Page 17 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

The CagA pathogenicity island
The diversity of the H. pylori genome is responsible for the differences in clinical prognosis. H.pylori can differ in quite a number of genetic factors expressed upon stomach tissue colonization; these factors include the virulence factors VacA and CagA and BabA, SabA, alphAB and HopZ which have all been reported to be associated with progression towards gastric cancer. The H. pylori virulence factor CagA (cytotoxin-associated gene A) is a 120–145 kDa protein encoded on a 40 kb cag pathogenicity island (denominated as PAI) and considered as one of the most relevant pathogenicity factors in relation to progression to gastric cancer. H. pylori strains are thus subdivided into CagA positive or negative strains. Approximately half of the H. pylori strains isolated in Western countries contain cag/PAI, whereas almost all of the East Asian isolates are cag/PAI-positive(31). A case-control study involving 778 gastric cancers from the non-cardia origin and 1409 matched controls revealed excess H. pylori CagA positive strains in the gastric cancer group resulting in an odds ratio (OR) of 2.01 CI (1.21–3.32) progression towards gastric cancer(34). Mechanistically the cag pathogenicity island is associated with the establishment of precancerous gastric lesions, implying a role for the bacterium in the early phases of progression towards full-blown disease. Plummer and colleagues(35), analyzed the results of a cross-sectional endoscopic survey of 2145 individuals from Venezuela, in which both DNA and CagA gene of H. pylori gene were determined by polymerase chain reaction on gastric biopsies. Infection with H. pylori cagA- positive strains but not negative cagA-strains appeared associated with severity of the precancerous lesions in this study. Using individuals with normal gastric mucosa or superficial gastritis as controls, the OR for dysplasia was 15.5(6.4–37.2) for H. pylori cagA-positive strains compared to 0.90(0.37–2.17) for cagA-negative H. pylori. Gonzalez and colleagues (35), analyzed the results of a follow-up study of 312 individuals from Spain with 12.8 years as an average follow-up time between two endoscopies, also involving the results of polymer chain reaction detection of cagA and genotyping of the H. pylori results. The relative risk for progression of precancerous lesions was 2.28 (1.13–4.58) for cagA-positive strains compared to cagA-negative strains. It is clear. However, that cagA alone does not explain the presentation of gastric cancer in the population in relation to H. pylori and this thesis I endeavor to identify other markers differing between H. pylori strains that may explain alternative gastric cancer risk.
Chapter 1
General introduction
10
15
1