K-ras and p53 gene mutations in noncancerous biliary lesions of patients with pancreaticobiliary maljunction.

Abstract

We investigated the molecular mechanisms of carcinogenesis in the biliary epithelium in patients with pancreaticobiliary maljunction. Point mutations of the K- ras gene and the p53 gene, and the overexpression of p53 gene products were examined in the cancerous and noncancerous biliary epithelium of 37 patients with pancreaticobiliary maljunction, with or without biliary dilatation. In the gallbladder epithelium of 5 patients with pancreaticobiliary maljunction associated with biliary carcinoma, K- ras gene mutations were detected in 3 (60%), p53 gene mutations in 3 (60%), and the overexpression of p53 gene products in 4 (80%), while in the bile duct epithelium of these patients, these features were found in 2 of 3 (66.7%), in all of 3 (100%), and none of 3 (0%) specimens, respectively. In the gallbladder epithelium of patients with pancreaticobiliary maljunction without biliary carcinoma, K- ras gene mutations were detected in 8 of 24 (33.3%) specimens, p53 gene mutations were detected in 16 of 27 specimens (59.3%), and the overexpression of p53 protein was detected in 5 of 27 (18.5%) specimens, while in the bile duct epithelium of these patients, these features were found in 10 of 25 (40%) specimens, 14 of 25 (56%) specimens, and 6 of 24 (25%) specimens, respectively. These results suggest that noncancerous lesions of the biliary epithelium in patients with pancreaticobiliary maljunction have mutations of the K- ras gene and/or the p53 gene, which provides genetic evidence that biliary epithelium has high carcinogenic potential.