Fig. 1

Mechanisms of induction of aberrant DNA methylation by H. pylori infection. Acute inflammation following infection by H. pylori develops into chronic inflammation characterized by the transition of neutrophil infiltration to that of lymphocytes and macrophages. Chronic inflammation signals, including cytokines such as IL-1β and TNF-α and/or nitric oxide production, are associated with the induction of aberrant DNA methylation. Aberrant DNA methylation is induced both in driver genes (schematically represented by genes 1 and 2) that are causally involved in gastric cancer development and in passenger genes (genes 3 and 4) that are methylated in association with gastric carcinogenesis in normal-appearing tissues. Driver genes are methylated only at very low levels (shown in blue), showing that such events are present only in a very small fraction of cells, whereas many passenger genes are methylated at high levels (shown in black), showing that their methylation is present in a large fraction of cells. The accumulation of aberrant DNA methylation in normal-appearing tissues produces an ‘epigenetic field for cancerization’, which is an area of tissue or an entire tissue without clonal growth but predisposed to cancer development