| Summary: | <i>Helicobacter pylori</i> (<i>Hp</i>) is the major recognized risk factor for non-cardia gastric cancer (GC), but only a fraction of infected subjects develop GC, thus GC risk might reflect other genetic/environmental cofactors and/or differences in virulence among infectious <i>Hp</i> strains. Focusing on a high GC risk area of Northern Italy (Cremona, Lombardy) and using archived paraffin-embedded biopsies, we investigated the associations between the <i>Hp vacA</i> and <i>cagA</i> genotype variants and gastric intraepithelial neoplasia (GIN, 33 cases) versus non-neoplastic gastroduodenal lesions (NNGDLs, 37 cases). The <i>glmM</i> gene and the <i>cagA</i> and <i>vacA</i> (s and m) genotypes were determined by polymerase chain reaction (PCR) and sequencing. <i>Hp</i> was confirmed in 37/37 (100%) NNGDLs and detected in 9/33 GINs (27%), consistently with the well-known <i>Hp</i> loss in GC. <i>CagA</i> was detected in 4/9 <i>Hp</i>-positive GINs and in 29/37 NNGDLs. The <i>vacA</i> s1a and m1 subtypes were more common in GINs than in NNGDLs (6/7 vs. 12/34, p=0.014, for s1a; 7/7 vs. 18/34, p=0.020 for m1), with significant <i>vacA</i> s genotype-specific variance. The GIN-associated <i>vacA</i> s1a sequences clustered together, suggesting that aggressive <i>Hp</i> strains from a unique founder contribute to GC in the high-risk area studied.
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