Journal of Gastroenterology

, Volume 43, Issue 2, pp 115–123 | Cite as

RANTES-403 polymorphism is associated with reduced risk of gastric cancer in women

  • Jyh-Ming Liou
  • Jaw-Town Lin
  • Shih-Pei Huang
  • Chun-Ying Wu
  • Hsiu-Po Wang
  • Yi-Chia Lee
  • Han-Mo Chiu
  • Chia-Tung Shun
  • Ming-Tsan Lin
  • Ming-Shiang Wu
Alimmentary Tract



Men are more susceptible to gastric cancer (GC) than women. However, the genetic factors associated with the sex difference are not well understood. Chemokines have been shown to modulate tumor behavior, and the sex-specific effect of the chemokine polymorphisms on the host susceptibility to several diseases has been reported. We aimed to determine the role of chemokine polymorphisms on host susceptibility to GC, with special interest on their sex-specific effect.


A hospital-based case-control study, including 177 patients with GC and 217 age-matched unaffected healthy controls, was performed in three major tertiary care hospitals. Genotyping for regulated upon activation, normal T-cell expressed and secreted (RANTES) −403 A/G and −28 C/G, CC chemokine receptor 5 (CCR5) deletion, and CCR2-V64I was performed using peripheral blood DNA.


The RANTES −403 GA and AA genotypes were independently associated with a 2.3-fold reduced risk of developing GC (OR = 0.44, 95% CI 0.22–0.90, P = 0.025) compared with GG genotype in women, but not in men. The RANTES −28C/G and CCR2-V64I polymorphisms were not associated with different risk of developing GC. The tumor stage, histological features, and survival rate were not different when stratified by RANTES −403 and −28 and CCR2-V64I genotypes.


Our data indicate that women who inherit A allele at RANTES −403 may be at reduced risk of GC.

