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We thank Dr Peyrin‐Biroulet for his comments on our study and we would like to make some further observations. It is well accepted that H pylori is a group 1 carcinogen. The mechanisms whereby the microorganism induces gastric carcinogenesis are not completely understood but are linked to bacterial virulence factors, host genetics, and environmental factors. In human gastric carcinogenesis, epithelial cells accumulate molecular alterations by genetic and epigenetic mechanisms, such as regional hypermethylation as suggested by Chan et al1 and Maekita et al.2 Global DNA hypomethylation, cited by Dr Peyrin‐Biroulet, might also influence tumour development by predisposing to the expression of genes involved in neoplastic growth or by inhibiting the chromosome condensation that leads to alterations in chromosome pairing and disjunction.3 DNA hypomethylation has more often been associated with folate deficiency caused by alterations in the enzymes involved in folate metabolism, as seen when there is polymorphism in the gene that encodes methylene‐tetrahydrofolate reductase.4 Meth‐ionine is a precursor of S‐adenosyl‐methionine, the primary methyl donor for most biological methylation reactions, including that of DNA. As folate is involved in the remethylation of homocysteine to methionine, its deficiency leads to DNA hypomethylation and hyperhomocysteinaemia. Although the hyperhomocysteinaemia observed in the patients in our study was not due to folate deficiency but to cobalamin deficiency, it has been suggested that high concentrations of plasma homocysteine—independent of the cause—may increase the intracellular S‐adenosyl‐homocysteine (SAH) which inhibits DNA methyltransferases, leading also to global hypometh‐ylation.5 As hyperhomocysteinaemia also enhances the production of reactive oxygen species (ROS), it has been hypothesised that DNA hypomethylation mediated by SAH increases the vulnerability and sensitivity of DNA to homocysteine induced ROS.5
In the context of gastric carcinogenesis, however, bacterial and host factors have also to be considered. Among the H pylori virulence factors, CagA protein was recently identified as the major disease associated factor. Translocation of CagA into the host gastric epithelial cells through a specialised type IV secretion system encoded in the cag pathogenicity island is followed by CagA tyrosine phosphorylation which triggers abnormal intracellular signals. This abnormality deregulates cell growth, cell to cell contact, and cell migration, as well as enhancing epithelial cell turnover, which increases the risk of damaged cells acquiring precancerous genetic changes.6,7 Factors linked to the host—such as genetics—might affect the immune response to the infection, which per se may contribute to the progression to gastric cancer. Among these, IL1 gene cluster polymorphisms should be highlighted.8 Using logistic analysis, we have demonstrated that both cagA positive status and IL1RN polymorphisms are independently associated with distal gastric carcinoma in the Brazilian population.9
Finally, although the Maastricht III consensus states that eradication of H pylori has the potential to reduce the risk of gastric cancer development and that the optimal time to eradicate the bacterium is before preneoplastic lesions are present, the results of our study do not allow us to answer the question posed by Dr Peyrin‐Biroulet: “Should we screen and treat H pylori positive patients for cobalamin deficiency to reduce the risk of gastric cancer?” This is an unexplored area for future research, because it has not been established yet whether homocysteine is causally involved in gastric carcinogenesis or whether it is an indirect indicator of other involved mechanisms.
Conflict of interest: None declared.