Matsubara T, Sakurai Y, Sasayama Y, Hori H, Ochiai M, Funabiki T, Matsumoto K, Hirono I
Department of Surgery, Fujita Health University, School of Medicine, Aichi, Japan.
Cancer. 1996 Apr 15;77(8 Suppl):1752-7. doi: 10.1002/(SICI)1097-0142(19960415)77:8<1752::AID-CNCR51>3.0.CO;2-V.
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.
Mutations of the K-ras oncogene were examined in cancerous and noncancerous 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.
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.
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.
胰胆管合流异常（PBM），即胰管与胆总管的异常汇合，经常被证明与胆管癌有关。然而，其致癌机制尚不清楚。
通过从手术切除的组织学标本中提取DNA，检测20例PBM患者癌性和非癌性胆道上皮中的K-ras癌基因突变情况。采用聚合酶链反应单链构象多态性（PCR-SSCP）方法和直接测序对DNA进行分析。
在PBM患者中，不仅在癌性上皮中检测到异常迁移的DNA条带，在胆囊和/或胆总管的增生、化生和炎性上皮中也检测到。在PBM患者的胆道上皮中，5例癌性上皮中有4例（80%）、12例增生和化生上皮中有7例（58%）、18例炎性上皮中有8例（44%）检测到K-ras癌基因的点突变，而3例无PBM的对照患者的胆囊上皮中未检测到K-ras癌基因的点突变。对K-ras癌基因的直接序列分析显示，PBM患者所有癌性病变中密码子12处的突变均将野生型甘氨酸（GGT）替换为天冬氨酸（GAT）。在1例胆囊癌和1例胆管癌中还发现了与密码子12处突变相关的密码子13处从野生型甘氨酸（GGC）到精氨酸（CGC）的同时两点突变。
K-ras基因突变参与了PBM患者胆道上皮的致癌过程，似乎是胆道致癌的一个高风险因素。