Key words

gastric cancer RANTES CCR5 CCR2 chemokine polymorphism women 


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  1. 1.
    Fuchs CS, Mayer RJ. Gastric carcinoma. N Engl J Med 1995;333:32–41.PubMedCrossRefGoogle Scholar
  2. 2.
    Wu MS, Chen CJ, Lin JT. Host-environment interactions: their impact on progression from gastric inflammation to carcinogenesis and on development of new approaches to prevent and treat gastric cancer. Cancer Epidemiol Biomark Prev 2005;14:1878–1882.CrossRefGoogle Scholar
  3. 3.
    Liou JM, Lin JT, Wang HP, Huang SP, Lee YC, Shun CT, et al. The optimal age threshold for screening upper endoscopy for uninvestigated dyspepsia in Taiwan, an area with a higher prevalence of gastric cancer in young adults. Gastrointest Endosc 2005;61:819–825.PubMedCrossRefGoogle Scholar
  4. 4.
    Roder DM. The epidemiology of gastric cancer. Gastric Cancer 2002;5(suppl 1):5–11.PubMedCrossRefGoogle Scholar
  5. 5.
    El-Omar EM, Rabkin CS, Gammon MD, Vaughan TL, Risch HA, Schoenberg JB, et al. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 2003;124:1193–1201.PubMedCrossRefGoogle Scholar
  6. 6.
    El-Omar EM. The importance of interleukin 1-beta in Helicobacter pylori associated disease. Gut 2001;48:743–747.PubMedCrossRefGoogle Scholar
  7. 7.
    Balkwill F. Cancer and the chemokine network. Nat Rev Cancer 2004;4:540–550.PubMedCrossRefGoogle Scholar
  8. 8.
    Mule JJ, Custer M, Averbook B, Yang JC, Weber JS, Goeddel DV, et al. RANTES secretion by gene-modified tumor cells results in loss of tumorigenicity in vivo: role of immune cell subpopulations. Hum Gene Ther 1996;7:1545–1553.PubMedCrossRefGoogle Scholar
  9. 9.
    Roda JM, Parihar R, Magro C, Nuovo GJ, Tridandapani S, Carson WE 3rd. Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. Cancer Res 2006;66:517–526.PubMedCrossRefGoogle Scholar
  10. 10.
    Nickel RG, Casolaro V, Wahn U, Beyer K, Barnes KC, Plunkett BS, et al. Atopic dermatitis is associated with a functional mutation in the promoter of the C-C chemokine RANTES. J Immunol 2000;164:1612–1616.PubMedGoogle Scholar
  11. 11.
    Fryer AA, Spiteri MA, Bianco A, Hepple M, Jones PW, Strange RC, et al. The −403 G->A promoter polymorphism in the RANTES gene is associated with atopy and asthma. Genes Immun 2000;1:509–514.PubMedCrossRefGoogle Scholar
  12. 12.
    Chen Y, Vaughan RW, Kondeatis E, Fortune F, Graham EM, Stanford MR, et al. Chemokine gene polymorphisms associate with gender in patients with uveitis. Tissue Antigens 2004;63:41–45.PubMedCrossRefGoogle Scholar
  13. 13.
    Liu H, Chao D, Nakayama EE, Taguchi H, Goto M, Xin X, et al. Polymorphism in RANTES chemokine promoter affects HIV-1 disease progression. Proc Natl Acad Sci USA 1999;96:4581–4585.PubMedCrossRefGoogle Scholar
  14. 14.
    Mlynarski WM, Placha GP, Wolkow PP, Bochenski JP, Warram JH, Krolewski AS. Risk of diabetic nephropathy in type 1 diabetes is associated with functional polymorphisms in RANTES receptor gene (CCR5): a sex-specific effect. Diabetes 2005;54:3331–3335.PubMedCrossRefGoogle Scholar
  15. 15.
    Zafiropoulos A, Crikas N, Passam AM, Spandidos DA. Significant involvement of CCR2-64I and CXCL12-3a in the development of sporadic breast cancer. J Med Genet 2004;41:e59.PubMedCrossRefGoogle Scholar
  16. 16.
    Coelho A, Matos A, Catarino R, Pinto D, Pereira D, Lopes C, et al. Protective role of the polymorphism CCR2-64I in the progression from squamous intraepithelial lesions to invasive cervical carcinoma. Gynecol Oncol 2005;96:760–764.PubMedCrossRefGoogle Scholar
  17. 17.
    Petrkova J, Cermakova Z, Drabek J, Lukl J, Petrek M. CC chemokine receptor (CCR)2 polymorphism in Czech patients with myocardial infarction. Immunol Lett 2003;88:53–55.PubMedCrossRefGoogle Scholar
  18. 18.
    Promrat K, McDermott DH, Gonzalez CM, Kleiner DE, Koziol DE, Lessie M, et al. Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C. Gastroenterology 2003;124:352–360.PubMedCrossRefGoogle Scholar
  19. 19.
    Goulding C, McManus R, Murphy A, MacDonald G, Barrett S, Crowe J, et al. The CCR5-delta32 mutation: impact on disease outcome in individuals with hepatitis C infection from a single source. Gut 2005;54:1157–1161.PubMedCrossRefGoogle Scholar
  20. 20.
    Zhao XY, Lee SS, Wong KH, Yuen KY, Ng MH, Zheng BJ. Effects of single nucleotide polymorphisms in the RANTES promoter region in healthy and HIV-infected indigenous Chinese. Eur J Immunogenet 2004;31:179–183.PubMedCrossRefGoogle Scholar
  21. 21.
    Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004;21, 137–148.PubMedCrossRefGoogle Scholar
  22. 22.
    Nishimura T, Iwakabe K, Sekimoto M, Ohmi Y, Yahata T, Nakui M, et al. Distinct role of antigen-specific T helper type 1 (Th1) and Th2 cells in tumor eradication in vivo. J Exp Med 1999;190:617–627.PubMedCrossRefGoogle Scholar
  23. 23.
    Mashino K, Sadanaga N, Tanaka F, Ohta M, Yamaguchi H, Mori M. Effective strategy of dendritic cell-based immunotherapy for advanced tumor-bearing hosts: the critical role of Th1-dominant immunity. Mol Cancer Ther 2002;1:785–794.PubMedGoogle Scholar
  24. 24.
    Kalinski P, Nakamura Y, Watchmaker P, Giermasz A, Muthuswamy R, Mailliard RB. Helper roles of NK and CD8+ T cells in the induction of tumor immunity. Polarized dendritic cells as cancer vaccines. Immunol Res 2006;36:137–146.PubMedCrossRefGoogle Scholar
  25. 25.
    Kutubuddin M, Federoff HJ, Challita-Eid PM, Halterman M, Day B, Atkinson M, et al. Eradication of pre-established lymphoma using herpes simplex virus amplicon vectors. Blood 1999;93:643–654.PubMedGoogle Scholar
  26. 26.
    Bai B, Tanaka K, Tazawa T, Yamamoto N, Sugiura H. Association between RANTES promoter polymorphism −401A and enhanced RANTES production in atopic dermatitis patients. J Dermatol Sci 2005;39:189–191.PubMedCrossRefGoogle Scholar
  27. 27.
    Duell EJ, Casella DP, Burk RD, Kelsey KT, Holly EA. Inflammation, genetic polymorphisms in proinflammatory genes TNF-A, RANTES, and CCR5, and risk of pancreatic adenocarcinoma. Cancer Epidemiol Biomark Prev 2006;15:726–731.CrossRefGoogle Scholar
  28. 28.
    Nahon P, Sutton A, Rufat P, Faisant C, Simon C, Barget N, et al. Lack of association of some chemokine system polymorphisms with the risks of death and hepatocellular carcinoma occurrence in patients with alcoholic cirrhosis: a prospective study. Eur J Gastroenterol Hepatol 2007;19:425–431.PubMedCrossRefGoogle Scholar
  29. 29.
    Lindblad M, Ye W, Rubio C, Lagergren J. Estrogen and risk of gastric cancer: a protective effect in a nationwide cohort study of patients with prostate cancer in Sweden. Cancer Epidemiol Biomark Prev 2004;13:2203–2207.Google Scholar
  30. 30.
    Frise S, Kreiger N, Gallinger S, Tomlinson G, Cotterchio M. Menstrual and reproductive risk factors and risk for gastric adenocarcinoma in women: findings from the Canadian national enhanced cancer surveillance system. Ann Epidemiol 2006;16:908–916.PubMedCrossRefGoogle Scholar
  31. 31.
    Mo R, Chen J, Grolleau-Julius A, Murphy HS, Richardson BC, Yung RL. Estrogen regulates CCR gene expression and function in T lymphocytes. J Immunol 2005;174:6023–6029.PubMedGoogle Scholar
  32. 32.
    Melgert BN, Postma DS, Kuipers I, Geerlings M, Luinge MA, van der Strate BW, et al. Female mice are more susceptible to the development of allergic airway inflammation than male mice. Clin Exp Allergy 2005;35:1496–1503.PubMedCrossRefGoogle Scholar
  33. 33.
    Akoum A, Lemay A, Maheux R. Estradiol and interleukin-1beta exert a synergistic stimulatory effect on the expression of the chemokine regulated upon activation, normal T cell expressed, and secreted in endometriotic cells. J Clin Endocrinol Metab 2002;87:5785–5792.PubMedCrossRefGoogle Scholar
  34. 34.
    Kanda N, Watanabe S. 17beta-estradiol inhibits the production of RANTES in human keratinocytes. J Invest Dermatol 2003;120:420–427.PubMedCrossRefGoogle Scholar
  35. 35.
    Luboshits G, Shina S, Kaplan O, Engelberg S, Nass D, Lifshitz-Mercer B, et al. Elevated expression of the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma. Cancer Res 1999;59:4681–4687.PubMedGoogle Scholar
  36. 36.
    Niwa Y, Akamatsu H, Niwa H, Sumi H, Ozaki Y, Abe A. Correlation of tissue and plasma RANTES levels with disease course in patients with breast or cervical cancer. Clin Cancer Res 2001;7:285–289.PubMedGoogle Scholar
  37. 37.
    Vaday GG, Peehl DM, Kadam PA, Lawrence DM. Expression of CCL5 (RANTES) and CCR5 in prostate cancer. Prostate 2006;66:124–134.PubMedCrossRefGoogle Scholar
  38. 38.
    Kim HK, Song KS, Park YS, Kang YH, Lee YJ, Lee KR, et al. Elevated levels of circulating platelet microparticles, VEGF, IL-6 and RANTES in patients with gastric cancer: possible role of a metastasis predictor. Eur J Cancer 2003;39:184–191.PubMedCrossRefGoogle Scholar
  39. 39.
    Moran CJ, Arenberg DA, Huang CC, Giordano TJ, Thomas DG, Misek DE, et al. RANTES expression is a predictor of survival in stage I lung adenocarcinoma. Clin Cancer Res 2002;8:3803–3812.PubMedGoogle Scholar
  40. 40.
    Kondo T, Ito F, Nakazawa H, Horita S, Osaka Y, Toma H. High expression of chemokine gene as a favorable prognostic factor in renal cell carcinoma. J Urol 2004;171:2171–2175.PubMedCrossRefGoogle Scholar
  41. 41.
    Kurt RA, Baher A, Wisner KP, Tackitt S, Urba WJ. Chemokine receptor desensitization in tumor-bearing mice. Cell Immunol 2001;207:81–88.PubMedCrossRefGoogle Scholar
  42. 42.
    Mellado M, de Ana AM, Moreno MC, Martinez C, Rodriguez-Frade JM. A potential immune escape mechanism by melanoma cells through the activation of chemokine-induced T cell death. Curr Biol 2001;11:691–696.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2008

