, a Gram-negative bacterium that infects the stomach of approximately half the world’s population, is associated with the development of gastroduodenal diseases including gastric and duodenal peptic ulcer, distal gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma [1
]. It is estimated that individuals infected with H. pylori
have more than two-fold increased risk of developing gastric cancer compared with non-infected ones [2
] although Japanese studies might suggest that nearly all gastric cancer is related to Helicobacter
]. Why only 1 to 5% of H. pylori-
infected persons develop gastric cancer remains unknown and it seems to depend on the relationship between environmental, host genetics and bacterial virulence factors.
Several studies have shown an increased risk of developing gastric cancer in relatives of patients with the disease [2
]. Similarly, an increased prevalence of precancerous gastric lesions has been observed in relatives of gastric cancer patients [5
]. However, molecular mechanisms by which H. pylori
triggers the process leading to gastric carcinoma remain largely unknown.
The most investigated H. pylor
i virulence determinant, the cag-
PAI (cytotoxin associated gene pathogenicity island), encodes a type IV secretion system (T4SS) that is responsible for the entrance of an effector protein, CagA, into host gastric epithelial cells [6
]. Once translocated, CagA localizes to the inner surface of the plasma membrane where it is phosphorylated on the tryrosine residues within phosphorylation motifs in carboxy-terminal variable region of the protein by multiple members of the src-family tyrosine kinases. Once phosphorylated, CagA forms a physical complex with SHP-2 phosphatase and triggers abnormal cellular signals, which enhance the risk of damaged cells acquiring precancerous genetic changes [8
The phosphorylation motifs, defined as a sequence of five amino acids (Glu-Pro-Ile-Tyr-Ala), are classified as EPIYA-A, EPIYA-B, EPIYA-C and EPIYA-D, according to amino acid sequences flanking the motifs. CagA proteins nearly always possess EPIYA-A and -B segments, that are followed by none, one, two or three C segments in strains circulating in the Western countries, or a D segment, in East Asia strains [10
]. It has also been shown that infection with CagA strains having high number of EPIYA-C segments imparts a greater risk of precancerous gastric lesions and cancer [12
Another virulence factor of H. pylori
is a protein known as vacuolating cytotoxin A (VacA), which causes cytoplasmatic vacuolization in gastric epithelial cells, increasing the plasma cell and mitochondrial membrane permeability leading to apoptosis. The production of the cytotoxin is associated with the cag-PAI but depends on the vac
A genotype [16
]. The vac
A is a polymorphic gene with two main signal region genotypes s1 and s2, and two different alleles in the mid region of the gene named m1 and m2. Infection with strains possessing the s1m1 genotype has been associated with precancerous gastric hypochlorhydria [17
] and gastric carcinoma [19
In a recent study conducted in Fortaleza, Northeastern, Brazil, in an area of high prevalence of gastric cancer and H. pylori
infection, our group has shown a high prevalence of either pangastritis or precancerous lesions in relatives of gastric cancer patients infected with H. pylori
Furthermore, Argent et al
., (2008) observed an association between vac
A s1m1 genotype of H. pylori
strains and low gastric acid secretion in first-degree relatives of gastric cancer patients from Scotland [21
]. Otherwise, the authors did not find associations between CagA positive status and or number of tyrosine phosphorylated motifs and gastric lesions in that population.
Since geographical differences have been observed among studies that evaluated association between H. pylori virulence factors and diseases, the aim of this cross-sectional prospective study was to evaluate the CagA EPIYA motifs of H. pylori strains in first-degree relatives of gastric cancer patients comparing the results with those obtained from a control group composed of subjects with no family history of gastric cancer. Because the s1m1 genotype of the vacA H. pylori was seen to be more frequently observed in the strains of gastric cancer patients, we also evaluated the vacA mosaicism in the strains.