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Polymorphic Bacteria Persisting in Polymorphic Hosts: Assessing Helicobacter pylori-Related Risks for Gastric Cancer

Polymorphic Bacteria Persisting in Polymorphic Hosts: Assessing Helicobacter pylori-Related Risks... It is becoming increasingly evident that Helicobacter pylori have been normal inhabitants of the human stomach since the earliest times (1) and that, over the course of the twentieth century, H. pylori has been disappearing (2). Because large groups of people can be identified who either do or do not carry the organism, we now can assess the consequences of its presence (and absence). Such studies have shown that the presence of H. pylori is associated with the development of all of the important precursor lesions for adenocarcinoma of the stomach, including chronic gastritis, atrophic gastritis, and intestinal metaplasia and that, in consequence, it is the major risk factor for non-cardia gastric cancers (3,4). However, most H. pylori-positive individuals never develop gastric cancer (or peptic ulcer disease, for which it also is a risk factor). Why does illness develop in only some colonized individuals? Possible explanations include the characteristics of the colonizing H. pylori strains, the genotype of the host, exposure to environmental cofactors (e.g. those present in tobacco smoke or diet), or interactions among two or more of these factors. Discerning among these possibilities is important, because there also is increasing evidence that the absence of H. pylori may be associated with increased risks of diarrheal disease in children (5) and of reflux esophagitis and its sequelae—Barrett’s esophagus and adenocarcinoma of the esophagus—in adults (6–10). Because of these potential benefits, campaigns to rid humans of H. pylori may result in a rise in some illnesses as others are reduced. Nevertheless, because persistence of H. pylori is clearly involved in the pathogenesis of gastric cancer, medical scientists must be able to establish who is at greatest risk for the adverse consequences of this essentially lifelong colonization. In this issue of the Journal, Figueiredo and colleagues explored this problem (11). Beginning with a population that was H. pylori-positive, they sought to find modifying factors whose presence was associated with the diagnosis of gastric cancer. They examined bacterial genotypes that could be readily measured and for which prior work, including their own, suggested risk modification for gastric cancer (12–16). Similarly, they studied host genotypes previously shown to affect gastric cancer risk (17,18) and, importantly, also examined the interactions between microbial and host genotypes. In so doing, they both confirmed the prior work and extended our knowledge of gastric cancer risk factors, identifying combinations with lowest or highest risk, with 20- to 80-fold differences! The effect of combining several factors was synergistic, indicating the promise of such approaches. Why was this study so powerful? One reason may be that the markers that Figueiredo and colleagues assessed all relate to the intensity of gastric inflammation in H. pylori-positive individuals. The host factors studied relate to the functional activity of interleukin 1 (IL-1): IL-1β is a strongly pro-inflammatory cytokine and the IL-1 receptor antagonist binds competitively to IL-1 receptors (19). The genetic loci coding for these proteins and governing their expression are polymorphic, with phenotypic differences that are measurable. The H. pylori factors studied relate to the presence of the cag “pathogenicity” island and to the vacA genotype. Strains with the cag island inject the CagA protein into the gastric epithelium (20) and induce higher levels of pro-inflammatory cytokines (including IL-1β) (4), gastric inflammation (21), atrophic gastritis, and intestinal metaplasia (22). There are two major polymorphic sites within vacA, which encodes a vacuolating cytotoxin. These sites affect either the signal sequence (s region) or the middle of the protein (m region) (10). The vacAs genotype and cagA status are closely linked, and studies of these two markers may thus be examining the same phenomenon. The vacAm genotype, which is less closely linked to cag status, is also a marker of both inflammation and cancer risk (14,15). The findings of Figueiredo et al. (11) suggest that the interactions between these specific host and bacterial characteristics are biologically significant. Although the study is limited by its retrospective nature and by the multiple