Multifactorial Etiology of Gastric Cancer

The prevalence of gastric cancer is associated with several factors including geographical location, diet, and genetic background of the host. However, it is evident that infection with Helicobacter pylori (H. pylori ) is crucial for the development of the disease. Virulence of the bacteria is also important in modulating the risk of the disease. After infection, H. pylori gains access to the gastric mucosa and triggers the production of cytokines that promote recruitment of inflammatory cells, probably involved in tissue damage. Once the infection is established, a cascade of inflammatory steps associated with changes in the gastric epithelia that may lead to cancer is triggered. H. pylori -induced gastritis and H. pylori -associated gastric cancer have been the focus of extensive research aiming to discover the underlying mechanisms of gastric tissue damage. This research has led to the association of host genetic components with the risk of the disease. Among these is the presence of single nucleotide polymorphisms (SNPs) in several genes, including cytokine genes, which are able to differentially modulate the production of inflammatory cytokines and then modulate the risk of gastric cancer. Interestingly, the frequency of some of these SNPs is different among populations and may serve as a predictive factor for gastric cancer risk within that specific population. However, the role played by other genetic modifications should not be minimized. Methylation of gene promoters has been recognized as a major mechanism of gene expression regulation without changing the primary structure of the DNA. Most DNA methylation occurs in cytosine residues in CpG dinucleotide, but it can also be found in other DNA bases. DNA methyltransferases add methyl groups to the CpG dinucleotide, and when this methylation level is too high, the gene expression is turned off. In H. pylori infection as well as in gastric cancer, hypermethylation of promoters of genes involved in cell cycle control, metabolism of essential nutrients, and production of inflammatory mediators, among others, has been described. Interestingly, DNA changes like SNPs or mutations can create CpG sites in sequences where transcription factors normally sit, affecting transcription.