Authors and Affiliations

  • Jyh-Ming Liou
    • 1
  • Jaw-Town Lin
    • 1
    • 2
  • Shih-Pei Huang
    • 1
  • Chun-Ying Wu
    • 3
  • Hsiu-Po Wang
    • 1
    • 4
  • Yi-Chia Lee
    • 1
  • Han-Mo Chiu
    • 1
  • Chia-Tung Shun
    • 5
  • Ming-Tsan Lin
    • 6
  • Ming-Shiang Wu
    • 1
    • 2
  1. 1.Department of Internal MedicineNational Taiwan University Hospital, National Taiwan University College of MedicineTaipeiTaiwan
  2. 2.Department of Primary Care MedicineNational Taiwan University Hospital, National Taiwan University College of MedicineTaipeiTaiwan
  3. 3.Division of GastroenterologyTaichung Veterans General HospitalTaipeiTaiwan
  4. 4.Department of Emergency MedicineNational Taiwan University Hospital, National Taiwan University College of MedicineTaipeiTaiwan
  5. 5.Department of PathologyNational Taiwan University Hospital, National Taiwan University College of MedicineTaipeiTaiwan
  6. 6.Department of SurgeryNational Taiwan University Hospital, National Taiwan University College of MedicineTaipeiTaiwan

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