Abundant clinical data suggest a critical role of chronic inflammation in the pathogenesis of gallstones (cholelithiasis) and of biliary tract cancer (including cancers of the gallbladder, extrahepatic bile duct, and ampulla of Vater). Since cholecystitis, cholelithiasis, and cholangitis have been linked to excess risk of biliary tract cancer, it seems likely that chronic inflammation of the biliary tree, often in association with gallstones, plays an important role in the pathogenesis of biliary tract cancer and that individuals with certain variants of genes in the inflammation pathway may have an increased susceptibility to cancer. Using a pathway approach, we examined 57 single nucleotide polymorphisms (SNPs) in 14 genes in the inflammatory pathway, including ILs (IL1-alpha, IL1-beta, IL4, IL5, IL6, IL8, IL10, IL13), TNF-α, RNASEL, VEGF, VCAM1, MnSOD2, and COX2, in a population-based case-control study of biliary tract cancer in Shanghai, China. Although the roles of these genes have not been investigated in biliary tract cancer, many of them have been linked to other cancers that are closely related to inflammation. Genomic DNA from 522 biliary tract cancer cases (238 gallbladder cancers, 128 bile duct cancers, 56 ampulla of Vater cancers), 782 population controls, and 889 biliary stone cases was purified from buffy coat samples and genotyped at the NCI Core Genotyping Facility using the Taqman assay. Concordance of genotyping results on duplicate samples was over 99%. Despite the strong biological plausibility that chronic inflammation may be a key factor in the pathogenesis of gallstones and biliary tract cancer, of the 57 SNPs examined, only a few were associated with gallstones and biliary tract cancer, with inconsistent patterns in men and women. For example, 4 SNPs in the TNF-alpha, MnSOD2, and COX2 genes were associated with an increased risk of biliary stones in men, while 3 SNPs in the MnSOD2, VEGF, and COX2 genes were associated with bile duct cancer in men and one SNP in the RNASEL gene with a higher risk of bile duct cancer in women. Preliminary results from this population-based study suggest that chronic inflammation may be associated with gallstones and biliary tract cancer in a complex manner that involves an interplay among multiple susceptibility genes, gender-related exposures, and gallstones or cholangitis. Larger studies with a more comprehensive genomic approach are needed to dissect the relationships among these putative factors and clarify the mechanisms involved.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]