Epidemiology of Helicobacter pylori and CagA-Positive Infections and Global Variations in Gastric Cancer

Abstract

Gastric cancer is a major health burden and is the fifth most common malignancy and the third most common cause of death from cancer worldwide. Development of gastric cancer involves several aspects, including host genetics, environmental factors, and Helicobacter pylori infection. There is increasing evidence from epidemiological studies of the association of H. pylori infection and specific virulence factors with gastric cancer. Studies in animal models indicate H. pylori is a primary factor in the development of gastric cancer. One major virulence factor in H. pylori is the cytotoxin-associated gene A (cagA), which encodes the CagA protein in the cag pathogenicity island (cag PAI). Meta-analysis of studies investigating CagA seropositivity irrespective of H. pylori status identified that CagA seropositivity increases the risk of gastric cancer (OR = 2.87, 95% CI: 1.95⁻4.22) relative to the risk of H. pylori infection alone (OR = 2.31, 95% CI: 1.58⁻3.39). Eradicating H. pylori is a strategy for reducing gastric cancer incidence. A meta-analysis of six randomised controlled trials (RCTs) suggests that searching for and eradicating H. pylori infection reduces the subsequent incidence of gastric cancer with a pooled relative risk of 0.66 (95% CI: 0.46⁻0.95). The introduction in regions of high gastric cancer incidence of population-based H. pylori screening and treatment programmes, with a scientifically valid assessment of programme processes, feasibility, effectiveness and possible adverse consequences, would impact the incidence of H. pylori-induced gastric cancer. Given the recent molecular understanding of the oncogenic role of CagA, targeting H. pylori screening and treatment programmes in populations with a high prevalence of H. pylori CagA-positive strains, particularly the more oncogenic East Asian H. pylori CagA strains, may be worth further investigation to optimise the benefits of such strategies.

Keywords: CagA; Helicobacter pylori; epidemiology; gastric cancer; randomised controlled trial.

Figure 1

Estimated frequency of new cancer cases and deaths Worldwide in 2012, both sexes combined (Source: GLOBOCAN 2012, adapted from [1], 2013, International Agency for Research on Cancer).

Figure 2

Estimated age-standardised (world) incidence rates of gastric cancer per 100,000 by country among males in 2012 (Source: GLOBOCAN 2012, adapted from [1], 2013, International Agency for Research on Cancer).

Figure 3

Gastric cancer: number of new cases and deaths with proportions by major regions (both genders combined) in 2012 (Source: GLOBOCAN 2012, adapted from [1], 2013, International Agency for Research on Cancer).

Figure 4

Gastric cancer: age-standardised (world) incidence rates by year for cancer registries in CI5 I-X (Source: Cancer Incidence in Five Continents, CI5plus, adapted from [4], 2014, International Agency for Research on Cancer). (a) Males (all ages); (b) Females (all ages).

Figure 5

Histopathology of gastric mucosa of Mongolian gerbils infected with 3GX Chinese strain of Helicobacter pylori. Adapted from the Journal of Pathology [28], 2006, Wiley. Haematoxylin and eosin-stained sections of corpus gastric mucosa of Mongolian gerbils 30 weeks post-infection with H. pylori strain 3GX. (A) High-grade dysplasia involving intramucosal and herniating glands. Bar = 50 μm; (B) Breakup of the architecture of intramucosal glands with isolated clusters of epithelial cells in the lamina propria indicative of intramucosal carcinoma. Bar = 100 μm.

Figure 6

Pathology of gastric mucosa of H. pylori-infected Mongolian gerbils treated with an epidermal growth factor receptor (EGFR) inhibitor diet and control diet. Haematoxylin and eosin-stained sections of gastric antral mucosa of Mongolian gerbils 38 weeks post-infection with H. pylori SS1 strain. (A) H. pylori-infected gerbil on the control diet. Bar = 800 µm. White arrows indicate the muscularis mucosa, which is discontinuous on the right-hand side, and the three black arrows indicate large submucosal herniations. The right-hand side herniation is sectioned longitudinally reaching the gastric lumen. (B) Antral mucosa of H. pylori-infected gerbil on the EKB-569 diet lack submucosal herniations but have an intact muscularis mucosa (MM) indicated by the white arrow. Bar = 100 μm. Reproduced with permission of Pathogens [32], 2013, MDPI.