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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Gastric inflammation and cell proliferation
  5. Multistep process of intestinal type gastric cancer ‘correa's model’
  6. Chronic atrophic gastritis
  7. Intestinal metaplasia
  8. Dysplasia
  9. Are precancerous lesions reversible?
  10. Helicobacter pylori and diffuse type gastric cancer
  11. Molecular alteration pathways
  12. Conclusions
  13. Acknowledgements
  14. References

Gastric cancer can be divided into intestinal type and diffuse type that differ substantially in epidemiology and pathogenesis. The most important aetiological factor associated both with intestinal and diffuse gastric cancer, is Helicobacter pylori.

Exposure of gastric epithelial cells to H. pylori results in an inflammatory reaction with the production of reactive oxygen species and nitric oxide that, in turn, deaminates DNA causing mutations. The complex interplay between H. pylori strain, inflammation and host characteristics may directly promote diffuse type gastric cancer or induce a cascade of morphological events, i.e. atrophy, intestinal metaplasia and dysplasia, finally leading to intestinal type gastric cancer. Two mechanisms, genetic and epigenetic have been held to play a role in the molecular alterations underlying gastric carcinogenesis. The former, comprising changes in the DNA sequence, is irreversible; the latter, involving DNA methylation, is potentially reversible by eliminating the triggering agents. If H. pylori is eradicated before development of stable mutations, the risk of gastric cancer will likely be prevented. Thus, eradication of H. pylori might immediately reduce the risk of diffuse type gastric cancer, whereas prevention of intestinal type gastric cancer may be less effective if patients are treated later in the evolution of the carcinogenic process.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Gastric inflammation and cell proliferation
  5. Multistep process of intestinal type gastric cancer ‘correa's model’
  6. Chronic atrophic gastritis
  7. Intestinal metaplasia
  8. Dysplasia
  9. Are precancerous lesions reversible?
  10. Helicobacter pylori and diffuse type gastric cancer
  11. Molecular alteration pathways
  12. Conclusions
  13. Acknowledgements
  14. References

Despite the decreasing incidence and mortality rates observed worldwide over the last 50 years, gastric cancer (GC) still ranks as a leading cause of cancer-related deaths in many parts of the world.1 After lung cancer, GC kills more people than any other malignant tumour. The American Cancer Society reported about 800 000 new cases and more than 600 000 people died of GC, in 2000, estimating that the 5-year relative survival rate is <20%.2

Gastric cancers are often resistant to radio- and chemotherapy and, indeed, surgery represents the only treatment with a curative potential. However, two-thirds of Western GC patients are still diagnosed in advanced stages, when surgery can be only palliative.3 The only exception to these dismal statistics is Japan where, for various reasons, the condition is often identified at an early stage, and in younger and fitter patients.4 GC still remains a major clinical challenge and a public health concern.5, 6 At present, primary or secondary prevention are likely to be the most effective means of reducing the incidence and mortality from this disease. However, to be successful, this strategy depends upon knowledge of the aetiological factors and pathogenetic mechanisms involved in gastric carcinogenesis.

Over the last few years, it has become apparent that the most important single factor responsible for the development of GC is Helicobacter pylori infection which affects more than 50% of the world population.7, 8 The risk of patients with H. pylori infection developing GC is in the order of two- to sixfold according to most retrospective, case–control, and prospective epidemiological studies.9–13 However, if the selection of patients and methodology is optimized the risk increases to 20 times.14, 15Helicobacter pylori colonizes the gastric epithelium inducing an inflammatory reaction that may persist throughout the patient's life despite a strong local immune reaction.16 The extent and severity of gastric mucosal inflammation, as well as the clinical outcome of the infection depend on a number of factors including the virulence of the bacterium, host genetic susceptibility, immune response, age at the time of initial infection and environmental factors.16 The complex interplay between these factors may explain why only a minority (<1%) of those infected ultimately develop GC.17

The multistep process starts with H. pylori-related inflammatory reaction, thereafter progressing through a cascade of molecular and morphological changes.17

Histologically, gastric adenocarcinoma is prevalently divided into two types according to Lauren's classification.18 The intestinal type consists of a gland-like structure that mimics the intestinal glands, and recognizes a series of precancerous lesions. The diffuse type, more prevalent in females younger than 50 years, lacks any glandular structure and arises closer to the advancing border of inflammation but without any identifiable histological precursor lesion.19 The intestinal and the diffuse types of GC both show an equally strong association with H. pylori infection.10

The aim of the present review is to provide a comprehensive examination of precancerous gastric lesions and the underlying molecular alterations, focusing on the role of H. pylori infection.

Gastric inflammation and cell proliferation

  1. Top of page
  2. Summary
  3. Introduction
  4. Gastric inflammation and cell proliferation
  5. Multistep process of intestinal type gastric cancer ‘correa's model’
  6. Chronic atrophic gastritis
  7. Intestinal metaplasia
  8. Dysplasia
  9. Are precancerous lesions reversible?
  10. Helicobacter pylori and diffuse type gastric cancer
  11. Molecular alteration pathways
  12. Conclusions
  13. Acknowledgements
  14. References

Exposure of gastric epithelial cells to H. pylori results in an inflammatory reaction with the generation of reactive oxygen species (ROS) and an increased level of nitric oxide (NO) synthase.20–22 NO synthase deaminates DNA and causes mutations which may be the initial step in the genetic alterations of gastric epithelial cells.17, 23, 24 Higher concentrations of 8-hydroxydeoxy-guanosine (8-OH-dG), a well-known marker of oxidative DNA stress, have been reported in H. pylori-positive patients with atrophic gastritis and intestinal metaplasia (IM).25 Furthermore, ROS and NO increase cell proliferation.21 The dynamic balance between cell proliferation and apoptosis is essential for maintaining normal mucosal integrity.21 Sustained stimulation of apoptosis could ultimately result in excessive cell loss and ulcer development, while inhibition of apoptosis has been reported to be associated with the early phases of carcinogenesis.26–28 Prolonged survival of abnormal cells can favour the accumulation of sequential genetic mutations that would result in tumour promotion.20, 21 Moss et al. reported an increased rate of cell proliferation and a decrease in the apoptotic index in H. pylori infection.21 Increased proliferation of epithelial cells is an early event observed during H. pylori infection.

