01.07.2008 - 30.06.2009

Is Helicobacter pylori infection a necessary condition for the occurrence of



Ref
PTDC/SAU-ESA/71517/2006

Financing Instituitions
Administração Regional de Saúde do Norte

Participating Institutions
Serviço de Higiene e Epidemiologia, Faculdade de Medicina da Universidade doPorto.Unidade de Investigaçao e Desenvolvimento Cardiovascular do Porto

Summary

The infection with Helicobacter pylori is strongly associated with gastric cancer and affects nearly 50% of the world adult population. It was estimated that 40% to 70% of all gastric cancers were attributable to H. pylori infection, which is the most likely target for preventive strategies.

However, its role in the web of gastric cancer causation is far from being fully understood. On the one hand, the infection is largely prevalent but only a small proportion of the infected subjects develop cancer, and the factors that modulate the progression to cancer are still poorly understood, despite differences in the host response to infection, its genetic profile, environmental hazards and lifestyles, H. pylori virulence, or combined bacterial/host genotypic features have been proposed as explanations for the differences in gastric cancer rates across settings with high H. pylori prevalence. On the other hand, in studies addressing the association between H. pylori infection and gastric cancer, approximately 20% of the cases are seronegative, arguing against the hypothesis of H. pylori being a necessary condition for gastric cancer, even if it appears to be present in most cases of intestinal metaplasia, a precursor of gastric carcinomas of the intestinal type.

However, H. pylori-negative cases may occur in specific types of cancer not associated with infection, as seems to be the case for those located on the cardia, or may result from misclassification of the infection status within the relevant time window (at the time of carcinogenesis initiation).

Gastric cancer patients tend to have more severe mucosal atrophy and intestinal metaplasia in the stomach as disease progresses, leading to the clearance of bacteria from the gastric mucosa and false negative results when history of infection is evaluated. This interpretation is further supported by the stronger associations found between gastric cancer (non-cardia) and H. pylori when infection status is evaluated through the detection of Cag-A antibodies through immunobloting, a more sensitive method for the detection of previous long-term H. pylori infection. One may hypothesize that H. pylori infection is present in all cases of specific types of gastric cancer (e.g. distal cancers of the intestinal type), and that H. pylori-negative cases may result from misclassification of infection status or may occur in subjects with high genetic susceptibility or high risk environmental exposures.

To address the potential role of H. pylori infection as a necessary condition for the occurrence of specific types of gastric cancer we will accomplish the following specific objectives:

1) Systematic review of published studies providing data on H. pylori prevalence in gastric cancer, to evaluate the variability of results with methodological aspects (e.g. study design, diagnostic tests), cancer characteristics (e.g. topography, histological type, staging) and source populations (e.g. country, setting, prevalence of infection in general population);

2) Case-control study (400 cases and 800 controls) to quantify the risk of gastric cancer associated with H. pylori infection, assessing infection status by ELISA and Western blot.

3) Comparison of H. pylori-positive and -negative gastric cancer cases (400 cases with infection status defined based on ELISA and Western blot analysis) regarding tumour characteristics (topography, histology, staging, CDX2 expression), genetic susceptibility (pro-inflammatory polymorphisms), behavioural (diet, smoking) and socio-demographic (age, gender, socioeconomic status) features of the host. 

Sample size was conservatively calculated to allow the detection of differences in the proportion of infected cases corresponding to an odds ratio of 4 (we expect to identify tumour or patient characteristics strongly associated with infection) for the evaluation of exposures that are present in 10% of the noninfected, assuming that approximately 10% of the gastric cancer cases will be classified as non-infected.

The quantification of the association between gastric cancer and H. pylori infection using methods that allows a more accurate assessment of a previous infection status, especially in cases, will provide more truthful risk estimates, allowing the re-evaluation of the estimates on the proportion of cases attributable to infection and the relative weight of other exposures for the occurrence of cancer. If H. pylori infection is considered a necessary condition for the occurrence of specific types of gastric cancer, a shift will have to be made in the gastric cancer etiologic research towards the evaluation of factors that modulate the progression to cancer in infected subjects.


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