H. pylori strains colonizing some hosts, the findings are consistent with previous work and are biologically plausible. The data fit best with a negative-feedback (homeostatic) model, in which cross-signal-ing between the H. pylori (bacterial) populations and cells of the colonized host lead to a dynamic equilibrium (23). In this model, the specific bacterial and host genotypes influence the “gain” or amplitude of the interaction, with its secondary pathologic and tertiary clinical consequences. Although human genotypes do not vary over the course of a life, the H. pylori subpopulations within a host are complex and changing (24,25). Thus, although the work reported (11) must be considered a first approximation, the model may in fact be a general paradigm for tumors induced by microbes (26). For persistent, well-adapted microbes like H. pylori [or Epstein-Barr virus, for example (27)], specific combinations of microbial and host genotypes may shape the equilibrium in ways that augment or lessen risk of disease. Is the work by Figueiredo et al. (11) ready for the clinic? Although promising, it is still too early to generalize from this work. The study needs confirmation, different ethnic groups must be examined, the techniques must be simplified for general use, and our understanding of the risks and benefits of H. pylori must grow (28). In particular, the observations relating cagA and vacA genotypes to disease in the West are not clearly present in East Asia, because a preponderance of Asian strains carry the alleles most strongly associated with disease (29). However, Figueiredo’s work is a step in the right direction, and recent work has focused on other host polymorphisms in relation to H. pylori-associated diseases (30,31). Gastric adenocarcinoma remains one of the leading causes of cancer death in the world, and new approaches to its prevention are needed. Translational research that stratifies patients according to pathogenetically relevant factors, as done here, may also lead to new types of therapy. Because H. pylori are polymorphic, because subpopulations colonizing a host are ever changing in both phenotype and dominance (32), and because humans are genetically diverse and also show age-related accumulation of somatic mutations, the range of potential interactions is vast. Nevertheless, assessing risk for gastric diseases now is becoming a tractable problem and may ultimately prove to be a paradigm for other microbially induced diseases. As a co-discoverer of the cagA and vacA genes at Vanderbilt University, Dr. Blaser is eligible to receive royalty income for tests based on these discoveries. There is no commercially licensed test at present. Supported in part by grant R01GM63270 from the National Institutes of Health, and by the Senior Scholar Award in Infectious Diseases from the Ellison Medical Foundation. References 1 Ghose C, Perez-Perez GI, Dominguez-Bello MG, Pride DT, Bravi CM, Blaser MJ. East Asian genotypes of Helicobacter pylori strains in Amerindians provide evidence for its ancient human carriage. Proc Natl Acad Sci U S A. In press 2002. Google Scholar 2 Perez-Perez GI, Salomaa A, Kosunen TU, Daverman B, Rautelin H, Aromaa A, et al. Evidence that cagA+ Helicobacter pylori strains are disappearing more rapidly than cagA– strains. Gut  2002; 50: 295–8. Google Scholar 3 Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of twelve case-control studies nested within prospective cohorts. Gut  2001; 49: 347–53. Google Scholar 4 Peek RM, Blaser MJ. Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer  2002; 2: 28–37. Google Scholar 5 Rothenbacher D, Blaser MJ, Bode G, Brenner H. An inverse relationship between gastric colonization by Helicobacter pylori and diarrheal illnesses in children: results of a population-based cross-sectional study. J Infect Dis  2000; 182: 1446–9. Google Scholar 6 Vaezi MF, Falk GW, Peek RM, Vicari JJ, Goldblum JR, Perez-Perez GI, et al. cagA-positive strains of Helicobacter pylori may protect against Barrett’s esophagus. Am J Gastroenterol  2000; 95: 2206–11. Google Scholar 7 Quierioz DM, Rocha G, de Oliveira CA, Rocha AM, Santos A, Cabral MM, et al. Role of corpus gastritis and cagA-positive Helicobacter pylori infection in reflux esophagitis. J Clin Microbiol  2002; 40: 2849–53. Google Scholar 8 Warburton-Timms VJ, Charlett A, Valori RM, Uff JS, Shepherd NA, Barr H, et al. The significance of cagA+ Helicobacter pylori in reflux oesophagitis. Gut  2001; 49: 341–6. Google Scholar 9 Koike T, Ohara S, Sekine H, Iijima K, Abe Y, Kato K, et al. Helicobacter pylori infection prevents erosive reflux oesophagitis by decreasing gastric acid secretion. Gut  2001; 49: 330–4. Google Scholar 10 Chow WH, Blaser MJ, Blot WJ, Gammon MD, Vaughan TL, Risch HA, et al. An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma. Cancer Res  1998; 58: 588–90. Google Scholar 11 Figueiredo C, Machado JC, Pharoah P, Seruca R, Sousa S, Carvalho R, et al. Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. JNCI  2002; 94: 1680–7. Google Scholar 12 Blaser MJ, Perez-Perez GI, Kleanthous H, Cover TL, Peek RM, Chyou PH, et al. Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res  1995; 55: 2111–5. Google Scholar 13 Atherton JC, Cao P, Peek RM, Tummuru MK, Blaser MJ, Cover TL. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem  1995; 270: 17771–7. Google Scholar 14 Atherton JC, Peek RM, Tham KT, Cover TL, Blaser MJ. Clinical and pathological importance of heterogeneity in vacA, the vacuolating cytotoxin gene of Helicobacter pylori. Gastroenterology  1997; 112: 92–9. Google Scholar 15 Gerhard M, Lehn N, Neumayer N, Boren T, Rad R, Schepp W, et al. Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesion. Proc Natl Acad Sci U S A  1999; 96: 12778–83. Google Scholar 16 Nogueira C, Figueiredo C, Carneiro F, Taveira-Gomes A, Barreira R, Figueira P, et al. Helicobacter pylori genotypes may determine gastric histopathology. Am J Pathol  2001; 158: 647–54. Google Scholar 17 El Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature  2000; 404: 398–402. Google Scholar 18 Figueiredo C, van Doorn LJ, Nogueira C, Soares JM, Pinho C, Figueira P, et al. Helicobacter pylori genotypes are associated with clinical outcome in Portuguese patients and reveal a high prevalence of infections with multiple strains. Scand J Gastroenterol  2001; 36: 128–35. Google Scholar 19 El-Omar EM. The importance of interleukin 1 in Helicobacter pylori associated disease. Gut  2001; 48: 743–7. Google Scholar 20 Odenbreit S, Puls J, Sedlmaier B, Gerland E, Fischer W, Haas R. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science  2000; 287: 1497–500. Google Scholar 21 Crabtree JE, Farmery SM. Helicobacter pylori and gastric mucosal cytokines: evidence that cagA-positive strains are more virulent. Lab Invest  1995; 73: 742–5. Google Scholar 22 Kuipers EJ, Perez-Perez GI, Meuwissen SG, Blaser MJ. Helicobacter pylori and atrophic gastritis: importance of the cagA status. J Natl Cancer Inst  1995; 87: 1777–80. Google Scholar 23 Blaser MJ, Kirschner D. Dynamics of Helicobacter pylori colonization in relation to the host response. Proc Natl Acad Sci U S A  1999; 96: 8359–64. Google Scholar 24 Kuipers EJ, Israel DA, Kusters JG, Gerrits MM, Weel J, van der Ende A, et al. Quasispecies development of Helicobacter pylori observed in paired isolates obtained years apart in the same host. J Infect Dis  2000; 181: 273–82. Google Scholar 25 Israel DA, Salama N, Krishna U, Rieger UM, Atherton JC, Falkow S, et al. Helicobacter pylori genetic diversity within the gastric niche of a single human host. Proc Natl Acad Sci U S A  2001; 98: 14625–30. Google Scholar 26 Blaser MJ, Berg DE. Helicobacter pylori genetic diversity and risk of human disease. J Clin Invest  2001; 107: 767–73. Google Scholar 27 Wu MS, Huang SP, Chang YT, Shun CT, Chang MC, Lin MT, et al. Tumor necrosis factor- and interleukin-10 promoter polymorphisms in Epstein-Barr virus-associated gastric carcinoma. J Infect Dis  2002; 185: 106–9. Google Scholar 28 Blaser MJ. The changing relationships of Helicobacter pylori and humans: implications for health and disease. J Infect Dis  1999; 179: 1523–30. Google Scholar 29 Maeda S, Ogura K, Yoshida H, Kanai F, Ikenoue T, Kato N, et al. Major virulence factors, VacA and CagA, are commonly positive in Helicobacter pylori isolates in Japan. Gut  1998; 42: 338–43. Google Scholar 30 Yea SS, Yang YI, Jang WH, Lee YJ, Bae HS, Paik KH. Association between TNF-alpha promoter polymorphism and Helicobacter pylori cagA subtype infection. J Clin Pathol  2001; 54: 703–6. Google Scholar 31 Hiyama T, Tanaka S, Kitadai Y, Ito M, Sumii M, Yoshihara M, et al. p53 codon 72 polymorphism in gastric cancer susceptibility in patients with Helicobacter pylori associated chronic gastritis. Int J Cancer  2002; 100: 304–8. Google Scholar 32 Webb GF, Blaser MJ. Dynamics of bacterial phenotype selection in a colonized host. Proc Natl Acad Sci U S A  2002; 99: 3135–40. Google Scholar © Oxford University Press http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI: Journal of the National Cancer Institute Oxford University Press

Polymorphic Bacteria Persisting in Polymorphic Hosts: Assessing Helicobacter pylori-Related Risks for Gastric Cancer