The expression of c-fos (mRNA and protein), which regulates the transcription of genes related to cell cycle control was significantly higher in the H. pylori-infected mucosa than in normal mucosa and in precancerous lesions.29 Cyclo-oxygenase-2 (COX-2) interferes with the balance between cell proliferation and apoptosis,30 and is also abnormally expressed in the H. pylori-infected mucosa.31–35 Overexpression of COX-2 has been detected in H. pylori-positive gastritis, in precancerous lesions and in GC, suggesting an early role of COX-2 in gastric carcinogenesis.31–35 A positive correlation between COX-2 expression and the Ki-67 labelling index, as well as an inverse correlation between COX-2 expression and the apoptosis index have been demonstrated.34

Multistep process of intestinal type gastric cancer ‘correa's model’

  1. Top of page
  2. Summary
  3. Introduction
  4. Gastric inflammation and cell proliferation
  5. Multistep process of intestinal type gastric cancer ‘correa's model’
  6. Chronic atrophic gastritis
  7. Intestinal metaplasia
  8. Dysplasia
  9. Are precancerous lesions reversible?
  10. Helicobacter pylori and diffuse type gastric cancer
  11. Molecular alteration pathways
  12. Conclusions
  13. Acknowledgements
  14. References

According to Correa, intestinal type GC may be considered a multistep process starting from chronic gastritis and progressing through chronic atrophic gastritis, IM and dysplasia.17 This sequence is usually triggered by H. pylori infection and affected by a variety of genetic and environmental factors that may act synergistically.36

Chronic atrophic gastritis

  1. Top of page
  2. Summary
  3. Introduction
  4. Gastric inflammation and cell proliferation
  5. Multistep process of intestinal type gastric cancer ‘correa's model’
  6. Chronic atrophic gastritis
  7. Intestinal metaplasia
  8. Dysplasia
  9. Are precancerous lesions reversible?
  10. Helicobacter pylori and diffuse type gastric cancer
  11. Molecular alteration pathways
  12. Conclusions
  13. Acknowledgements
  14. References

Long-standing H. pylori-induced gastric inflammation often leads to atrophic gastritis which is considered the first important step in the histogenesis of GC.17 In a large population study on 2455 subjects in Japan, Asaka reported gastric atrophy in 80% of H. pylori-infected patients compared with 10% of H. pylori-negative patients.37 According to previous European studies, the overall prevalence of gastric atrophy, in asymptomatic adults, ranges from 22 to −37%, with a GC incidence ranging from 7 to −13%, in patients with chronic atrophic gastritis, after a follow-up of more than 11 years.38, 39 Recently, observing 5375 subjects for a 10-year follow-up period, 117 GCs were identified. The risk of GC was greatest among the subjects with moderate atrophy at baseline (HR: 2.22; 95% CI: 1.08–4.58) and 4–6 years of follow-up (HR: 4.6–5.0).40

Gastric atrophy, particularly when it affects a large part of the gastric body, is associated with acid hyposecretion and impaired pepsinogen levels.41 The low acidity of the gastric juice will, moreover, allow colonization with other bacteria, that, in turn, may promote the formation of carcinogenic factors, i.e. N-nitroso formation, inducing cellular DNA methylation.36, 42 This finding is particularly important since in chronic atrophic gastritis, the increased proliferation of mucosal epithelium, results in the presence of relatively immature cells in the glands.43 Ornithine decarboxylase (ODC), the first and rate-limiting enzyme in the biosynthesis of polyamines, is required for normal and neoplastic growth.44, 45 ODC is up-regulated by H. pylori and strongly expressed in atrophic and IM areas.46, 47 Therefore, the expression of ODC may be considered an important marker of premalignancy in the stomach.46

Intestinal metaplasia

  1. Top of page
  2. Summary
  3. Introduction
  4. Gastric inflammation and cell proliferation
  5. Multistep process of intestinal type gastric cancer ‘correa's model’
  6. Chronic atrophic gastritis
  7. Intestinal metaplasia
  8. Dysplasia
  9. Are precancerous lesions reversible?
  10. Helicobacter pylori and diffuse type gastric cancer
  11. Molecular alteration pathways
  12. Conclusions
  13. Acknowledgements
  14. References

Chronic atrophic gastritis is often associated with IM, both lesions being closely related to H. pylori infection.17, 48, 49 Indeed, the prevalence of IM was significantly higher in H. pylori-positive (43%) than in H. pylori-negative subjects (6.2%).37 In Japan, using a GC index, IM was the only criterion associated with the development of intestinal type GC.50

Intestinal metaplasia has been classified according to Jass and Filipe as complete or type I, or incomplete which comprises types II and III.51 The expression of mucin core proteins (MUC) differs in the different types of IM. Whilst all types showed de novo expression of MUC2, the expression of MUC1, MUC5AC and MUC6 was decreased in the complete type of IM and preserved in the incomplete type.52, 53

Based on retrospective data, the risk of GC is related to the type of IM.54, 55 In a 10-year follow-up study from Slovenia, patients with IM showed an overall 10-fold increased risk of GC compared with those without IM.54 In another study, the risk of GC was fourfold higher in patients with IM type III than in those with type I.56 In a cohort study of 4655 healthy asymptomatic subjects observed for a mean period of 7.7 years, the risk of GC increased in a stepwise fashion from H. pylori-positive chronic gastritis group (HR: 7.13; 95% CI: 0.95–53.33) to H. pylori-positive chronic atrophic gastritis group (HR: 14.85; 95% CI: 1.96–107.7) and finally to severe chronic atrophic gastritis with extensive IM (HR: 61.85; 95% CI: 5.6–682.64).57 The association between the risk of GC development and IM subtypes is, however, not universally accepted. Cassaro et al. have recently shown that IM involving the lesser curvature, from the cardia to the pylorus, or the entire stomach, was associated with a higher risk of GC than focal or antral predominant IM.58 Thus, the distribution of IM rather than IM subtype may provide a higher predictive value of cancer risk. Molecular alterations could be involved in the progression of IM to GC.59–64 The pattern of gene expression determining the cell phenotype is under the control of a complex hierarchy of transcription factors of which homeodomain proteins are important members.65CDX1 and CDX2, homeobox genes are intestinal transcription factors regulating the proliferation and differentiation of intestinal epithelial cells.65 CDX1 and CDX2 proteins are expressed predominantly in the small intestine and colon but not in the normal adult stomach.65 In a recent study from Japan, CDX2 expression was found in patients with chronic gastritis closely associated with IM.66

Telomerases, generally activated in GC, were reported to be elevated in 18% (eight of 43) of patients with type III IM.60 Microsatellite instability (MSI) can be detected in IM obtained both from cancer and non-cancer patients thus suggesting that MSI may be an early event in the multistep progression of GC.61, 67, 68 Accumulation or mutations of the p53 protein have been demonstrated in IM, particularly in type III and in IM areas adjacent to GC.63, 69–71 Overexpression of COX-2 and cyclin D2 and decreased p27 expression, all involved in cell cycle regulation, were detected in H. pylori-associated IM (Table 1).33, 35, 64 Interestingly, type III IM, carrying a higher risk for GC, is that harbouring more numerous genetic changes than type I or II IM.67, 69–72

Table 1.  Molecular changes in precancerous gastric lesions
GeneMolecular changeStudyAtrophy (%)IM (%)Dysplasia (%)Reference
  1. ODC, ornithine decarboxylase; MSI, microsatellite instability; LOH, loss of heterozygosity; IM, intestinal metaplasia; COX-2, cyclo-oxygenase-2.

