Schematic diagram of the adaptive differentiation and neoplastic transformation of newly fixed stem cells. In the newly fixed stem cells in the gastric mucosa, the gene-adjacent retroelements (R) drive the concurrent methylation of CpG-island genes in a distance-dependent manner. Given the interaction of the stomach-specific genes lacking CpG-islands and the housekeeping genes containing CpG-islands, which share the limited amount of nuclear proteins in a nuclear space, the overmethylation of CpG-islands down-regulates the housekeeping genes and up-regulate the stomach-specific genes. A high expression of stomach-specific genes promotes the non-dividing terminal differentiation of newly fixed stem cells in the stomach tissue-environment. The LOH events reducing a gene dose lead to 1) dose-compensatory demethylation, 2) the interruption of terminal differentiation, and 3) reactivation of a stem-cell intrinsic program for cell migration. Additionally, the highly expressed stomach-specific genes are overmethylated in a subset of gastric cancers and the overmethylated genes facilitate the interruption of terminal differentiation.