Differentiation and adaptation epigenetic networks: Translational research in gastric carcinogenesis

There are several kinds of epigenetic networks in the human body including the cell differentiation epigenetic network (DiEN) and the host adaptation epigenetic network (AdEN). DiEN networks are static and cell/tissue-specific. AdEN networks are variable and dependent upon environmental factors. DiEN and AdEN alterations can respectively serve as biomarkers for different kinds of diseases. Cancer is a consequence of accumulated pathophysiological adaptations of tissue stem cells to exposure of environmental carcinogens. Cancer cells are de-differentiated cells that obtain the capacity of unrestricted proliferation, local invasion, and distant migration/metastasis. Both DiEN and AdEN changes can be observed in cancer tissues. Alterations of DNA methylation are the most stable epigenetic modifications and can be sensitively detected in a small cell population. These advantages make DNA methylation the optimal biomarkers for detection of initiated cells in precancerous lesions and metastasis stem cells in cancer tissues. It has been proven that p16 methylation can be used as a diagnostic biomarker to determine malignant potential of epithelium dysplasia in many organs including the stomach. In a large-scale validation study on the DNA methylome of gastric carcinomas (GC), the methylation status of more than 90 CpG islands has been analyzed by DHPLC. Furthermore, GFRA1 demethylation and methylation of SRF and ZNF382 are frequent events during gastric carcinogenesis and consistently correlate to GC metastasis and overall survival of GC patients from China, Japan, and Korea, respectively. In a population study, it has been demonstrated that gradual increasing of plasma miR-211 and other miRNA levels may be an early risk predictor for GC development.