ODCUp-regulationHuman8544
COX-2Up-regulationHuman65–10010010031–35
KRASMutationHuman19.459
TelomeraseUp-regulationHuman1860
MSIInstabilityHuman2661
p53MutationHuman37.558.371
p53Up-regulationHuman300–301563, 69, 70
c-mycUp-regulationHuman15335069
Cyclin DUp-regulationHuman2064
p27Down-regulationHuman45.864
APC/MCCLOHHuman253179

Dysplasia

  1. Top of page
  2. Summary
  3. Introduction
  4. Gastric inflammation and cell proliferation
  5. Multistep process of intestinal type gastric cancer ‘correa's model’
  6. Chronic atrophic gastritis
  7. Intestinal metaplasia
  8. Dysplasia
  9. Are precancerous lesions reversible?
  10. Helicobacter pylori and diffuse type gastric cancer
  11. Molecular alteration pathways
  12. Conclusions
  13. Acknowledgements
  14. References

The next step in the cascade of morphological changes in gastric carcinogenesis is dysplasia that usually develops in the IM setting.17 This process includes a continuum of progressively dedifferentiated phenotypes which may result in a new cell. According to the definition of the World Health Organization, dysplasia is now called non-invasive gastric neoplasia, indicating a preinvasive neoplastic change in the gastric glands.73 In dysplasia, cellular morphology is characterized by uncontrolled growth and the potential to migrate and implant in other areas. The higher the grade of dysplasia, the greater the risk of developing invasive GC.74Helicobacter pylori is clearly associated with the progressive development of metaplastic changes.75

From a molecular viewpoint, dysplastic cells are endowed with an increased amount of DNA, partly due to the increased number of proliferating cells. A mixture of polyploidy and aneuploidy cells, in high grade dysplasia, has been demonstrated.76, 77 Several markers, such as APC/MCC loss of heterozygosity, carcinoembryonic antigen, p21ras, tumour suppressor gene p53 and the apoptosis inhibitor bcl-2 gene, which are overexpressed in GC, have also been detected in dysplastic areas.63, 69, 70, 78, 79 According to our current understanding, dysplastic cells resemble malignant cells, and, in fact, may sometimes already be malignant. The majority of carcinoma found in follow-up studies and which were discovered within 1 year of the diagnosis of dysplasia may indicate that the carcinoma was already present at the time of diagnosis of dysplasia.36

Are precancerous lesions reversible?

  1. Top of page
  2. Summary
  3. Introduction
  4. Gastric inflammation and cell proliferation
  5. Multistep process of intestinal type gastric cancer ‘correa's model’
  6. Chronic atrophic gastritis
  7. Intestinal metaplasia
  8. Dysplasia
  9. Are precancerous lesions reversible?
  10. Helicobacter pylori and diffuse type gastric cancer
  11. Molecular alteration pathways
  12. Conclusions
  13. Acknowledgements
  14. References

The risk of GC is related to the severity and extent of atrophy, IM and dysplasia. Helicobacter pylori is the initial triggering factor but its role in further progression is still uncertain. This leads to the critical question of whether eradication of H. pylori can reverse these precancerous lesions and thus interrupt the gastric carcinogenic process. Many studies have focused on the issue of reversibility and the results have been controversial.80–85

In a randomized 1-year follow-up study, H. pylori eradication was beneficial in preventing progression of atrophy and IM of the gastric mucosa.80 The same author confirmed these results at 5-year follow-up.49 In a prospective study, there was no significant change in antral IM during 4-year follow-up, although antral atrophy decreased significantly.81 Ito et al., in a 5-year prospective study of 22 patients, found that both gastric atrophy and IM were reversible events, in some patients.82 Recently, Hojo et al. have evaluated indexed literature on the effects of H. pylori cure on the dynamics of gastric atrophy and/or IM from 1992 to June 2001.85 Focusing on the changes in atrophy, 11 of 25 reports, described a significant improvement, one reported a significant worsening and the remaining 13 found no significant change. On the contrary, of 28 studies focusing on IM changes, only four described a significant improvement. We have updated the literature reports, on this issue, until February 200486–96, but no significant changes were observed with respect to the previous findings (Table 2). A review of data collected only from Japan, revealed that there were more studies showing regression following eradication than progression.93

Table 2.  Histopathological changes in atrophy and intestinal metaplasia following Helicobacter pylori eradication: review of 12 years (1992–2004)
 Reports (N)Patients (N)Follow-up (months range)Significant improvementNo significant changesSignificant aggravation
  1. IM, intestinal metaplasia.

Atrophy3419051–8418151
IM3419611–846271

To fully understand the effect of eradication therapy, diet style should be taken into account. Indeed, in an Italian study, co-administration of ascorbic acid with H. pylori eradication led to a significant improvement in IM of the gastric mucosa.94 Likewise, Correa, in Columbia, has shown that effective anti-H. pylori treatment and dietary supplementation, with antioxidant micronutrients, have a similar beneficial effect with regression of cancer precursor lesions.95 Finally, in a recent large population-based prospective study with a 10-year follow-up, vegetable and fruit intake, even in low amounts, was associated with a lower risk of GC.96

A critical revision of the data obtained from various studies raises major questions: (i) How representative are the studies? (ii) How accurate is the diagnosis of atrophy? (iii) What is the biological function of molecular markers in preneoplastic lesions?

