Helicobacter pylori Diversity and Gastric Cancer Risk

Abstract

Gastric cancer is a leading cause of cancer-related death worldwide. Helicobacter pylori infection is the strongest known risk factor for this malignancy. An important goal is to identify H. pylori-infected persons at high risk for gastric cancer, so that these individuals can be targeted for therapeutic intervention. H. pylori exhibits a high level of intraspecies genetic diversity, and over the past two decades, many studies have endeavored to identify strain-specific features of H. pylori that are linked to development of gastric cancer. One of the most prominent differences among H. pylori strains is the presence or absence of a 40-kb chromosomal region known as the cag pathogenicity island (PAI). Current evidence suggests that the risk of gastric cancer is very low among persons harboring H. pylori strains that lack the cag PAI. Among persons harboring strains that contain the cag PAI, the risk of gastric cancer is shaped by a complex interplay among multiple strain-specific bacterial factors as well as host factors. This review discusses the strain-specific properties of H. pylori that correlate with increased gastric cancer risk, focusing in particular on secreted proteins and surface-exposed proteins, and describes evidence from cell culture and animal models linking these factors to gastric cancer pathogenesis. Strain-specific features of H. pylori that may account for geographic variation in gastric cancer incidence are also discussed.

FIG 1

Diversity in amino acid sequences of CagA and VagA proteins. Dark blue coloration indicates regions of diversity that influence gastric cancer risk. (A) CagA is a translocated into host cells through a type IV secretion system-dependent process. Within host cells, CagA undergoes tyrosine phosphorylation at sites known as EPIYA motifs. Most CagA proteins contain multiple EPIYA motifs, which are designated EPIYA-A, EPIYA-B, EPIYA-C, or EPIYA-D based on the flanking sequences. Among CagA proteins produced by different H. pylori strains, there is variation in the number and type of EPIYA motifs. EPIYA-D motifs are found almost exclusively in CagA proteins produced by H. pylori strains from East Asia. Nucleotide sequence variation in an untranslated region upstream of the ATG start codon in the vicinity of an AATAAGATA motif influences levels of CagA production. TS, transcription start site. (B) VacA is secreted by a type V (autotransporter) secretion system. A 140-kDa VacA precursor protein undergoes cleavage of an amino-terminal signal sequence and C-terminal proteolytic processing, resulting in an 88-kDa secreted passenger domain, a small secreted peptide, and a β-barrel domain localized to the outer membrane. There are three main regions of diversity within the 88-kDa passenger domain, designated the s, i, and m regions; within each region, sequences can be classified into one of two main types (s1 or s2, i1 or i2, and m1 or m2). Multiple possible combinations (s1/i1/i1, s2/i2/i2, s1/i2/m2, etc.) can be present in different H. pylori strains as a result of recombination.