Ki-ras point mutations and proliferation activity in biliary tract carcinomas

Abstract

Summary The association between Ki-ras mutations and proliferation activity was investigated in a comprehensive series of biliary tract carcinomas (BTCs). We precisely microdissected samples of tissue from paraffin-embedded sections of 77 BTCs including 22 intrahepatic cholangiocarcinomas (ICCs), 36 extrahepatic cholangiocarcinomas (ECCs), and 19 gall bladder carcinomas (GBCs). Ki-ras mutations at exons 1 and 2 were determined by the polymerase chain reaction -single strand conformation polymorphism (PCR-SSCP) method and confirmed by direct sequencing. Proliferation activity was immunohistochemically assessed to generate proliferating cell nuclear antigen labelling indices (PCNA LIs). Ki-ras mutations were detected in 10 of 22 ICCs (45%), 24 of 36 ECCs (67%), and in 16 of 19 GBCs (84%). The frequency of Ki-ras mutations in peripheral type ICCs was 33% (4 of 12) and that in the hilar type ICCs was 60% (6 of 10). In ECCs the highest value of 82% (9 of 11) was found for carcinomas located in the lower part of the biliary tree. Mean PCNA LI in mutation-positive BTCs was significantly elevated compared with the mutation-negative value. These results indicate frequent involvement of Ki-ras mutations in BTCs, especially in GBCs and in distal ECCs, and that carcinomas harbouring a mutation feature high cell proliferation activity.

Genetic Aberrations Detected by Comparative Genomic Hybridization in Biliary Tract Cancers

“…The minimum overlapping region was 12p12, which corresponds to the chromosomal locus of the K-ras gene (12p12.1). Although it is well known that K-ras mutation is frequent in biliary tract cancers [3, 4, 5, 6, 7, 8], there are only a few reports of K-ras gene amplification in cancers [28, 29]. Accordingly, it is likely that the gain at 12p12 is attributable to an increase in the copy number of gene(s) other than K-ras in biliary tract cancer.…”

“…However, existing genetic information concerning biliary tract cancers is very limited, although several genes, such as K-ras [3, 4, 5, 6, 7, 8], p53 [8, 9, 10, 11]and c-erbB-2 [11, 12, 13], have been reported to be involved in the development and/or progression of biliary tract cancers. Frequent inactivation of p16 INK4 /CDKN2 and loss of heterozygosity at 3p, 5p and 9p have also been shown in biliary tract cancers [7, 9].…”

Cholangiocarcinoma: Molecular targeting strategies for chemoprevention and therapy

“…Nevertheless, the current data make it feasible to attempt separating some of these alterations in terms of specific morphological, pathological, and clinical presentations of cholangiocarcinoma. K-ras mutations, typically at codon 12, have been reported to be less frequently detected in peripheral cholangiocarcinomas than in hilar cholangiocarcinomas 48,49 and seem to be occurring at an increasingly higher incidence in bile duct cancers arising distally in the common bile duct. 48,50 Intrahepatic cholangiocarcinomas of the mass-forming type were further found to harbor K-ras mutations less frequently than those of the periductal infiltrating type, 51,52 with the incidence of K- Abbreviations: pt.…”

Knock-in of Oncogenic Kras Does Not Transform Mouse Somatic Cells But Triggers a Transcriptional Response that Classifies Human Cancers

“…Mutations of the KRAS gene are among the most common genetic alterations in human cancer occurring in f50% of colorectal cancers, 75% to 100% of pancreatic cancers, 50% of cholangiocarcinomas, and almost 50% of lung adenocarcinomas (2,3). Interestingly, activation of the Ras/Raf/Mek/Erk pathway seems also present in cancer lacking KRAS mutations (4).…”