Selection of study population, age of patients, genetic make-up of the host, H. pylori strains, and diet, together with biopsy protocols and follow-up time account for major differences that may explain the significant discrepancies between the data emerging from the various studies.83 The literature is largely biased by the inconsistency of the histological criteria used to classify atrophy, particularly when inflammatory infiltrate is present.97–99 Furthermore, a large study from Houston showed that IM was missed in more than 50% of biopsies from patients with confirmed IM on multiple site sampling.100 Moreover, major differences exist between the Western and Japanese systems as far as concerns terminology and definition of dysplasia.101

Atrophy is defined as the loss of specialized glands as a result of a prolonged inflammatory process. There are two principal pathways leading to atrophy, one in which the stem cell compartment and/or glands are destroyed and the second in which the selective destruction of specialized epithelial cells occurs with preservation of stem cells.102 If the stem cell compartment is preserved by the inflammatory process, the removal of the injurious factor, i.e. H. pylori could lead to regeneration of parietal and chief cells with full restoration of function. In contrast, if glands and their associated stem cells have been completely destroyed, regeneration of parietal cells is impossible.102

Intestinal metaplasia represents a non-neoplastic change in cell phenotype which is usually a result of selection pressures exerted by the modified microenvironment.103 Cytokines from chronic inflammatory cells and, in particular, Th2 helper lymphomonocytes may be responsible for adaptive IM in H. pylori infection.104 IM is more likely to be reversible if it develops as an adaptation to an adverse factor that can be identified and removed. However, the change in phenotype is either a consequence of genetic mutations in stem cells or of epigenetic events which produce divergent differentiation in progeny cells.102 If IM is a consequence of stable genetic mutations in stem cells, changes in the immediate mucosal environment are unlikely to lead to reversal of IM. Genetic stable mutations, generally found in type III IM, are similar to those found in gastric dysplasia, while epigenetic mutations are detected in all types of IM.105

In the attempt to overcome the discrepancies regarding gastric dysplasia, a consensus was held in Vienna in 1998.106 Gastric dysplasia, now defined as ‘non-invasive neoplasia’ is classified in a five-tier system: (i) negative for neoplasia/dysplasia; (ii) indefinite for neoplasia/dysplasia; (iii) non-invasive neoplasia, low grade; (iv) non-invasive neoplasia, high grade, and (v) invasive neoplasia. In agreement with this classification, a recent long-term prospective follow-up study on the clinico-pathological outcome of gastric dysplasia, confirmed that high-grade dysplasia never regresses. Lesions, indefinite for dysplasia, are the only entities suitable for regression after eradication therapy. This may be explained by the fact that lowering the inflammatory infiltrate of the gastric mucosa, the regenerative epithelial changes may regress.107

Helicobacter pylori and diffuse type gastric cancer

  1. Top of page
  2. Summary
  3. Introduction
  4. Gastric inflammation and cell proliferation
  5. Multistep process of intestinal type gastric cancer ‘correa's model’
  6. Chronic atrophic gastritis
  7. Intestinal metaplasia
  8. Dysplasia
  9. Are precancerous lesions reversible?
  10. Helicobacter pylori and diffuse type gastric cancer
  11. Molecular alteration pathways
  12. Conclusions
  13. Acknowledgements
  14. References

Diffuse GC, often associated with familial distribution, is more prevalent in younger women and blood group A patients.108 The cancer develops in the stomach following chronic inflammation without passing through the intermediate steps of atrophic gastritis or IM. The severity of the mucosal inflammation and host characteristic may directly induce mutagenetic events ultimately leading to cancer.109, 110 Many molecular alterations have been detected in diffuse type GC that differ substantially from those found in the intestinal type, i.e. MSI-H phenotype, implicated in the repair of spontaneous and toxic DNA damage; SC-1 antigen, an apoptotic receptor; E-cadherin mutation and the growth factors c-met and k-sam.68, 105, 111–114 The onset of these molecular alterations is strongly associated with H. pylori infection. Indeed, a recent meta-analysis showed a close correlation between diffuse type GC and H. pylori infection, similar to those found between intestinal type and H. pylori (OR: 2.58, 95% CI: 1.47–4.53; OR: 2.49, 95% CI: 1.41–4.43, respectively).10 Therefore, even if intestinal and diffuse type GCs are characterized by a different genetic pathway, they depend prevalently upon the same triggering factor. It is likely that H. pylori-associated inflammatory reaction may trigger a cascade of events (atrophy, IM and dysplasia) progressing to intestinal type GC or directly induce diffuse type GC. Once the cascade of events is activated, it may also progress independently of the bacterium. A prospective, randomized, placebo-controlled, population study, has recently been carried out in a high-risk area of China.115 Healthy carriers of H. pylori infection (1630 subjects) were observed from 1994 until 2002. A comparable incidence of GC development was found in the subjects receiving H. pylori eradication treatment and those receiving placebo. However, in a subgroup of H. pylori carriers not presenting precancerous lesions, eradication of H. pylori significantly decreased the development of GC. Therefore, eradication of H. pylori might immediately reduce the risk of diffuse cancer whereas cancers of the intestinal type may be less effectively prevented if patients are treated later in the evolution of their carcinogenic process.

Molecular alteration pathways

  1. Top of page
  2. Summary
  3. Introduction
  4. Gastric inflammation and cell proliferation
  5. Multistep process of intestinal type gastric cancer ‘correa's model’
  6. Chronic atrophic gastritis
  7. Intestinal metaplasia
  8. Dysplasia
  9. Are precancerous lesions reversible?
  10. Helicobacter pylori and diffuse type gastric cancer
  11. Molecular alteration pathways
  12. Conclusions
  13. Acknowledgements
  14. References

Human stomach carcinogenesis occurs after a multistep process originating from epithelial stem cells which is driven by the accumulation of molecular alterations involving either the suppressor pathway (defect in tumour suppressor genes) or mutator pathway (defect in DNA mismatch repair genes).116 The scenario of these alterations shows different genetic pathways for well-differentiated or intestinal type and poorly differentiated or diffuse type GCs.103, 117

Two mechanisms have been implicated in the molecular alterations: genetic and epigenetic.118–120 The former includes changes in the DNA sequence, the latter involves methylation of CpG islands which occurs without DNA sequence changes. The most important difference between genetic and epigenetic alterations is that epigenetic changes are potentially reversible by eliminating the toxic agents or with the use of therapeutic interventions and chemical agents.118–120

The stomach is one of the organs, the epithelial cells of which frequently undergo aberrant methylation of CpG islands because of direct contact with the environment.121 Furthermore, H. pylori, infecting the gastric mucosa, may induce methylation of promoters containing CpG islands by release of ROS and NO and by activation of DNA methyltransferase.122, 123

Methylation of CpG islands of multiple genes including APC, COX-2, DAP-kinase, E-cadherin, GSTP1, hMLH1, MGMT, p16, p14, RASSF1A, THBS1, and TIMP3, in precancerous gastric lesions have been investigated and it was shown that aberrant CpG island methylation tends to accumulate along the multistep process of gastric carcinogenesis.62, 121 Elimination of H. pylori infection has the potential to induce regression of epigenetic alterations and restore normal phenotype.117, 119, 123 An intense survey of the literature revealed that precancerous lesions, such as atrophy and even IM or non-invasive neoplasia, may undergo regression after eradication of H. pylori infection.82–85 In fact, IM and lesions so-called indefinite for dysplasia are typical abnormalities of differentiation which dependent upon epigenetic changes.21, 100