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References (34)

Publisher
Oxford University Press
Copyright
© Oxford University Press
ISSN
0027-8874
eISSN
1460-2105
DOI
10.1093/jnci/94.22.1662
Publisher site
See Article on Publisher Site

Abstract

It is becoming increasingly evident that Helicobacter pylori have been normal inhabitants of the human stomach since the earliest times (1) and that, over the course of the twentieth century, H. pylori has been disappearing (2). Because large groups of people can be identified who either do or do not carry the organism, we now can assess the consequences of its presence (and absence). Such studies have shown that the presence of H. pylori is associated with the development of all of the important precursor lesions for adenocarcinoma of the stomach, including chronic gastritis, atrophic gastritis, and intestinal metaplasia and that, in consequence, it is the major risk factor for non-cardia gastric cancers (3,4). However, most H. pylori-positive individuals never develop gastric cancer (or peptic ulcer disease, for which it also is a risk factor). Why does illness develop in only some colonized individuals? Possible explanations include the characteristics of the colonizing H. pylori strains, the genotype of the host, exposure to environmental cofactors (e.g. those present in tobacco smoke or diet), or interactions among two or more of these factors. Discerning among these possibilities is important, because there also is increasing evidence that the absence of H. pylori may be associated with increased risks of diarrheal disease in children (5) and of reflux esophagitis and its sequelae—Barrett’s esophagus and adenocarcinoma of the esophagus—in adults (6–10). Because of these potential benefits, campaigns to rid humans of H. pylori may result in a rise in some illnesses as others are reduced. Nevertheless, because persistence of H. pylori is clearly involved in the pathogenesis of gastric cancer, medical scientists must be able to establish who is at greatest risk for the adverse consequences of this essentially lifelong colonization. In this issue of the Journal, Figueiredo and colleagues explored this problem (11). Beginning with a population that was H. pylori-positive, they sought to find modifying factors whose presence was associated with the diagnosis of gastric cancer. They examined bacterial genotypes that could be readily measured and for which prior work, including their own, suggested risk modification for gastric cancer (12–16). Similarly, they studied host genotypes previously shown to affect gastric cancer risk (17,18) and, importantly, also examined the interactions between microbial and host genotypes. In so doing, they both confirmed the prior work and extended our knowledge of gastric cancer risk factors, identifying combinations with lowest or highest risk, with 20- to 80-fold differences! The effect of combining several factors was synergistic, indicating the promise of such approaches. Why was this study so powerful? One reason may be that the markers that Figueiredo and colleagues assessed all relate to the intensity of gastric inflammation in H. pylori-positive individuals. The host factors studied relate to the functional activity of interleukin 1 (IL-1): IL-1β is a strongly pro-inflammatory cytokine and the IL-1 receptor antagonist binds competitively to IL-1 receptors (19). The genetic loci coding for these proteins and governing their expression are polymorphic, with phenotypic differences that are measurable. The H. pylori factors studied relate to the presence of the cag “pathogenicity” island and to the vacA genotype. Strains with the cag island inject the CagA protein into the gastric epithelium (20) and induce higher levels of pro-inflammatory cytokines (including IL-1β) (4), gastric inflammation (21), atrophic gastritis, and intestinal metaplasia (22). There are two major polymorphic sites within vacA, which encodes a vacuolating cytotoxin. These sites affect either the signal sequence (s region) or the middle of the protein (m region) (10). The vacAs genotype and cagA status are closely linked, and studies of these two markers may thus be examining the same phenomenon. The vacAm genotype, which is less closely linked to cag status, is also a marker of both inflammation and cancer risk (14,15). The findings of Figueiredo et al. (11) suggest that the interactions between these specific host and bacterial characteristics are biologically significant. Although the study is limited by its retrospective