<i>Helicobacter pylori</i> geographic variation: a window into global differences in gastric cancer incidence

SUMMARY Helicobacter pylori infection is the strongest known risk factor for gastric cancer, a leading cause of cancer-related deaths worldwide. There is marked global geographic variation in both the incidence of gastric cancer and genetic features of H. pylori strains. Geographic diversity among H. pylori strains can be linked to ancestral human migrations and subsequent H. pylori evolution within human population groups. In this review, we discuss how geographic diversity among H. pylori strains is an important factor contributing to geographic variations in gastric cancer incidence. We focus on geographic variations in genes encoding secreted H. pylori proteins (CagA and VacA), outer membrane proteins (BabA, HopQ, HopH/OipA, HomB, AlpA, and AlpB), and enzymes required for lipopolysaccharide synthesis, and we discuss how these variations can impact gastric cancer pathogenesis. We discuss the concept of H. pylori -human co-evolution, including selective forces that may influence H. pylori evolution within human populations. Finally, we discuss recent changes in H. pylori –human relationships, including a declining prevalence of H. pylori , changes in H. pylori populations, and potential adverse consequences of mismatch between the ancestry of H. pylori strains and the ancestry of human hosts.