Figure 5

Schematic diagram of the LOH-related genetic and epigenetic alterations that underlie gastric carcinogenesis. The general paradigm is that the LOH events exert an adverse effect on cell proliferation and they induce a dose-compensatory response in addition to a key function of the second hit that targets cancer-associated genes. Newly fixed stem cells are increasingly resistant to the adverse effect of LOH events during long-term adaptation to the gastric mucosa, since stem cells establish the high expression of stomach-specific genes that is restricted to some chromosomes. A baseline-level LOH is common in the diffuse-type cancers of young-aged patients at the initial stage of the adapting stem cells. A high-level LOH has a minimal adverse effect on stem cells at a late adaptation stage in old gastric cancer patients who harbor a few highly expressed genes on cancer-associated chromosomes. The dose-compensatory demethylation can lead to the interruption of terminal differentiation and to the persistent expansion of migratory stem cells. The extensive high-dose demethylation leads to the persistent expansion of lineage-committed migratory cells even in distant foreign tissue-environments.