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Functional polymorphisms of the cyclooxygenase (PTGS2) gene and risk for gallbladder cancer in a North Indian population

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Cyclooxygenase-2 (PTGS2) overexpression has been implicated in various cancers. We aimed to evaluate the role of PTGS2 −1195G>A [reference sequence (rs) 689466], −765G>C (rs20417) and +8473T>C (rs5275) polymorphisms in conferring interindividual susceptibility to gallbladder cancer.

Materials and methods

The study included 167 gallbladder cancer cases and 184 controls. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism. Risk was estimated using unconditional logistic regression.

Results

Significant risk was observed in the presence of PTGS2 −1195GA (P = 0.006; odds ratio = 2.00; 95% confidence interval = 1.2–3.3) and AA genotypes (P = 0.050; odds ratio = 2.98; 95% confidence interval = 1.0–8.9). Combined risk due to GA + AA genotypes was 2.12 (P = 0.002; 95% confidence interval = 1.3–3.3; P-trend = 0.001). Sub-grouping showed a risk due to the PTGS2 −1195(GA + AA) genotype in males (P = 0.007; odds ratio = 2.97; 95% confidence interval = 1.3–6.5), patients without gallstones (P = 0.001; odds ratio = 2.53; 95% confidence interval = 1.4–4.7) and with late-onset gallbladder cancer (P = 0.012; odds ratio = 1.99; 95% confidence interval = 1.1–3.4). Gallbladder cancer patients who used tobacco were at increased risk in the presence of the PTGS2 −765GC genotype (P = 0.018; odds ratio = 2.96; 95% confidence interval = 1.2–7.2).

Discussion

An association of PTGS2 −1195G>A polymorphism with gallbladder cancer, particularly in patients without gallstones, suggests a direct role of PTGS2 in cancer development.

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References

  1. Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer. 2006;118:1591–602.

    Article  PubMed  CAS  Google Scholar 

  2. Hsing AW, Rashid A, Devesa SS, Fraumeni JFJ. Biliary tract cancer. In: Schottenfeld D, Fraumeni JFJ, editors. Cancer epidemiology and prevention. 3rd ed. New York: Oxford University Press; 2006. p. 794–805.

    Google Scholar 

  3. Wistuba II, Gazdar AF. Gallbladder cancer: lessons from a rare tumour. Nat Rev Cancer. 2004;4:695–706.

    Article  PubMed  CAS  Google Scholar 

  4. Bartsch H, Nair J. Oxidative stress and lipid peroxidation-derived DNA-lesions in inflammation driven carcinogenesis. Cancer Detect Prev. 2004;28:385–91.

    Article  PubMed  CAS  Google Scholar 

  5. Coogan PF, Rosenberg L, Palmer JR, Strom BL, Zauber AG, Stolley PD, et al. Nonsteroidal anti-inflammatory drugs and risk of digestive cancers at sites other than the large bowel. Cancer Epidemiol Biomark Prev. 2000;9:119–23.

    CAS  Google Scholar 

  6. Gonzalez-Perez A, Garcia Rodriguez L, Lopez-Ridaura R. Effects of non-steroidal anti-inflammatory drugs on cancer sites other than the colon and rectum: a meta-analysis. BMC Cancer. 2003;3:28.

    Article  PubMed  Google Scholar 

  7. Wang D, DuBois RN. Prostaglandins and cancer. Gut. 2006;55:115–22.

    Article  PubMed  CAS  Google Scholar 

  8. Fujita H, Koshida K, Keller ET, Takahashi Y, Yoshimito T, Namiki M. Mizokami A cyclooxygenase-2 promotes prostate cancer progression. Prostate. 2002;53:232–40.

    Article  PubMed  CAS  Google Scholar 

  9. Chen WS, Wei SJ, Liu JM, Hsiao M, Kou-Lin J, Yang WK. Tumor invasiveness and liver metastasis of colon cancer cells correlated with cyclooxygenase-2 (COX-2) expression and inhibited by a COX-2-selective inhibitor, etodolac. Int J Cancer. 2001;91:894–9.

    Article  PubMed  CAS  Google Scholar 

  10. Zha S, Yegnasubramanian V, Nelson WG, Isaacs WB, De Marzo AM. Cyclooxygenases in cancer: progress and perspective. Cancer Lett. 2004;215:1–20.

    Article  PubMed  CAS  Google Scholar 

  11. Gasparini G, Longo R, Sarmiento R, Morabito A. Inhibitors of cyclo-oxygenase 2: a new class of anticancer agents? Lancet Oncol. 2003;4:605–15.

    Article  PubMed  CAS  Google Scholar 

  12. Tazawa R, Xu XM, Wu KK, Wang LH. Characterization of the genomic structure, chromosomal location and promoter of human prostaglandin H synthase-2 gene. Biochem Biophys Res Commun. 1994;203:190–9.