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Gastric inflammation and cell proliferation
  5. Multistep process of intestinal type gastric cancer ‘correa's model’
  6. Chronic atrophic gastritis
  7. Intestinal metaplasia
  8. Dysplasia
  9. Are precancerous lesions reversible?
  10. Helicobacter pylori and diffuse type gastric cancer
  11. Molecular alteration pathways
  12. Conclusions
  13. Acknowledgements
  14. References

At the present state of our knowledge chronic atrophic gastritis, IM and dysplasia are well proven premalignant gastric lesions albeit only a subset of patients with these lesions will progress to cancer. The molecular alterations underlying these lesions will provide us with the clues regarding the clinical outcome and may offer new targets for GC chemoprevention. Currently, the most realistic outcome achieved with H. pylori eradication is disappearance of inflammation, elimination of the DNA damage exerted by ROS and NO, reduction in cell turnover, increase in acid output and ascorbic acid secretion into the gastric juice. If these alterations can be reversed before the development of stable mutations, i.e. the ‘point of no return’ then H. pylori eradication will most likely prevent the risk of GC in H. pylori-positive patients.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Gastric inflammation and cell proliferation
  5. Multistep process of intestinal type gastric cancer ‘correa's model’
  6. Chronic atrophic gastritis
  7. Intestinal metaplasia
  8. Dysplasia
  9. Are precancerous lesions reversible?
  10. Helicobacter pylori and diffuse type gastric cancer
  11. Molecular alteration pathways
  12. Conclusions
  13. Acknowledgements
  14. References
  • 1
    Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 1997; 349: 1498504.
  • 2
    American Cancer Society. Estimated New Cancer Cases and Deaths by Sex for all Sites. American Cancer Society, United States, 2000 (Table). http://www.cancer.org/statistics/cff2000/data/newCaseSex.html. Accessed March 13 2001.
  • 3
    Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J Clin 1999; 49: 831.
  • 4
    Hohenberger P, Gretschel S. Gastric cancer. Lancet 2003; 362: 30515.
  • 5
    Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, 1996. CA Cancer J Clin 1996; 46: 527.
  • 6
    Fuchs CS, Mayer RJ. Gastric carcinoma. N Engl J Med 1995; 333: 3241.
  • 7
    Danesh J. Helicobacter pylori infection and gastric cancer: systematic review of the epidemiological studies. Aliment Pharmacol Ther 1999; 13: 8516.
  • 8
    Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984; 1: 13115.
  • 9
    The EUROGAST Study Group. An international association between Helicobacter pylori infection and gastric cancer. Lancet 1993; 341: 135962.
  • 10
    Huang JQ, Sridhar S, Chen Y, Hunt RH. Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology 1998; 114: 116979.
  • 11
    Eslick GD, Lim LL, Byles JE, Xia HH, Talley NJ. Association of Helicobacter pylori infection with gastric carcinoma: a meta-analysis. Am J Gastroenterol 1999; 94: 23739.
    Direct Link:
  • 12
    Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut 2001; 49: 34753.
  • 13
    Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001; 345: 7849.
  • 14
    Ekstrom AM, Held M, Hansson LE, Engstrand L, Nyren O. Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. Gastroenterology 2001; 121: 78491.
  • 15
    Brenner H, Arndt V, Stegmaier C, Ziegler H, Rothenbacher D. Is Helicobacter pylori infection a necessary condition for noncardia gastric cancer? Am J Epidemiol 2004; 159: 2528.
  • 16
    Graham DY, Go MF. Helicobacter pylori: current status. Gastroenterology 1993; 105: 27982.
  • 17
    Correa P. Helicobacter pylori and gastric carcinogenesis. Am J Surg Pathol 1995; 19: S3743.
  • 18
    Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. Acta Pathol Microbiol Scand 1965; 64: 3149.
  • 19
    Yoshimura T, Shimoyama T, Fukuda S, Tanaka M, Axon AT, Munakata A. Most gastric cancer occurs on the distal side of the endoscopic atrophic border. Scand J Gastroenterol 1999; 34: 107781.
  • 20
    Sepulveda AR. Molecular testing of Helicobacter pylori-associated chronic gastritis and premalignant gastric lesions: clinical implications. J Clin Gastroenterol 2001; 32: 37782.
  • 21
    Moss SF. Cellular markers in the gastric precancerous process. Aliment Pharmacol Ther 1998; 12: 91109.
  • 22
    Li CQ, Pignatelli B, Ohshima H. Increased oxidative and nitrative stress in human stomach associated with cagA+ Helicobacter pylori infection and inflammation. Dig Dis Sci 2001; 46: 83644.
  • 23
    Davies GR, Simmonds NJ, Stevens TR, et al. Helicobacter pylori stimulates antral mucosal reactive oxygen metabolite production in vivo. Gut 1994; 35: 17985.
  • 24
    Kuipers EJ, Meuwissen SG. Helicobacter pylori and gastric carcinogenesis. Scand J Gastroenterol 1996; 218: 1035.
  • 25
    Farinati F, Cardin R, Degan P, et al. Oxidative DNA damage accumulation in gastric carcinogenesis. Gut 1998; 42: 3516.
  • 26
    Peek RM Jr, Moss SF, Tham KT, et al. Helicobacter pylori cagA+ strains and dissociation of gastric epithelial cell proliferation from apoptosis. J Natl Cancer Inst 1997; 89: 8638.
  • 27
    Rokkas T, Ladas S, Liatsos C, et al. Relationship of Helicobacter pylori CagA status to gastric cell proliferation and apoptosis. Dig Dis Sci 1999; 44: 48793.
  • 28
    Scotiniotis IA, Rokkas T, Furth EE, Rigas B, Shiff SJ. Altered gastric epithelial cell kinetics in Helicobacter pylori-associated intestinal metaplasia: implications for gastric carcinogenesis. Int J Cancer 2000; 85: 192200.
