Skip to main content
Log in

Serum Antibodies Against Helicobacter pylori Proteins VacA and CagA Are Associated with Increased Risk for Gastric Adenocarcinoma

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Infection with Helicobacter pylori is associatedwith the development of gastric cancer. To study whetherthe infection with H. pylori strains expressing thevacuolating cytotoxin (VacA) and/or thecytotoxin-associated protein (CagA) is associated with an increasedrisk of developing gastric adenocarcinoma, sera of 90patients with gastric cancer and 90 matched controlswith cardiovascular diseases were investigated for the presence of antibodies to VacA and CagA byimmunoblot. Although no significant difference in theoverall H. pylori seropositivity was found betweencancer patients and controls, antibodies against VacA or CagA were significantly more frequent incancer patients than in control subjects. Seventyfive(97.4%) of 77 H. pylori-positive patients in the cancergroup, but only 60 (84.5%) of 71 H. pylori-positive control patients had antibodies against eitherVacA or CagA (χ2 6.63; relative risk,2.00; 95% confidence interval, 1.18–3.39; P =0.01). The presence of antibodies against VacA or CagAalone was also associated with an increased cancer risk (92.2%vs 80.3%; χ2 = 5.30; relative risk, 1.74;95% confidence interval, 1.08–2.78; P = 0.021, forVacA; and 87.0% vs 74.6%; χ2 4.90;relative risk, 1.61; 95% confidence interval, 1.06–2.45; P =0.037, for CagA). The relative risk for gastric cancerwas mainly elevated in patients under 65 years, but notin patients at or over 65 years. There is evidence that infection with VacA- or CagA-producing H.pylori strains increases the risk of developing gastriccancer, especially in younger patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Parkin DM, Laara E, Muir CS: Estimates of the worldwide frequency of sixteen major cancers in 1980. Int J Cancer 41:184–97, 1988

    Google Scholar 

  2. Correa P, Haenszel W: Epidemiology of gastric cancer. In Epidemiology of Cancer of the Digestive Tract. P Correa, W Haenszel (eds). The Hague, M. Nijhoff, 1982, pp 58–84

    Google Scholar 

  3. Joossens JV, Geboers J: Diet and environment in the etiology of gastric cancer. In Frontiers in Gastrointestinal Cancer. B Levin, RH Riddell (eds). New York, Elsevier, 1984, pp 168–183

    Google Scholar 

  4. Forman D, Newell DG, Fullerton F, Yarnell JGW, Stacey AR, Wald N, Sitas F: Association between infection with Helicobacter pylori and risk of gastric cancer: Evidence from a prospective investigation. BMJ 302:1302–1305, 1991

    Google Scholar 

  5. Talley NJ, Zinsmeister AR, Weaver A, DiMagno EP, Carpenter HA, Perez-Perez GI, Blaser MJ: Gastric adenocarcinoma and Helicobacter pylori infection. J Natl Cancer Inst 83:1734–1739, 1991

    Google Scholar 

  6. Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orenteich N, Sibley RK: Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 325:1127–1131, 1991

    Google Scholar 

  7. Nomura A, Stemmermann GN, Chyou P-H, Kato I, Perez-Perez GI, Blaser MJ: Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med 325:1132–1136, 1991

    Google Scholar 

  8. Hansson L-E, Engstrand L, Nyren O, Evans DJ, Lindgren A, Bergström R, Andersson B, Athlin L, Bendtsen O, Tracz P: Helicobacter pylori infection: Independent risk factor of gastric adenocarcinoma. Gastroenterology 105:1098–1103, 1993

    Google Scholar 

  9. The Eurogast Study Group: An international association between Helicobacter pylori infection and gastric cancer. Lancet 341:1359–1362, 1993

    Google Scholar 

  10. Taylor DN, Blaser MJ: The epidemiology of Helicobacter pylori infection. Epidemiol Rev 13:42–59, 1991

    Google Scholar 

  11. Cover T, Dooley C, Blaser M: Characterisation of and human serologic response to proteins in Helicobacter pylori broth culture supernatants with vacuolizing cytotoxin activity. Infect Immun 58:603–610, 1990

    Google Scholar 

  12. Phadnis SH, Ilver D, Janzon L, Normark S, Westblom TU: Pathological significance and molecular characterization of the vacuolating toxin gene of Helicobacter pylori. Infect Immun 62:1557–1565, 1994

    Google Scholar 

  13. Schmitt W, Haas R: Genetic analysis of the Helicobacter pylori vacuolating cytotoxin: Structural similarities with the IgA protease type of exported protein. Mol Microbiol 12:307–319, 1994

    Google Scholar 

  14. Figura N, Guglielmetti P, Rossolini A, Barberi A, Cusi G, Musmanno RA, Russi M, Quaranta SI: Cytotoxin production by Campylobacter pylori strains isolated from patients with peptic ulcers and from patients with chronic gastritis. J Clin Microbiol 27:225–226, 1989

