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Gastric cancer and Helicobacter pylori: the bug, the host or the environment?
  1. Marjorie M Walker1,
  2. Louise Teare2,
  3. Cliodna McNulty3
  1. 1
    Department of Histopathology, Faculty of Medicine, St Mary’s Campus, Imperial College, London, UK
  2. 2
    Department of Microbiology, Mid Essex Hospital NHS Trust, Broomfield Hospital, Chelmsford, Essex, UK
  3. 3
    HPA Primary Care Unit, Microbiology Department, Gloucestershire Royal Hospital, Gloucester, UK
  1. Dr M M Walker, Department of Histopathology, Faculty of Medicine, St Mary’s Campus, Imperial College, London W2 1PG, UK; mm.walker{at}imperial.ac.uk

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Worldwide, gastric cancer is still a leading cause of cancer deaths. The association of Helicobacter pylori and gastric cancer is well established, and the bacterium was declared a class one carcinogen by the International Agency for Research on Cancer and the World Health Organisation in 1994. H pylori infection is responsible for 5.5% of all global cancers, 75% of non-cardia gastric cancer and lymphoma, and 65% of gastric cancers worldwide.1

In 2005, Marshall and Warren were awarded the Nobel Prize for Medicine for their pioneering work on H pylori (in 1984) showing the association between this bacterium and gastritis and that antibiotics could cure peptic ulcers.2 Parsonnet et al3 formally demonstrated the link to gastric cancer in 1991. However, although more than 50% of people worldwide are infected with H pylori, only a small percentage of those infected will have clinical complications, which include gastric and duodenal ulcers, precancerous lesions, atrophy and intestinal metaplasia, and progression to cancer or lymphoma. However, all those infected will have some degree of histological gastritis, likely to be present long term. It is the distribution and extent of gastritis that to some extent determines outcome: 10–15% of subjects will have antral-predominant gastritis, which is the duodenal ulcer phenotype, and 1% will have a body (corpus)-predominant phenotype, with the risk of gastric cancer.4 It has been estimated that 60–80% of gastric cancers would be preventable if H pylori was eradicated.1

So what determines whether you live quietly with this potential carcinogen or whether it causes mayhem and havoc in your stomach? Conceptually, there are three contributing factors that determine your risk of cancer: the bug, the host and the environment. In this issue of the Postgraduate Medical Journal (see page 193), a study from India5 on the prognostic significance of genotyping H pylori infection in patients from younger age groups with gastric cancer explores the role of the bug. This study showed that young subjects with the H pylori genotype cagT+ve/hrgA+ve/cagA+ve/cagE+ve/vacAs1+ve have an increased risk of cancer. Other studies have shown that cagA is associated with a 20-fold risk of gastric cancer compared with controls.1 These studies demonstrate the importance of the bacterial strain in contributing to cancer risk. However, Tiwari et al5 did not evaluate the role of the host or environmental factors in these studies, as no genotyping of the host was performed. These may certainly have a bearing on outcome, functional polymorphisms in the host’s interleukin-1 gene cluster, and tumour necrosis-α (TNF-α-308) genes significantly increase the risk of gastric cancer in subjects, particularly if they are also infected with virulent strains of the bacterium.6 7

What role does the environment play in infection and cancer? In Colombia, intervention studies with antioxidant supplements have shown that vitamin C and β-carotene, in addition to H pylori eradication therapy, produced significant regression of gastric precancerous lesions, atrophy and intestinal metaplasia in the stomach. The Columbian study concluded that continual supplements are required to maintain protection, as the benefits of antioxidants were no longer evident after 6 years.8 The improving hygiene in developed countries has also contributed to the decline of infection and therefore H pylori-associated cancer. In the UK, H pylori infection has declined rapidly, to about 20%, and, in the USA, only 10% of the population is now infected, but in Asia and South America prevalence of infection still runs at 70–80% and rates of gastric cancer are also high.

Studies showing the importance of bacterial molecular markers, host genotypes and the environment in H pylori-related gastric cancer are unravelling the steps in carcinogenesis. These studies have characterised the complex pathway in which inflammation leads to cancer. An exciting breakthrough has been the establishment of the role of stem cells in gastric cancer: in inflammation there is local stem cell failure and recruitment of cells derived from bone marrow to damaged gastric mucosa. In this abnormal environment of cytokines and tissue dysregulation, these stem cells fail to differentiate correctly and progress to cancer.9 This shows that distant rather than local (gastric) factors may be important in determining response.

Therefore, the practical role of bacterial and genetic markers in routine clinical practice remains to be defined. The current policy in the UK for management of H pylori, as recommended by the HPA Helicobacter Working Group and NICE guidelines for treatment of dyspepsia in England, is test and treat.1 It is also recognised that even symptoms of different upper gastrointestinal diseases such as gastro-oesophageal reflux (not attributable to H pylori) and gastric cancer (attributable to H pylori) may overlap and it is therefore practical to offer test and treat to eradicate H pylori in the Asia Pacific region.10

Until molecular markers are cost effective, should we not adopt the screen and treat approach to eradicate all H pylori identified as being more carcinogenic? Although this is recognised as a potential answer to this problem in countries with a high rate of gastric cancer such as in Asia, there is a growing problem of antibiotic resistance. In Europe, resistance to clarithromycin and metronidazole is increasing, and some patients may harbour resistant strains. It is in this setting that host and bug profiling may be of value in patient reassurance or determining antibiotic sensitivity. Although the aim should be to develop a vaccine, which has proved effective in reducing the incidence of other infection-related cancers such as hepatitis B, the development of either a protective or prophylactic vaccine for H pylori infection is as yet an elusive goal. Currently, enhancing host immunity to generate a protective response holds promise, but translation from animal to human studies remains ethereal.11 As always in medicine, it seems that worthwhile global policies for dealing with H pylori will still have to be tailored to the individual patient.

REFERENCES

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Footnotes

  • Competing interests: None declared.

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