nature and by the multiple H. pylori strains colonizing some hosts, the findings are consistent with previous work and are biologically plausible. The data fit best with a negative-feedback (homeostatic) model, in which cross-signal-ing between the H. pylori (bacterial) populations and cells of the colonized host lead to a dynamic equilibrium (23). In this model, the specific bacterial and host genotypes influence the “gain” or amplitude of the interaction, with its secondary pathologic and tertiary clinical consequences. Although human genotypes do not vary over the course of a life, the H. pylori subpopulations within a host are complex and changing (24,25). Thus, although the work reported (11) must be considered a first approximation, the model may in fact be a general paradigm for tumors induced by microbes (26). For persistent, well-adapted microbes like H. pylori [or Epstein-Barr virus, for example (27)], specific combinations of microbial and host genotypes may shape the equilibrium in ways that augment or lessen risk of disease. Is the work by Figueiredo et al. (11) ready for the clinic? Although promising, it is still too early to generalize from this work. The study needs confirmation, different ethnic groups must be examined, the techniques must be simplified for general use, and our understanding of the risks and benefits of H. pylori must grow (28). In particular, the observations relating cagA and vacA genotypes to disease in the West are not clearly present in East Asia, because a preponderance of Asian strains carry the alleles most strongly associated with disease (29). However, Figueiredo’s work is a step in the right direction, and recent work has focused on other host polymorphisms in relation to H. pylori-associated diseases (30,31). Gastric adenocarcinoma remains one of the leading causes of cancer death in the world, and new approaches to its prevention are needed. Translational research that stratifies patients according to pathogenetically relevant factors, as done here, may also lead to new types of therapy. Because H. pylori are polymorphic, because subpopulations colonizing a host are ever changing in both phenotype and dominance (32), and because humans are genetically diverse and also show age-related accumulation of somatic mutations, the range of potential interactions is vast. Nevertheless, assessing risk for gastric diseases now is becoming a tractable problem and may ultimately prove to be a paradigm for other microbially induced diseases. As a co-discoverer of the cagA and vacA genes at Vanderbilt University, Dr. Blaser is eligible to receive royalty income for tests based on these discoveries. There is no commercially licensed test at present. Supported in part by grant R01GM63270 from the National Institutes of Health, and by the Senior Scholar Award in Infectious Diseases from the Ellison Medical Foundation. References 1 Ghose C, Perez-Perez GI, Dominguez-Bello MG, Pride DT, Bravi CM, Blaser MJ. East Asian genotypes of Helicobacter pylori strains in Amerindians provide evidence for its ancient human carriage. Proc Natl Acad Sci U S A. In press 2002. Google Scholar 2 Perez-Perez GI, Salomaa A, Kosunen TU, Daverman B, Rautelin H, Aromaa A, et al. Evidence that cagA+ Helicobacter pylori strains are disappearing more rapidly than cagA– strains. Gut  2002; 50: 295–8. Google Scholar 3 Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of twelve case-control studies nested within prospective cohorts. Gut  2001; 49: 347–53. Google Scholar 4 Peek RM, Blaser MJ. Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer  2002; 2: 28–37. Google Scholar 5 Rothenbacher D, Blaser MJ, Bode G, Brenner H. An inverse relationship between gastric colonization by Helicobacter pylori and diarrheal illnesses in children: results of a population-based cross-sectional study. J Infect Dis  2000; 182: 1446–9. Google Scholar 6 Vaezi MF, Falk GW, Peek RM, Vicari JJ, Goldblum JR, Perez-Perez GI, et al. cagA-positive strains of Helicobacter pylori may protect against Barrett’s esophagus. Am J Gastroenterol  2000; 95: 2206–11. Google Scholar 7 Quierioz DM, Rocha G, de Oliveira CA, Rocha AM, Santos A, Cabral MM, et al. Role of corpus gastritis and cagA-positive Helicobacter pylori infection in reflux esophagitis. J Clin Microbiol  2002; 40: 2849–53. Google Scholar 8 Warburton-Timms VJ, Charlett A, Valori RM, Uff JS, Shepherd NA, Barr H, et al. The significance of cagA+ Helicobacter pylori in reflux oesophagitis. Gut  2001; 49: 341–6. Google Scholar 9 Koike T, Ohara S, Sekine H, Iijima K, Abe Y, Kato K, et al. Helicobacter pylori infection prevents erosive reflux oesophagitis by decreasing gastric acid secretion. Gut  2001; 49: 330–4. Google Scholar 10 Chow WH, Blaser MJ, Blot WJ, Gammon MD, Vaughan TL, Risch HA, et al. An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma. Cancer Res  1998; 58: 588–90. Google Scholar 11 Figueiredo C, Machado JC, Pharoah P, Seruca R, Sousa S, Carvalho R, et al. Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. JNCI  2002; 94: 1680–7. Google Scholar 12 Blaser MJ, Perez-Perez GI, Kleanthous H, Cover TL, Peek RM, Chyou PH, et al. Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res  1995; 55: 2111–5. Google Scholar 13 Atherton JC, Cao P, Peek RM, Tummuru MK, Blaser MJ, Cover TL. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem  1995; 270: 17771–7. Google Scholar 14 Atherton JC, Peek RM, Tham KT, Cover TL, Blaser MJ. Clinical and pathological importance of heterogeneity in vacA, the vacuolating cytotoxin gene of Helicobacter pylori. Gastroenterology  1997; 112: 92–9. Google Scholar 15 Gerhard M, Lehn N, Neumayer N, Boren T, Rad R, Schepp W, et al. Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesion. Proc Natl Acad Sci U S A  1999; 96: 12778–83. Google Scholar 16 Nogueira C, Figueiredo C, Carneiro F, Taveira-Gomes A, Barreira R, Figueira P, et al. Helicobacter pylori genotypes may determine gastric histopathology. Am J Pathol  2001; 158: 647–54. Google Scholar 17 El Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature  2000; 404: 398–402. Google Scholar 18 Figueiredo C, van Doorn LJ, Nogueira C, Soares JM, Pinho C, Figueira P, et al. Helicobacter pylori genotypes are associated with clinical outcome in Portuguese patients and reveal a high prevalence of infections with multiple strains. Scand J Gastroenterol  2001; 36: 128–35. Google Scholar 19 El-Omar EM. The importance of interleukin 1 in Helicobacter pylori associated disease. Gut  2001; 48: 743–7. Google Scholar 20 Odenbreit S, Puls J, Sedlmaier B, Gerland E, Fischer W, Haas R. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science  2000; 287: 1497–500. Google Scholar 21 Crabtree JE, Farmery SM. Helicobacter pylori and gastric mucosal cytokines: evidence that cagA-positive strains are more virulent. Lab Invest  1995; 73: 742–5. Google Scholar 22 Kuipers EJ, Perez-Perez GI, Meuwissen SG, Blaser MJ. Helicobacter pylori and atrophic gastritis: importance of the cagA status. J Natl Cancer Inst  1995; 87: 1777–80. Google Scholar 23 Blaser MJ, Kirschner D. Dynamics of Helicobacter pylori colonization in relation to the host response. Proc Natl Acad Sci U S A  1999; 96: 8359–64. Google Scholar 24 Kuipers EJ, Israel DA, Kusters JG, Gerrits MM, Weel J, van der Ende A, et al. Quasispecies development of Helicobacter pylori observed in paired isolates obtained years apart in the same host. J Infect Dis  2000; 181: 273–82. Google Scholar 25 Israel DA, Salama N, Krishna U, Rieger UM, Atherton JC, Falkow S, et al. Helicobacter pylori genetic diversity within the gastric niche of a single human host. Proc Natl Acad Sci U S A  2001; 98: 14625–30. Google Scholar 26 Blaser MJ, Berg DE. Helicobacter pylori genetic diversity and risk of human disease. J Clin Invest  2001; 107: 767–73. Google Scholar 27 Wu MS, Huang SP, Chang YT, Shun CT, Chang MC, Lin MT, et al. Tumor necrosis factor- and interleukin-10 promoter polymorphisms in Epstein-Barr virus-associated gastric carcinoma. J Infect Dis  2002; 185: 106–9. Google Scholar 28 Blaser MJ. The changing relationships of Helicobacter pylori and humans: implications for health and disease. J Infect Dis  1999; 179: 1523–30. Google Scholar 29 Maeda S, Ogura K, Yoshida H, Kanai F, Ikenoue T, Kato N, et al. Major virulence factors, VacA and CagA, are commonly positive in Helicobacter pylori isolates in Japan. Gut  1998; 42: 338–43. Google Scholar 30 Yea SS, Yang YI, Jang WH, Lee YJ, Bae HS, Paik KH. Association between TNF-alpha promoter polymorphism and Helicobacter pylori cagA subtype infection. J Clin Pathol  2001; 54: 703–6. Google Scholar 31 Hiyama T, Tanaka S, Kitadai Y, Ito M, Sumii M, Yoshihara M, et al. p53 codon 72 polymorphism in gastric cancer susceptibility in patients with Helicobacter pylori associated chronic gastritis. Int J Cancer  2002; 100: 304–8. Google Scholar 32 Webb GF, Blaser MJ. Dynamics of bacterial phenotype selection in a colonized host. Proc Natl Acad Sci U S A  2002; 99: 3135–40. Google Scholar © Oxford University Press

Journal

JNCI: Journal of the National Cancer InstituteOxford University Press

Published: Nov 20, 2002

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