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Carcinogenesis Advance Access published online on December 16, 2005
Carcinogenesis, doi:10.1093/carcin/bgi314
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Published by Oxford University Press 2005
Received November 2, 2005
Accepted December 11, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Prostaglandin-endoperoxide synthase 2 (PTGS2) gene polymorphisms and risk of biliary tract cancer and gallstones: a population-based study in Shanghai, China

Lori C. Sakoda 1 *, Yu-Tang Gao 2, Bingshu E. Chen 1, Jinbo Chen 1, Philip S. Rosenberg 1, Asif Rashid 3, Jie Deng 2, Ming-Chang Shen 4, Bing-Sheng Wang 5, Tian-Quan Han 6, Bai-He Zhang 7, Hope Cohen-Webb 8, Meredith Yeager 9, Robert Welch 9, Stephen Chanock 9, Joseph F. Fraumeni Jr. 1, and Ann W. Hsing 1

1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
2 Shanghai Cancer Institute, Shanghai, China
3 Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA
4 Shanghai Tumor Hospital, Fudan University, Shanghai, China
5 Zhongshan Hospital, Fudan University, Shanghai, China
6 Department of Surgery, Ruijin Hospital, Shanghai Second Medical University, Shanghai, China
7 Institute of Oriental Hepatobiliary Surgery, Second Military Medical University, Shanghai, China
8 Westat, Rockville, MD, USA
9 Core Genotyping Facility, National Cancer Institute, National Institutes of Health, Gaithersburg, MD, USA

* To whom correspondence should be addressed.
Lori C. Sakoda, E-mail: sakodal{at}mail.nih.gov


  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 (674 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.

Keywords: Biliary tract neoplasm; gallstones; PTGS2; genetic polymorphism; inflammation.
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