Probes for KRAS

AIMS: To investigate whether genetic or inflammatory pro-oncogenic factors are relevant to the increased risk of gallbladder cancers in patients with pancreaticobiliary maljunction (PBM). METHODS: Mutations in KRAS exon 2 were examined by a highly sensitive, droplet digital PCR platform using surgically resected specimens of PBM-associated (n=31) and non-associated gallbladder cancers (n=49). The tissue expression of IL-6 and IL-33, which are suspected to promote biliary carcinogenesis, was analyzed by quantitative real-time PCR and in situ hybridization. RESULTS: The incidence of KRAS mutations was similarly low in PBM-associated (5/32 cases; 16%) and non-associated cancers (4/49 cases; 8%) (p=0.272). The tissue expression of IL-33 mRNA, but not IL-6 mRNA, was significantly higher in PBM-associated gallbladder cancers than in gallbladder cancers without PBM (p=0.004). A similar degree of IL-33 overexpression was also observed in the background non-cancerous mucosa in cases of PBM-associated gallbladder cancers, and was significantly greater than that in PBM cases with cholecystitis alone (p<0.001). The results of in situ hybridization indicated that the source of IL-33 production in PBM-associated carcinomas was the endothelium, cancer cells, and non-neoplastic biliary epithelium. In a combined PBM-associated and non-associated cohort, IL-33 overexpression in gallbladder cancers correlated with less aggressive features (e.g., a lower pT stage and longer overall survival), similar to recently reported findings on large-duct cholangiocarcinomas. CONCLUSIONS: KRAS mutations do not appear to be associated with a high risk of malignancy in PBM, while IL-33 overexpression may provide a pro-oncogenic microenvironment in the gallbladder mucosa of patients with PBM. This article is protected by copyright. All rights reserved.