K-ras point mutations in cancerous and noncancerous biliary epithelium in patients with pancreaticobiliary maljunction

Abstract

BACKGROUND Pancreaticobiliary maljunction (PBM), an anomalous union of the pancreatic duct with the common bile duct, has frequently been shown to be associated with biliary carcinoma. However, the mechanism of carcinogenesis is unknown. METHODS Mutations of the K‐ras oncogene were examined in cancerous and non‐cancerous biliary tract epithelium of 20 patients with PBM by an extraction of DNA from surgically resected histologic specimens. DNA was analyzed by a polymerase chain reaction single strand conformation polymorphism (PCR‐SSCP) method and direct sequencing. RESULTS An abnormally mobilized DNA band was detected not only in cancerous epithelium but also in hyperplastic, metaplastic, and inflammatory epithelium of the gallbladder and/or common bile duct in patients with PBM. Among the biliary epithelium of patients with PBM, point mutation of K‐ras oncogenes were detected in 4 of 5 (80%) cancerous epithelium, 7 of 12 (58%) hyperplastic and metaplastic epithelium, and 8 of 18 (44%) inflammatory epithelium, whereas no point mutation of the K‐ras oncogene was detected in the gallbladder epithelium in 3 control patients without PBM. Direct sequence analysis of the K‐ras oncogene revealed the mutation at codon 12 substituting the wild‐type glycine (GGT) for aspartic acid (GAT) in all cancerous lesions of patients with PBM. Simultaneous two‐point mutations from the wild‐type glycine (GGC) to arginine (CGC) at codon 13 associated with the mutation at codon 12 were also found in one case of gallbladder carcinoma and one case of bile duct carcinoma. CONCLUSIONS K‐ras gene mutation is involved in the carcinogenesis of biliary tract epithelium in patients with PBM, and appears to be a high risk factor for carcinogenesis of the biliary tract. Cancer 1996;77:1752‐7.

Proliferative potential and K-ras mutation in epithelial hyperplasia of the gallbladder in patients with anomalous pancreaticobiliary ductal union

“…As for K‐ ras mutations in APBD patients, Hanada et al reported that K‐ ras mutations were detected in 3 (50%) of 6 gallbladder carcinomas in APBD patients and in 1 (6%) of 16 gallbladder carcinomas in patients without APBD 13. Matsubara et al demonstrated that K‐ ras mutations were found in noncancerous biliary epithelium, including hyperplasia, metaplasia, and inflammation at an incidence of approximately 50% before the neoplastic changes were histologically detected 39. As for the type of K‐ ras codon 12 mutation, Watanabe et al reported that 5 of 6 gallbladder carcinoma cases (83%) showed transitions from GGT (Gly) to GAT (Asp) 36.…”

End-to-side choledochoduodenostomy: A widely applicable procedure for biliary reconstruction

“…We have since extended the indications for ESCD for biliary reconstruction in patients with PBM not associated with dilatation of the bile duct. We have also shown high carcinogenicity of the bile10 and alterations of the K‐ ras oncogene in both cancerous and noncancerous biliary epithelium in patients with PBM not associated with dilatation of the bile duct 11. We have therefore advocated resection of the bile duct and diversion of the bile from the pancreatic juice to reduce the possibility of biliary carcinoma.…”

Long-term Results of Treatment for Pancreaticobiliary Maljunction Without Bile Duct Dilatation

“…12,19 Several investigators have reported that K-ras and p53 mutations may be important in the early stage of carcinogenesis in patients with PBM. [20][21][22] We previously reported that the oxidative DNA injury might possibly be related to carcinogenesis in such patients. 23 Thus, PBM itself is an important risk factor for biliary tract carcinogenesis, but the risk of gallbladder carcinoma and bile duct carcinoma is different in the presence or absence of bile duct dilatation.…”