellite instability, K-ras gene mutation and p53 protein overexpression in intrahepatic cholangiocarcinoma.

BACKGROUND/AIMS: Genetic alterations are considered to play an important role in both the carcinogenesis and biological behavior of human malignancies. However, the clinical implications of intrahepatic cholangiocarcinoma are poorly understood. We investigated the microsatellite instability, K-ras gene mutations and p53 protein overexpression and their correlation with clinicopathological features to elucidate the clinical implications of genetic alterations in intrahepatic cholangiocarcinoma.

METHODOLOGY

In twenty-three cases of surgically treated intrahepatic cholangiocarcinoma, microsatellite instability was examined by a PCR-SSCP analysis and K-ras gene mutation by a PCR-RFLP analysis, p53 protein overexpression by immunohistochemistry. We evaluated the correlation between genetic alterations and clinicopathological features.

RESULTS

Microsatellite instability was observed in one case (4.7%), K-ras gene mutation in 9 (39.1%) and positive staining for p53 protein in 5 (21.7%). The incidence of K-ras gene mutations in hilar type intrahepatic cholangiocarcinoma (6 of 8, 75.0%) was significantly higher than that in peripheral type intrahepatic cholangiocarcinoma (3 of 15, 20.0%) (P < 0.05). Furthermore, the incidence of K-ras gene mutations in patients with lymph node metastasis (58.3%) tended to be higher than that in patients without lymph node metastasis (18.2%). The patients with K-ras gene mutations showed a statistically significant worse survival rate than those without such mutations (P < 0.05). No statistically significant correlations were observed between the p53 overexpression and clinicopathological features.

CONCLUSIONS

These data suggest that K-ras gene mutations may be involved in the carcinogenesis of intrahepatic cholangiocarcinoma, especially in hilar type intrahepatic cholangiocarcinoma, and thus may be correlated with aggressive biological behavior.