  • 29
    Yang YL, Xu B, Song YG, Zhang WD. Overexpression of c-fos in Helicobacter pylori-induced gastric precancerosis of Mongolian gerbil. World J Gastroenterol 2003; 9: 5214.
  • 30
    Williams CS, DuBois RN. Prostaglandin endoperoxide synthase: why two isoforms? Am J Physiol 1996; 270: G393400.
  • 31
    Chan FK, To KF, Ng YP, et al. Expression and cellular localization of COX-1 and -2 in Helicobacter pylori gastritis. Aliment Pharmacol Ther 2001; 15: 18793.
  • 32
    Tatsuguchi A, Sakamoto C, Wada K, et al. Localisation of cyclooxygenase 1 and cyclooxygenase 2 in Helicobacter pylori related gastritis and gastric ulcer tissues in humans. Gut 2000; 46: 7829.
  • 33
    Sung JJ, Leung WK, Go MY, et al. Cyclooxygenase-2 expression in Helicobacter pylori-associated premalignant and malignant gastric lesions. Am J Pathol 2000; 157: 72935.
  • 34
    Wambura C, Aoyama N, Shirasaka D, et al. Effect of Helicobacter pylori-induced cyclooxygenase-2 on gastric epithelial cell kinetics: implication for gastric carcinogenesis. Helicobacter 2002; 7: 12938.
  • 35
    Nardone G, Rocco A, Vaira D, et al. Expression of COX-2, mPGE-synthase1, MDR-1 (P-gp), and Bcl-xL: a molecular pathway of Helicobacter pylori-related gastric carcinogenesis. J Pathol 2004; 202: 30512.
  • 36
    Ming SC. Cellular and molecular pathology of gastric carcinoma and precursor lesions: a critical review. Gastric Cancer 1998; 1: 3150.
  • 37
    Asaka M, Sugiyama T, Nobuta A, Kato M, Takeda H, Graham DY. Atrophic gastritis and intestinal metaplasia in Japan: results of a large multicenter study. Helicobacter 2001; 6: 2949.
  • 38
    Cheli R, Giacosa A, Pirasso A. Chronic gastritis: a dynamic process toward cancer. In: Ming, SC, ed. Precursor of Gastric Cancer. New York: Praeger Scientific, 1984: 11729.
  • 39
    Borchard F. Precancerous conditions and lesions of stomach. In: Rugge, M, Arslan-Pagnini, C, Di Mario, F, eds. Carcinoma gastrico e lesioni precancerose dello stomaco. Milano: Edizioni Unicopi, 1986: 175210.
  • 40
    Inoue M, Tajima K, Matsuura A, et al. Severity of chronic atrophic gastritis and subsequent gastric cancer occurrence: a 10-year prospective cohort study in Japan. Cancer Lett 2000; 161: 10512.
  • 41
    McColl KE, El-Omar E, Gillen D, Banerjee S. The role of Helicobacter pylori in the pathophysiology of duodenal ulcer disease and gastric cancer. Semin Gastrointest Dis 1997; 8: 14255.
  • 42
    Leach SA, Thompson M, Hill M. Bacterially catalysed N-nitrosation reactions and their relative importance in the human stomach. Carcinogenesis 1987; 8: 190712.
  • 43
    Lipkin M, Correa P, Mikol YB, et al. Proliferative and antigenic modifications in human epithelial cells in chronic atrophic gastritis. J Natl Cancer Inst 1985; 75: 6139.
  • 44
    Konturek PC, Rembiasz K, Konturek SJ, et al. Gene expression of ornithine decarboxylase, cyclooxygenase-2, and gastrin in atrophic gastric mucosa infected with Helicobacter pylori before and after eradication therapy. Dig Dis Sci 2003; 48: 3646.
  • 45
    Heby O. Role of polyamines in the control of cell proliferation and differentiation. Differentiation 1981; 9: 120.
  • 46
    Patchett SE, Alstead EM, Butruk L, Przytulski K, Farthing MJ. Ornithine decarboxylase as a marker for premalignancy in the stomach. Gut 1995; 37: 136.
  • 47
    Russo F, Linsalata M, Giorgio I, Caruso ML, Armentano R, Di Leo A. Polyamine levels and ODC activity in intestinal-type and diffuse-type gastric carcinoma. Dig Dis Sci 1997; 42: 5769.
  • 48
    Testino G, Valentini M, Cornaggia M, Testino R. Chronic atrophic gastritis and gastric cancer. Dig Liver Dis 2000; 32: 544.
  • 49
    Leung WK, Sung JJ. Review article: intestinal metaplasia and gastric carcinogenesis. Aliment Pharmacol Ther 2002; 16: 120916.
  • 50
    Shimoyama T, Fukuda S, Tanaka M, Nakaji S, Munakata A. Evaluation of the applicability of the gastric carcinoma risk index for intestinal type cancer in Japanese patients infected with Helicobacter pylori. Virchows Arch 2000; 436: 5857.
  • 51
    Jass JR, Filipe MI. Sulphomucins and precancerous lesions of the human stomach. Histopathology 1980; 4: 2719.
  • 52
    Ho SB, Shekels LL, Toribara NW, et al. Mucin gene expression in normal, preneoplastic, and neoplastic human gastric epithelium. Cancer Res 1995; 55: 268190.
  • 53
    Reis CA, David L, Correa P, et al. Intestinal metaplasia of human stomach displays distinct patterns of mucin (MUC1, MUC2, MUC5AC, and MUC6) expression. Cancer Res 1999; 59: 10037.
  • 54
    Filipe MI, Munoz N, Matko I, et al. Intestinal metaplasia types and the risk of gastric cancer: a cohort study in Slovenia. Int J Cancer 1994; 57: 3249.
  • 55
    Matsukura N, Suzuki K, Kawachi T, et al. Distribution of marker enzymes and mucin in intestinal metaplasia in human stomach and relation to complete and incomplete types of intestinal metaplasia to minute gastric carcinomas. J Natl Cancer Inst 1980; 65: 23140.
  • 56
    You WC, Li JY, Blot WJ, et al. Evolution of precancerous lesions in a rural Chinese population at high risk of gastric cancer. Int J Cancer 1999; 83: 6159.
  • 57
    Ohata H, Kitauchi S, Yoshimura N, et al. Progression of chronic atrophic gastritis associated with Helicobacter pylori infection increases risk of gastric cancer. Int J Cancer 2004; 109: 13843.
  • 58
    Cassaro M, Rugge M, Gutierrez O, Leandro G, Graham DY, Genta RM. Topographic patterns of intestinal metaplasia and gastric cancer. Am J Gastroenterol 2000; 95: 14318.
    Direct Link:
  • 59
    Gong C, Mera R, Bravo JC, et al. KRAS mutations predict progression of preneoplastic gastric lesions. Cancer Epidemiol Biomarkers Prev 1999; 8: 16771.
