p53 Gene mutations and overexpression of p53 product in cancerous and noncancerous biliary epithelium in patients with pancreaticobiliary maljunction

Abstract

To investigate the molecular mechanisms of the high incidence of carcinogenesis in the biliary epithelium of patients with pancreaticobiliary maljunction, we examined p53 gene mutations, loss of heterozygosity of p53, and overexpression of p53 gene product in the cancerous and noncancerous biliary epithelium of 27 patients with pancreaticobiliary maljunction. Mutations of the p53 gene were examined by polymerase chain reaction-single strand conformation polymorphism and a direct sequencing method. Loss of heterozygosity of the p53 gene was determined using a double-targeted fluorescence in situ hybridization method. Expression of p53 gene product was examined using immunohistochemical staining. Mutations of the p53 gene were found in 4 of 5 biliary carcinomas (80%) and in 10 of 26 noncancerous biliary lesions (38.5%). Point mutations of the p53 gene were detected at codons 207, 212, and 217 on exons 5 through 8. The incidence of p53 gene mutations on exons 5, 6, 7, and 8 was 12. 9%, 36.4%, 0.0%, and 13.8%, respectively. Loss of heterozygosity of p53 was shown in 72% of the cells obtained from the cancerous lesion, and in an average of 14% obtained from the noncancerous lesions. Overexpression of p53 protein was found in 57.1% of carcinoma, and in 31.3% of the noncancerous lesions. These results suggest that p53 gene mutations are involved in the carcinogenesis of biliary epithelium in patients with pancreaticobiliary maljunction.

Well-Differentiated Endocrine Carcinoma Originating From the Bile Duct in Association With a Congenital Choledochal Cyst

“…14 Multicentric development of biliary carcinoma may occur in patients with PBM, and mutations of oncogenes, such as K-ras, 15,16 and tumor-suppressing genes, such as p53, 17 are detected in noncancerous biliary epithelium with hyperplasia, metaplasia, and even inflammation before neoplastic changes were histologically detected. In the present case, chronic inflammation of the bile duct due to PBM could first lead to metaplasia, resulting in an increase in the number of Kulchitsky cells that acted as a predisposing factor for the development of neuroendocrine carcinoma.…”

Expression of GalNAc-T3 and its relationships with clinicopathological factors in 61 extrahepatic bile duct carcinomas analyzed using stepwise sections—Special reference to its association with lymph node metastases—

“…2,3 A number of EBDCs arise in bile ducts with an abnormal pancreatico-biliary duct junction, and their tumorigenesis is considered to be associated with inflow of pancreatic juice into the bile duct. [4][5][6][7] However, more common mechanisms for the tumorigenesis and the reasons for the biological aggressiveness of EBDCs have not yet been sufficiently elucidated, and further investigations are required.…”

K‐ras, p53 mutations, and microsatellite instability (MSI) in gallbladder cancer

“…Gallbladder carcinomas associated with APBDJ present the highest prevalence of K-ras mutation, suggesting that the pancreatic juice reflux may constitute a risk factor for the development of GC [9,11]. It has also been reported that K-ras mutation at codon 12 is associated with early stage gallbladder carcinoma with APBDJ than in that without APBDJ [30].…”

“…A third pathway involving an anomalous pancreaticobiliary duct junction (APBDJ), determined as hyperplasia-carcinoma sequence, occurs frequently in East Asia (incidence 0.9-3.2% in Japan) [7,8] and is characterized by a higher incidence of K-ras gene mutations than that observed in carcinomas without APBDJ [9,10], and high incidence of p53 mutations [10,11]. The involvement of an alternative molecular pathway, that of microsatellite instability (MSI) (i.e., the length alterations at simple repetitive sequences throughout the genome), has been established in the development of certain gastrointestinal neoplasms, such as colorectal and gastric.…”