Gastroenterology
Volume 135, Issue 1 , Pages 91-99 , July 2008

Clinical Relevance of Helicobacter pylori cagA and vacA Gene Polymorphisms

  • Daniela Basso

      Affiliations

    • Department of Laboratory Medicine, University of Padova, Padova, Italy
    • Corresponding Author InformationAddress requests for reprints to: Daniela Basso, MD, Department of Laboratory Medicine, University Hospital of Padova, Via Giustiniani 2, 35128 Padova, Italy. fax: (39) 0498212785.
    • ,
  • Carlo–Federico Zambon

      Affiliations

    • Department of Medical and Surgical Sciences, University of Padova, Padova, Italy
    • ,
  • Darren P. Letley

      Affiliations

    • Wolfson Digestive Diseases Centre, and Institute of Infection, Immunity and Inflammation, University of Nottingham, Queen's Medical Centre, Nottingham, England
    • ,
  • Alessia Stranges

      Affiliations

    • Department of Laboratory Medicine, University of Padova, Padova, Italy
    • ,
  • Alberto Marchet

      Affiliations

    • Department of Oncological and Surgical Sciences, University of Padova, Padova, Italy
    • ,
  • Joanne L. Rhead

      Affiliations

    • Wolfson Digestive Diseases Centre, and Institute of Infection, Immunity and Inflammation, University of Nottingham, Queen's Medical Centre, Nottingham, England
    • ,
  • Stefania Schiavon

      Affiliations

    • Department of Laboratory Medicine, University of Padova, Padova, Italy
    • ,
  • Graziella Guariso

      Affiliations

    • Department of Pediatrics, University of Padova, Padova, Italy
    • ,
  • Marco Ceroti

      Affiliations

    • Molecular and Nutritional Epidemiology Unit, CSPO-Scientific Institute of Tuscany, Firenze, Italy
    • ,
  • Donato Nitti

      Affiliations

    • Department of Oncological and Surgical Sciences, University of Padova, Padova, Italy
    • ,
  • Massimo Rugge

      Affiliations

    • Department of Oncological and Surgical Sciences, University of Padova, Padova, Italy
    • ,
  • Mario Plebani

      Affiliations

    • Department of Laboratory Medicine, University of Padova, Padova, Italy
    • ,
  • John C. Atherton

      Affiliations

    • Wolfson Digestive Diseases Centre, and Institute of Infection, Immunity and Inflammation, University of Nottingham, Queen's Medical Centre, Nottingham, England

Received 24 September 2007 ,Accepted 20 March 2008.