  • 60
    Chung IK, Hwang KY, Kim IH, et al. Helicobacter pylori and telomerase activity in intestinal metaplasia of the stomach. Korean J Intern Med 2002; 17: 22733.
  • 61
    Leung WK, Kim JJ, Kim JG, Graham DY, Sepulveda AR. Microsatellite instability in gastric intestinal metaplasia in patients with and without gastric cancer. Am J Pathol 2000; 156: 53743.
  • 62
    Kang GH, Shim YH, Jung HY, Kim WH, Ro JY, Rhyu MG. CpG island methylation in premalignant stages of gastric carcinoma. Cancer Res 2001; 61: 284751.
  • 63
    Shiao YH, Rugge M, Correa P, Lehmann HP, Scheer WD. p53 alteration in gastric precancerous lesions. Am J Pathol 1994; 144: 5117.
  • 64
    Yu J, Leung WK, Ng EK, et al. Effect of Helicobacter pylori eradication on expression of cyclin D2 and p27 in gastric intestinal metaplasia. Aliment Pharmacol Ther 2001; 15: 150511.
  • 65
    Silberg DG, Furth EE, Taylor JK, Schuck T, Chiou T, Traber PG. CDX1 protein expression in normal, metaplastic, and neoplastic human alimentary tract epithelium. Gastroenterology 1997; 113: 47886.
  • 66
    Satoh K, Mutoh H, Eda A, et al. Aberrant expression of CDX2 in the gastric mucosa with and without intestinal metaplasia: effect of eradication of Helicobacter pylori. Helicobacter 2002; 7: 1928.
  • 67
    Hamamoto T, Yokozaki H, Semba S, et al. Altered microsatellites in incomplete-type intestinal metaplasia adjacent to primary gastric cancers. J Clin Pathol 1997; 50: 8416.
  • 68
    Ottini L, Palli D, Falchetti M, et al. Microsatellite instability in gastric cancer is associated with tumor location and family history in a high-risk population from Tuscany. Cancer Res 1997; 57: 45239.
  • 69
    Nardone G, Staibano S, Rocco A, et al. Effect of Helicobacter pylori infection and its eradication on cell proliferation, DNA status, and oncogene expression in patients with chronic gastritis. Gut 1999; 44: 78999.
  • 70
    Brito MJ, Williams GT, Thompson H, Filipe MI. Expression of p53 in early (T1) gastric carcinoma and precancerous adjacent mucosa. Gut 1994; 35: 1697700.
  • 71
    Ochiai A, Yamauchi Y, Hirohashi S. p53 mutations in the non-neoplastic mucosa of the human stomach showing intestinal metaplasia. Int J Cancer 1996; 69: 2833.
  • 72
    Wu MS, Shun CT, Lee WC, et al. Gastric cancer risk in relation to Helicobacter pylori infection and subtypes of intestinal metaplasia. Br J Cancer 1998; 78: 1258.
  • 73
    Fenoglio-Preiser C, Carneiro F, Correa P, et al. Gastric carcinoma. In: Hamilton, SR, Aaltonen, LA, eds. Pathology and Genetics, Tumors of the Digestive System. Lyon: IARC press, 2000: 3952.
  • 74
    Genta RM, Rugge M. Gastric precancerous lesions: heading for an international consensus. Gut 1999; 45: 158.
  • 75
    Asaka M, Takeda H, Sugiyama T, Kato M. What role does Helicobacter pylori play in gastric cancer? Gastroenterology 1997; 113: S5660.
  • 76
    Macartney JC, Camplejohn RS. DNA flow cytometry of histological material from dysplastic lesions of human gastric mucosa. J Pathol 1986; 150: 1138.
  • 77
    Abdel-Wahab M, Attallah AM, Elshal MF, et al. Correlation between endoscopy, histopathology, and DNA flow cytometry in patients with gastric dyspepsia. Hepatogastroenterology 1996; 43: 131320.
  • 78
    Li J, Zhao A, Lu Y, Wang Y. Expression of p185erbB2 and p21ras in carcinoma, dysplasia, and intestinal metaplasia of the stomach: an immunohistochemical and in situ hybridization study. Semin Surg Oncol 1994; 10: 959.
  • 79
    Sanz-Ortega J, Sanz-Esponera J, Caldes T, Gomez de la Concha E, Sobel ME, Merino MJ. LOH at the APC/MCC gene (5Q21) in gastric cancer and preneoplastic lesions. Prognostic implications. Pathol Res Pract 1996; 192: 120610.
  • 80
    Sung JJ, Lin SR, Ching JY, et al. Atrophy and intestinal metaplasia one year after cure of H. pylori infection: a prospective, randomized study. Gastroenterology 2000; 119: 714.
  • 81
    Tepes B, Kavcic B, Zaletel LK, et al. Two- to four-year histological follow-up of gastric mucosa after Helicobacter pylori eradication. J Pathol 1999; 188: 249.
  • 82
    Ito M, Haruma K, Kamada T, et al. Helicobacter pylori eradication therapy improves atrophic gastritis and intestinal metaplasia: a 5-year prospective study of patients with atrophic gastritis. Aliment Pharmacol Ther 2002; 16: 144956.
  • 83
    Genta RM, Franceschi F. Gastric markers of pre-malignancy are not reversible. In: Hunt, RH, Tytgut, GNJ, eds. Helicobacter pylori– Basic Mechanisms to Clinical Cure 2000. Hamilton: Kluwer Academic Publisher, 2000: 52434.
  • 84
    Franceschi F, Genta RM, Sepulveda AR. Gastric mucosa: long-term outcome after cure of Helicobacter pylori infection. J Gastroenterol 2002; 37: 1723.
  • 85
    Hojo M, Miwa H, Ohkusa T, Ohkura R, Kurosawa A, Sato N. Alteration of histological gastritis after cure of Helicobacter pylori infection. Aliment Pharmacol Ther 2002; 16: 192332.
  • 86
    van Grieken NC, Meijer GA, Weiss MM, et al. Quantitative assessment of gastric corpus atrophy in subjects using omeprazole: a randomized follow-up study. Am J Gastroenterol 2001; 96: 28826.
    Direct Link:
  • 87
    Kokkola A, Sipponen P, Rautelin H, et al. The effect of Helicobacter pylori eradication on the natural course of atrophic gastritis with dysplasia. Aliment Pharmacol Ther 2002; 16: 51520.
  • 88
    Sugiyama T, Sakaki N, Kozawa H, et al. Sensitivity of biopsy site in evaluating regression of gastric atrophy after Helicobacter pylori eradication treatment. Aliment Pharmacol Ther 2002; 16: 18790.
  • 89