    Google Scholar 

  15. Goossens H, Glupczynski Y, Burette A, Lambert J-P, Vlaes L, Butzler J-P: Role of the vacuolating toxin form Helicobacter pylori in the pathogenesis of duodenal and gastric ulcer. Med Microbiol Lett 1:153–159, 1992

    Google Scholar 

  16. Covacci A, Censini S, Bugnoli M, Petracca R, Burroni D, Macchia G, Massone A, Papini E, Xiang Z, Figura N, Rappuoli RI: Molecular characterization of the 128-kDa immunodominat antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer. Proc Natl Acad Sci USA 90:5791–5795, 1993

    Google Scholar 

  17. Tummuru MK, Cover TL, Blaser MJ: Cloning and expression of a high-molecular-mass major antigen of Helicobacter pylori: Evidence of linkage to cytotoxin production. Infect Immun 61:1799–1809, 1993

    Google Scholar 

  18. Crabtree JE, Taylor JD, Wyatt JI, Heatley RV, Shallcross TM, Tompkins DS, Rathbone BJ: Mucosal IgA recognition of Helicobacter pylori 120 kDa protein, peptic ulceration and gastric pathology. Lancet 59:1264–1270, 1991

    Google Scholar 

  19. Cover TL, Glupczynski Y, Lage AP, Burette A, Tummuru MKR, Perez-Perez GI, Blaser MJ: Serologic detection of infection with cagA + Helicobacter pylori strains. J Clin Microbiol 33:1496–1500, 1995

    Google Scholar 

  20. Apel I, Jacobs E, Kist M, Bredt W: Antibody response of patients against a 120-kDa surface protein of Campylobacter pylori. Zentralbl Bakteriol Hyg A 268:271–276, 1988

    Google Scholar 

  21. Crabtree JE, Wyatt JI, Sobala GM, Tompkins DS, Primrose JN, Morgan AG: Systemic and mucosal humoral responses to Helicobacter pylori in gastric cancer. Gut 34:1339–1343, 1993

    Google Scholar 

  22. Blaser MJ, Perez-Perez GI, Kleanthous H, Cover TL, Peek RM, Chyou PH, Stemmermann GN, Nomura A: Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res 55:2111–2115, 1995

    Google Scholar 

  23. Hirai M, Azuma T, Ito S, Kato T, Kohli Y, Fujiki N: High prevalence of neutralizing activity to Helicobacter pylori cytotoxin in serum of gastric-carcinoma patients. Int J Cancer 56:56–60, 1994

    Google Scholar 

  24. Lauren P: The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. Acta Pathol Microbiol Scand 64:31–49, 1965

    Google Scholar 

  25. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275, 1951

    Google Scholar 

  26. Feldman RA, Deeks JJ, Evans SJW, Helicobacter pylori Serology Study Group: Multi-laboratory comparison of eight commercially available Helicobacter pylori serology kits. Eur J Clin Microbiol Infect Dis 14:428–433, 1995

    Google Scholar 

  27. Laemmli UK: Cleavage of structural proteins during assembly of the head of bacteriophage T4. Nature 227:680–685, 1970

    Google Scholar 

  28. Pena AS, Endtz HP, Offerhaus GJA, Hoogenboom-Verdegaal A, van Duijn W, de Vargas N, den Hartog G, Kreuning J, van der Reyden J, Mouton RP, Lamers CBHW: Value of serology (ELISA and immunoblotting) for the diagnosis of Campylobacter pylori infection. Digestion 44:131–141, 1989

    Google Scholar 

  29. Crabtree JE, Mahony MJ, Taylor JD, Heatley RV, Littlewood JM, Tompkins DS: Immune responses to Helicobacter pylori in children with recurrent abdominal pain. J Clin Pathol 44:768–771, 1991

    Google Scholar 

  30. SAS Institute Inc: SAS/STAT User's Guide for Personal Computers. Version 6.03, Cary, (North Carolina), SAS Institute, 1988, 1028 pp

    Google Scholar 

  31. Rudi J, Müller M, von Herbay A, Zuna I, Raedsch R, Stremmel W, Räth U: Lack of association of Helicobacter pylori seroprevalence and gastric cancer in a population with low gastric cancer incidence. Scand J Gastroenterol 30:958–963, 1995

    Google Scholar 

  32. Weel JFL, van der Hulst RWM, Gerrits Y, Roorde P, Feller M, Dankert J, Tytgat GNJ, van der Ende A. The interrelationsship between cytotoxin-associated gene A, vacuolating cytotoxin, and Helicobacter pylori-related diseases. J Infect Dis 173:1171–1175, 1996