    Article  PubMed  CAS  Google Scholar 

  13. Zhang X, Miao X, Tan W, Ning B, Liu Z, Hong Y, et al. Identification of functional genetic variants in cyclooxygenase-2 and their association with risk of esophageal cancer. Gastroenterology. 2005;129:565–76.

    PubMed  CAS  Google Scholar 

  14. Papafili A, Hill MR, Brull DJ, McAnulty RJ, Marshall RP, Humphries SE, et al. Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response. Arterioscler Thromb Vasc Biol. 2002;22:1631–6.

    Article  PubMed  CAS  Google Scholar 

  15. Cok SJ, Morrison AR. The 3′-untranslated region of murine cyclooxygenase-2 contains multiple regulatory elements that alter message stability and translational efficiency. J Biol Chem. 2001;276:23179–85.

    Article  PubMed  CAS  Google Scholar 

  16. Sakoda LC, Gao YT, Chen BE, Chen J, Rosenberg PS, Rashid A, et al. Prostaglandin-endoperoxide synthase 2 (PTGS2) gene polymorphisms and risk of biliary tract cancer and gallstones: a population-based study in Shanghai, China. Carcinogenesis. 2006;27:1251–6.

    Article  PubMed  CAS  Google Scholar 

  17. Devlin B, Roeder K. Genomic control for association studies. Biometrics. 1999;55:997–1004.

    Article  PubMed  CAS  Google Scholar 

  18. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucl Acids Res. 1988;16:1215.

    Article  PubMed  CAS  Google Scholar 

  19. Schneider S, Roessli D, Excoffier L. Arlequin ver 2.000: a software for population genetics data analysis [User manual]. Geneva, Switzerland: genetics and Biometry Laboratory, University of Geneva; 2000.

  20. Lazcano-Ponce EC, Miquel JF, Munoz N, Herrero R, Ferrecio C, Wistuba II, et al. Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J Clin 2001;51:349–64.

    Google Scholar 

  21. Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 1994;107:1183–8.

    PubMed  CAS  Google Scholar 

  22. Zhi H, Wang L, Zhang J, Zhou C, Ding F, Luo A, et al. Significance of COX-2 expression in human esophageal squamous cell carcinoma. Carcinogenesis. 2006;27:1214–21.

    Article  PubMed  CAS  Google Scholar 

  23. Zhang XM, Miao XP, Tan W, Sun T, Guo YL, Zhao D, et al. Genetic polymorphisms in the promoter region of cyclooxygenase-2 and their association with risk of gastric cancer. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2006;28:119–23.

    PubMed  Google Scholar 

  24. Ramsay RG, Barton AL, Gonda TJ. Targeting c-Myb expression in human disease. Expert Opin Ther Tar. 2003;7:235–48.

    Article  CAS  Google Scholar 

  25. Liu F, Pan K, Zhang X, Zhang Y, Zhang L, Ma J, et al. Genetic variants in cyclooxygenase-2: expression and risk of gastric cancer and its precursors in a Chinese population. Gastroenterology. 2006;130:1975–84.

    Article  PubMed  CAS  Google Scholar 

  26. Hamajima N, Takezaki T, Matsuo K, Saito T, Inoue M, Hirai T, et al. Genotype frequencies of cyclooxygenase 2 (COX2) rare polymorphisms for Japanese with and without colorectal cancer. Asian Pac J Cancer Prev. 2001;2:57–62.

    PubMed  Google Scholar 

  27. Cox D, Buring J, Hankinson S, Hunter D. A polymorphism in the 3′ untranslated region of the gene encoding prostaglandin endoperoxide synthase 2 is not associated with an increase in breast cancer risk: a nested case–control study. Breast Cancer Res. 2007;9:R3.

    Article  PubMed  Google Scholar 

  28. Gao J, Ke Q, Ma HX, Wang Y, Zhou Y, Hu ZB, et al. Functional polymorphisms in the cyclooxygenase 2 (COX-2) gene and risk of breast cancer in a Chinese population. J Toxicol Environ Health A. 2007;70:908–15.

    Article  PubMed  Google Scholar 

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Acknowledgment

The study was supported by fellowship grants from the Counsel of Scientific and Industrial Research (CSIR), Government of India.

Conflict of interest statement

The author(s) declare that they have no competing interests.

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Correspondence to Balraj Mittal.

Additional information

K. Srivastava and A. Srivastava contributed equally to the manuscript.

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Srivastava, K., Srivastava, A., Pandey, S.N. et al. Functional polymorphisms of the cyclooxygenase (PTGS2) gene and risk for gallbladder cancer in a North Indian population. J Gastroenterol 44, 774–780 (2009). https://doi.org/10.1007/s00535-009-0071-5

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  • DOI: https://doi.org/10.1007/s00535-009-0071-5

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