    Nada R, Bhasin DK, Joshi K, et al. Effect of eradication of Helicobacter pylori on gastric antrum histology. Trop Gastroenterol 2002; 23: 204.
  • 90
    Annibale B, Di Giulio E, Caruana P, et al. The long-term effects of cure of Helicobacter pylori infection on patients with atrophic body gastritis. Aliment Pharmacol Ther 2002; 16: 172331.
  • 91
    Yamada T, Miwa H, Fujino T, Hirai S, Yokoyama T, Sato N. Improvement of gastric atrophy after Helicobacter pylori eradication therapy. J Clin Gastroenterol 2003; 36: 40510.
  • 92
    Kuipers EJ, Nelis GF, Klinkenberg-Knol EC, et al. Cure of Helicobacter pylori infection in patients with reflux oesophagitis treated with long term omeprazole reverses gastritis without exacerbation of reflux disease: results of a randomised controlled trial. Gut 2004; 53: 1220.
  • 93
    Satoh K. Does eradication of Helicobacter pylori reverse atrophic gastritis or intestinal metaplasia? Data from Japan. Gastroenterol Clin North Am 2000; 29: 82935.
  • 94
    Zullo A, Rinaldi V, Hassan C, et al. Ascorbic acid and intestinal metaplasia in the stomach: a prospective, randomized study. Aliment Pharmacol Ther 2000; 14: 13039.
  • 95
    Correa P, Fontham ET, Bravo JC, et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-Helicobacter pylori therapy. J Natl Cancer Inst 2000; 92: 18818.
  • 96
    Kobayashi M, Tsubono Y, Sasazuki S, Sasaki S, Tsugane S. Vegetables, fruit and risk of gastric cancer in Japan: a 10-year follow-up of the JPHC Study Cohort I. Int J Cancer 2002; 102: 3944.
  • 97
    Rugge M, Cassaro M, Pennelli G, Leandro G, Di Mario F, Farinati F. Atrophic gastritis: pathology and endoscopy in the reversibility assessment. Gut 2003; 52: 13878.
  • 98
    Staibano S, Rocco A, Mezza E, De Rosa G, Budillon G, Nardone G. Diagnosis of chronic atrophic gastritis by morphometric image analysis. A new method to overcome the confounding effect of the inflammatory infiltrate. J Pathol 2002; 198: 4754.
  • 99
    Rugge M, Correa P, Dixon MF, et al. Gastric mucosal atrophy: interobserver consistency using new criteria for classification and grading. Aliment Pharmacol Ther 2002; 16: 124959.
  • 100
    El-Zimaity HM, Graham DY. Evaluation of gastric mucosal biopsy site and number for identification of Helicobacter pylori or intestinal metaplasia: role of the Sydney System. Hum Pathol 1999; 30: 727.
  • 101
    Schlemper RJ, Itabashi M, Kato Y, et al. Differences in diagnostic criteria for gastric carcinoma between Japanese and Western pathologists. Lancet 1997; 349: 17259.
  • 102
    Dixon MF. Prospects for intervention in gastric carcinogenesis: reversibility of gastric atrophy and intestinal metaplasia. Gut 2001; 49: 24.
  • 103
    Tosh D, Slack JM. How cells change their phenotype. Nat Rev Mol Cell Biol 2002; 3: 18794.
  • 104
    Ishikawa N, Wakelin D, Mahida YR. Role of T helper 2 cells in intestinal goblet cell hyperplasia in mice infected with Trichinella spiralis. Gastroenterology 1997; 113: 5429.
  • 105
    Tahara E. Molecular biology of gastric cancer. World J Surg 1995; 19: 4848.
  • 106
    Schlemper RJ, Riddell RH, Kato Y, et al. The Vienna classification of gastrointestinal epithelial neoplasia. Gut 2000; 47: 2515.
  • 107
    Rugge M, Cassaro M, Di Mario F, et al. The long term outcome of gastric non-invasive neoplasia. Gut 2003; 52: 11116.
  • 108
    Glober GA, Cantrell EG, Doll R, Peto R. Interaction between ABO and rhesus blood groups, the site of origin of gastric cancers, and the age and sex of the patient. Gut 1971; 12: 5703.
  • 109
    Go MF. Review article: Natural history and epidemiology of Helicobacter pylori infection. Aliment Pharmacol Ther 2002; 16: 315.
  • 110
    Asaka M, Kudo M, Kato M, Sugiyama T, Takeda H. Review article: Long-term Helicobacter pylori infection – from gastritis to gastric cancer. Aliment Pharmacol Ther 1998; 12: 915.
  • 111
    Perucho M. Cancer of the microsatellite mutator phenotype. Biol Chem 1996; 377: 67584.
  • 112
    Heyden JD, Martin IG, Cawkwell L. The role of microsatellite instability in gastric carcinoma. Gut 1998; 42: 3003.
  • 113
    Eshleman JR, Markowitz SD. Microsatellite instability in inherited and sporadic neoplasms. Curr Opin Oncol 1995; 7: 839.
  • 114
    Gayter SA, Gorringe KL, Ramus SJ, et al. Identification of germ-line E-cadherin mutations in gastric cancer families of European origin. Cancer Res 1998; 58: 40869.
  • 115
    Wong BC, Lam SK, Wong WM, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 2004; 291: 18794.
  • 116
    Kuniyasu H, Yasui W, Yokozaki H, Tahara E. Helicobacter pylori infection and carcinogenesis of the stomach. Langenbecks Arch Surg 2000; 385: 6974.
  • 117
    Tahara E. Molecular mechanism of human stomach carcinogenesis implicated in Helicobacter pylori infection. Exp Toxicol Pathol 1998; 50: 3758.
  • 118
    Sugimura T, Ushijima T. Genetic and epigenetic alterations in carcinogenesis. Mutat Res 2000; 462: 23546.
  • 119
    Verma M, Srivastava S. Epigenetics in cancer: implications for early detection and prevention. Lancet Oncol 2002; 3: 75563.
  • 120
    Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature 1998; 396: 6439.
  • 121
    Kang GH, Lee S, Kim JS, Jung HY. Profile of aberrant CpG island methylation along the multistep pathway of gastric carcinogenesis. Lab Invest 2003; 83: 63541.
  • 122
    Hmadcha A, Bedoya FJ, Sobrino F, Pintado E. Methylation-dependent gene silencing induced by interleukin 1ß via nitric oxide production. J Exp Med 2000; 190: 15951604.
  • 123
    Tamura G. Promoter methylation status of tumor suppressor and tumor-related genes in neoplastic and non-neoplastic gastric epithelia. Histol Histopathol 2004; 19: 2218.