Carcinogenetic potential of the WSR cagA region of Helicobacter pylori.

Within the H. pylori virulence factor CagA a different number of repeats of the EPIYA, the tyrosine phosphorylation site of CagA, might be found in different strains. A higher phosphorylated CagA interferes much more with intracellular signalling and it is suggested to worse the outcome of H. pylori CagA positive infected patients. The aim of this study was to ascertain whether a different number of the first repeat region (FR) or of the second repeat region (WSR) repeats of the cagA gene, which comprise the sequence encoding for the EPIYAs, correlates with different inflammation patterns and outcomes of H. pylori cagA positive infected patients. We studied Italian patients with antral (n=18) or diffuse (n=16) gastritis, with duodenal ulcer (n=16) and with histologically proven non-cardia gastric cancer (n=25). All patients were infected by cagA positive H. pylori strains, the diagnosis being made on the basis of histology, culture and genetic analysis (ureA, cagA, s and m vacA) of H. pylori isolates. FR and WSR regions were PCR analysed using isolates from the antrum; the number of repeats was evaluated on the basis of amplicons dimension (agarose gel electrophoresis). In a subset of 28 isolates, 14 from NCGC, the whole FR and WSR region was sequenced. In all patients the FR region contained one repeat. The WSR repeats ranged from 0 to 3. Some patients (n=22) were co-infected by strains with a different number of WSR repeats. H. pylori strains with less than 2 WSR repeats had more frequently the m1 vacA allele (X2=5.88, p<0.05) and the infection was correlated with more severe corpus activity (X2=13.74, p<0.005). NCGC was associated with infections caused by H. pylori strains with two WSR repeats or with co-infecting H. pylori strains exerting two or more WRS cagA repeats, while those with less than two repeats were correlated with duodenal ulcer (X2=12.45, p<0.05). No significant association was found between nucleotide sequences and disease diagnosis and degree of inflammation. In conclusion the FR region of cagA in Italian isolates does not vary. The variations of cagA WSR region are probably involved in causing different disease outcomes in patients infected by apparently similar H. pylori strains: those with less than two repeats mainly causing duodenal ulcer, those with two or more repeats probably being more carcinogenetic.