    Google Scholar 

  33. Cover TL, Cao P, Lind CD, Tham KT, Blaser MJ: Correlation between vacuolating cytotoxin production by Helicobacter pylori isolates in vitro and in vivo. Infect Immun 61:5008–5012, 1993

    Google Scholar 

  34. Correa P. Human gastric carcinogenesis: A multistep and multifactorial process—First American Cancer Society lecture on cancer epidemiology and prevention. Cancer Res 52:6735–6740, 1992

    Google Scholar 

  35. Fox JG, Correa P, Taylor NS, Thompson N, Fontham E, Janney F, Sobhan M, Ruiz B, Hunter F: High prevalence and persistence of cytotoxin-positive Helicobacter pylori strains in a population with high prevalence of atrophic gastritis. Am J Gastroenterol 87:1554–1560, 1992

    Google Scholar 

  36. Atherton JC, Cao P, Peek RM, Tummuru MKR, Blaser MJ, Cover TL: Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. J Biol Chem 270:17771–17777, 1995

    Google Scholar 

  37. Sipponen P, Kosunen TU, Valle J, Riihela M, Seppala K: Helicobacter pylori infection and chronic gastritis in gastric cancer. J Clin Pathol 33:1029–1032, 1992

    Google Scholar 

  38. Parsonnet J, Vandersteen D, Goates J, Sibley RK, Pritikin J, Chang Y: Helicobacter pylori infection in intestinal-and diffuse-type gastric adenocarcinomas. J Natl Cancer Inst 83:640–643, 1991

    Google Scholar 

  39. Loffeld RJLF, Willems I, Flendrig JA, Arends JW: Helicobacter pylori and gastric carcinoma. Histopathology 17:537–541, 1990

    Google Scholar 

  40. Asaka M, Kimura T, Kato M, Kudo K, Miki K, Ogoshi K, Kato T, Tatsuta M, Graham DY: Possible role of Helicobacter pylori infection in early gastric cancer development. Cancer 73:2691–2694, 1994

    Google Scholar 

  41. Endo S, Ohkusa T, Saito Y, Fujiki K, Okayasu I, Sato C: Detection of Helicobacter pylori infection in early stage gastric cancer. Cancer 75:2203–2208, 1995

    Google Scholar 

  42. Mendall MA, Goggin PM, Molineaux N, Levy J, Toosy T, Strachan D, Camm AJ, Northfield TC: Relation of Helicobacter pylori infection and coronary heart disease. Br Heart J 71:437–439, 1994

    Google Scholar 

  43. Patel P, Mendall MA, Carrington D, Strachan DP, Leatham E, Molineaux N, Levy J, Blakeston C, Seymour CA, Camm AJ, Northfield TC: Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors. Br Med J 311:711–714, 1995

    Google Scholar 

  44. Ponzetto A, La Rovere MT, Sanseverion P, Bazzoli F: Association of Helicobacter pylori infection with coronary heart disease. Study confirms previous findings. Br Med J 312:251, 1996 (letter)

    Google Scholar 

  45. Delaney BC, Hobbs FDR, Holder R: Association of Helicobacter pylori infection with coronary heart disease. Eradication of the infection on grounds of cardiovascular risk is not supported by current evidence. Br Med J 312:251–252, 1996 (letter)

    Google Scholar 

  46. Murray LJ, Bamford KB, O'Reilly DPJ, McCrum EE, Evans AE: Helicobacter pylori: Relation with cardiovascular risk factors, ischaemic heart disease, and social class. Br Heart J 74:497–501, 1995

    Google Scholar 

  47. McDonagh TA, Woodward M, Morrison C, McMurray J, Tunstall-Pedae H, Lowe GDO, Dargie HJ, McColl KEL: Lack of independent association of H. pylori and coronary heart disease. Gastroenterology 110(suppl):A190, 1996 (abstract)

    Google Scholar 

  48. Maier F, Auricchio A, Nilius M, Klein H, Malfertheiner P: Lack of association between Helicobacter pylori infection and angiographically documented coronary heart disease. Gastroenterology 110(suppl):A193, 1996 (abstract)

    Google Scholar 

  49. Khursid A, Puetz T, Fenske T, Bajwa T, Vakil N: Seroprevalence of Helicobacter pylori infection in patients with and without angiographic evidence of coronary heart disease. Gastroenterology 110(Suppl):A154, 1996 (abstract)

    Google Scholar 

  50. Sandifer Q, Vuilo S, Crompton G: Association of Helicobacter pylori infection with coronary heart disease. Association may not be crucial. Br Med J 312:251, 1996 (letter).

    Google Scholar 

Download references

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rudi, J., Kolb, C., Maiwald, M. et al. Serum Antibodies Against Helicobacter pylori Proteins VacA and CagA Are Associated with Increased Risk for Gastric Adenocarcinoma. Dig Dis Sci 42, 1652–1659 (1997). https://doi.org/10.1023/A:1018849112533

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1018849112533

Navigation