title: Prostaglandin-endoperoxide synthase 2 (PTGS2) gene polymorphisms and risk of biliary tract cancer and gallstones: a population-based study in Shanghai, China.
abstract: There is evidence that chronic inflammation predisposes to biliary tract cancer and that use of non-steroidal anti-inflammatory drugs (NSAIDs) is protective. Although the mechanisms by which NSAIDs lower cancer risk remain unclear, NSAIDs reduce prostaglandin production by blocking prostaglandin-endoperoxide synthase 2 (PTGS2, commonly known as COX-2), an enzyme induced by proinflammatory stimuli that is often overexpressed in malignant tissue. Since variants in the PTGS2 gene may modify the expression or function of its encoded enzyme to modulate the inflammatory response in the biliary tract, we examined the associations of eight PTGS2 polymorphisms (-645C-->T; Ex3 -8G-->C; IVS5 -275T-->G; IVS7 +111T-->C; Ex10 +127T-->C; Ex10 +686 --->ATTAT-->TTATA; Ex10 +837T-->C; Ex10 -90C-->T) with biliary tract cancer and stones in a population-based case-control study conducted in Shanghai, China. Genotyping was performed for 411 patients with biliary tract cancer (237 gallbladder, 127 extrahepatic bile duct and 47 ampulla of Vater), 895 patients with biliary stones (673 gallbladder, 222 bile duct), and 786 healthy individuals randomly selected from the population. Significant associations were seen only between the Ex10 +837T-->C marker and bile duct cancer risk. Relative to individuals with the TT genotype, those carrying the C allele (TC or CC genotype) had a 1.8-fold (95% confidence interval: 1.2-2.7) risk of bile duct cancer. Inferred haplotypes including this risk-conferring allele were also associated with increased bile duct cancer risk of similar magnitude. Our results suggest that a common PTGS2 variant increases bile duct cancer risk. Further investigation is needed to confirm and extend our findings in studies of biliary tract cancer that more comprehensively examine PTGS2 and other inflammation-related genes.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-7234, USA. sokadal@mail.nih.gov
authors.forename: Lori C
authors.initials: LC
authors.lastname: Sakoda
authors.forename: Yu-Tang
authors.initials: YT
authors.lastname: Gao
authors.forename: Bingshu E
authors.initials: BE
authors.lastname: Chen
authors.forename: Jinbo
authors.initials: J
authors.lastname: Chen
authors.forename: Philip S
authors.initials: PS
authors.lastname: Rosenberg
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.forename: Jie
authors.initials: J
authors.lastname: Deng
authors.forename: Ming-Chang
authors.initials: MC
authors.lastname: Shen
authors.forename: Bing-Sheng
authors.initials: BS
authors.lastname: Wang
authors.forename: Tian-Quan
authors.initials: TQ
authors.lastname: Han
authors.forename: Bai-He
authors.initials: BH
authors.lastname: Zhang
authors.forename: Hope
authors.initials: H
authors.lastname: Cohen-Webb
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Robert
authors.initials: R
authors.lastname: Welch
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Fraumeni
authors.forename: Ann W
authors.initials: AW
authors.lastname: Hsing
mesh_terms: D000367:Age Factors; D000368:Aged; D001661:Biliary Tract Neoplasms / Q000235:genetics*; D002681:China; D015331:Cohort Studies; D051546:Cyclooxygenase 2 / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics; D005260:Female; D042882:Gallstones / Q000175:diagnosis* / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012907:Smoking
chemical_list: D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human