References 

  1. Peek RM, Blaser MJ. Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer. 2002;2:28–37
  2. Palli D, Masala G, Del Giudice G, et al. CagA+ Helicobacter pylori infection and gastric cancer risk in the EPIC-EURGAST study. Int J Cancer. 2007;120:859–867
  3. Blaser MJ, Atherton JC. Helicobacter pylori persistence: biology and disease. J Clin Invest. 2004;113:321–333
  4. Segal ED, Cha J, Lo J, et al. Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proc Natl Acad Sci U S A. 1999;96:14559–14564
  5. Stein M, Rappuoli R, Covacci A. Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation. Proc Natl Acad Sci U S A. 2000;97:1263–1268
  6. Mimuro H, Suzuki T, Tanaka J, et al. Grb2 is a key mediator of Helicobacter pylori CagA protein activities. Mol Cell. 2002;10:745–755
  7. Hirata Y, Maeda S, Mitsuno Y, et al. Helicobacter pylori CagA protein activates serum response element-driven transcription independently of tyrosine phosphorylation. Gastroenterology. 2002;123:1962–1971
  8. Hatakeyama M. Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nat Rev Cancer. 2004;4:688–694
  9. Bagnoli F, Buti L, Tompkins L, et al. Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells. Proc Natl Acad Sci U S A. 2005;102:16339–16344
  10. Kurashima Y, Murata-Kamiya N, Kikuchi K, et al. Deregulation of beta-catenin signal by Helicobacter pylori CagA requires the CagA-multimerization sequence. Int J Cancer. 2008;122:823–831
  11. Higashi H, Tsutsumi R, Fujita A, et al. Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites. Proc Natl Acad Sci USA. 2002;99:14428–14433
  12. Zhang Y, Argent RH, Letley DP, et al. Tyrosine phosphorylation of CagA from Chinese Helicobacter pylori isolates in AGS gastric epithelial cells. J Clin Microbiol. 2005;43:786–790
  13. Azuma T, Yamazaki S, Yamakawa A, et al. Association between diversity in the Src homology 2 domain—containing tyrosine phosphatase binding site of Helicobacter pylori CagA protein and gastric atrophy and cancer. J Infect Dis. 2004;189:820–827
  14. Yamaoka Y, Kodama T, Kashima K, et al. Variants of the 3′ region of the cagA gene in Helicobacter pylori isolates from patients with different H. pylori-associated diseases. J Clin Microbiol. 1998;36:2258–2263
  15. Argent RH, Kidd M, Owen RJ, et al. Determinants and consequences of different levels of CagA phosphorylation for clinical isolates of Helicobacter pylori. Gastroenterology. 2004;127:514–523
  16. Naito M, Yamazaki T, Tsutsumi R, et al. Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA. Gastroenterology. 2006;130:1181–1190
  17. Cover TL, Blanke SR. Helicobacter pylori VacA, a paradigm for toxin multifunctionality. Nat Rev Microbiol. 2005;3:320–332
  18. Atherton JC, Cao P, Peek RM, et al. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori (Association of specific vacA types with cytotoxin production and peptic ulceration). J Biol Chem. 1995;270:17771–17777
  19. Atherton JC, Peek RM, Tham KT, et al. Clinical and pathological importance of heterogeneity in vacA, the vacuolating cytotoxin gene of Helicobacter pylori. Gastroenterology. 1997;112:92–99
  20. Letley DP, Lastovica A, Louw JA, et al. Allelic diversity of the Helicobacter pylori vacuolating cytotoxin gene in South Africa: rarity of the vacA s1a genotype and natural occurrence of an s2/m1 allele. J Clin Microbiol. 1999;37:1203–1205
  21. Ji X, Fernandez T, Burroni D, et al. Cell specificity of Helicobacter pylori cytotoxin is determined by a short region in the polymorphic mid region. Infect Immun. 2000;68:3754–3757
  22. Sundrud MS, Torres VJ, Unutmaz D, et al. Inhibition of primary human T cell proliferation by Helicobacter pylori vacuolating toxin (VacA) is independent of VacA effects on IL-2 secretion. Proc Natl Acad Sci U S A. 2004;101:7727–7732
  23. Yamasaki E, Wada A, Kumatori A, et al. Helicobacter pylori vacuolating cytotoxin induces activation of the proapoptotic proteins Bax and Bak, leading to cytochrome c release and cell death, independent of vacuolation. J Biol Chem. 2006;281:11250–11259
  24. Rhead JL, Letley DP, Mohammadi M, et al. A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer. Gastroenterology. 2007;133:926–936
  25. Dixon MF, Genta RM, Yardley JH, et al. Classification and grading of gastritis (The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994). Am J Surg Pathol. 1996;20:1161–1181
  26. Zambon CF, Basso D, Navaglia F, et al. Pro- and anti-inflammatory cytokines gene polymorphisms and Helicobacter pylori infection: interactions influence outcome. Cytokine. 2005;29:141–152
  27. Yamaoka Y, El-Zimaity HM, Gutierrez O, et al. Relationship between the cagA 3′ repeat region of Helicobacter pylori, gastric histology, and susceptibility to low pH. Gastroenterology. 1999;117:342–349
  28. Argent RH, Zhang Y, Atherton JC. Simple method for determination of the number of Helicobacter pylori CagA variable-region EPIYA tyrosine phosphorylation motifs by PCR. Clin Microbiol. 2005;43:791–795
  29. Basso D, Navaglia F, Brigato L, et al. Analysis of Helicobacter pylori vacA and cagA genotypes and serum antibody profile in benign and malignant gastroduodenal diseases. Gut. 1998;43:182–186
  30. Hansson LE, Nyrén O, Hsing AW, et al. The risk of stomach cancer in patients with gastric or duodenal ulcer disease. N Engl J Med. 1996;335:242–249
  31. Zambon CF, Navaglia F, Basso D, et al. Helicobacter pylori babA2, cagA, and s1 vacA genes work sinergistically in causing intestinal metaplasia. J Clin Pathol. 2003;56:287–291
  32. Atherton JC, Tham KT, Peek RM, et al. Density of Helicobacter pylori infection in vivo as assessed by quantitative culture and histology. J Infect Dis. 1996;174:552–556
  33. Rieder G, Merchant JL, Haas R. Helicobacter pylori cag-type IV secretion system facilitates corpus colonization to induce precancerous conditions in Mongolian gerbils. Gastroenterology. 2005;128:1229–1242
  34. Ogura K, Maeda S, Nakao M, et al. Virulence factors of Helicobacter pylori responsible for gastric diseases in Mongolian gerbil. J Exp Med. 2000;192:1601–1610
  35. Azuma T, Yamakawa A, Yamazaki S, et al. Correlation between variation of the 3′ region of the cagA gene in Helicobacter pylori and disease outcome in Japan. J Infect Dis. 2002;186:1621–1630
  36. Choi KD, Kim N, Lee DH, et al. Analysis of the 3′ variable region of the cagA gene of Helicobacter pylori isolated in Koreans. Dig Dis Sci. 2007;52:960–966
  37. Aras RA, Fischer W, Perez-Perez GI, et al. Plasticity of repetitive DNA sequences within a bacterial (Type IV) secretion system component. J Exp Med. 2003;198:1349–1360

 Supported by AIRC regional grant 2005 and by Cancer Research UK and CORE, the digestive diseases charity.

 The authors report they have no conflict to disclose.

PII: S0016-5085(08)00479-4

doi: 10.1053/j.gastro.2008.03.041

Gastroenterology
Volume 135, Issue 1 , Pages 91-99 , July 2008

Article Tools